Pattern Recognition Receptors and Aging

  • Karim H. ShalabyEmail author


Pattern recognition receptors (PRRs), such as the toll-like receptors (TLRs), C-type lectin receptors (CLRs), nucleotide-binding oligomerization domain and leucine-rich repeat-containing receptors (NLRs), and the more recently discovered cytosolic RNA- and DNA-sensing receptors, are a crucial element of the innate immune system owing to their function of enabling immune cells to detect macromolecules of foreign and potentially harmful origin, such as those of infectious agents, and instructing appropriate protective inflammatory and adaptive immune responses. However, PRRs and their signaling components are expressed on not only innate immune cells but various other immune and structural cells of the body including endothelial, epithelial, muscle, and stromal cells, as well as fibroblasts, adipocytes, and cells of the nervous system, and are increasingly being shown to play an active and diverse role in the regulation of cellular senescence and tissue homeostasis. For instance, PRRs maintain balanced immunity towards nonpathogenic commensals at host-environment interfaces such as the gut and skin, detect “danger signals” released during cell stress or injury, and interact with physiological processes such as autophagy, DNA repair, and cellular apoptosis. The regulation of many of these processes and PRR families is altered in the course of ageing, and the mechanisms underlying this dysregulation are discussed in this chapter. We also review the extensive evidence from gene association or functional studies indicating that loss or gain of PRR expression or activity is pertinent to the increased susceptibility to infection and poor responsiveness to vaccination of aged individuals and, furthermore, is implicated in numerous age-related diseases such as metabolic syndrome, cardiovascular and neurodegenerative diseases, and cancer. The hyperactivation of PRR pathways, to which both infectious agents and endogenous sources of ligands have been shown to contribute, may promote a state of persistent low-grade inflammation in elderly individuals, referred to as “inflammageing,” which in turn may also facilitate the emergence of chronic age-related diseases. Most notably, deficiency in TLR activity may be responsible for the impaired immunity to infection observed in ageing, whereas hyperactivation of TLRs and inflammasomes has been frequently associated with chronic age-related diseases, suggesting that these PRR families may be particularly amenable to therapies aimed at enhancing immunity in the elderly or treating age-related disorders.


  1. Abend JR, Ramalingam D, Kieffer-Kwon P, Uldrick TS, Yarchoan R, Ziegelbauer JM (2012) Kaposi’s sarcoma-associated herpesvirus microRNAs target IRAK1 and MYD88, two components of the toll-like receptor/interleukin-1R signaling cascade, to reduce inflammatory-cytokine expression. J Virol 86(21):11663–11674PubMedGoogle Scholar
  2. Aglipay JA, Lee SW, Okada S, Fujiuchi N, Ohtsuka T, Kwak JC, Wang Y, Johnstone RW, Deng C, Qin J, Ouchi T (2003) A member of the Pyrin family, IFI16, is a novel BRCA1-associated protein involved in the p53-mediated apoptosis pathway. Oncogene 22(55):8931–8938PubMedGoogle Scholar
  3. Agrawal A, Agrawal S, Cao JN, Su H, Osann K, Gupta S (2007) Altered innate immune functioning of dendritic cells in elderly humans: a role of phosphoinositide 3-kinase-signaling pathway. J Immunol 178(11):6912–6922PubMedGoogle Scholar
  4. Agrawal A, Tay J, Ton S, Agrawal S, Gupta S (2009) Increased reactivity of dendritic cells from aged subjects to self-antigen, the human DNA. J Immunol 182(2):1138–1145PubMedGoogle Scholar
  5. Al-Hertani W, Yan SR, Byers DM, Bortolussi R (2007) Human newborn polymorphonuclear neutrophils exhibit decreased levels of MyD88 and attenuated p38 phosphorylation in response to lipopolysaccharide. Clin Invest Med 30(2):E44–E53PubMedGoogle Scholar
  6. Alimirah F, Chen J, Davis FJ, Choubey D (2007) IFI16 in human prostate cancer. Mol Cancer Res 5(3):251–259PubMedGoogle Scholar
  7. Allavena P, Chieppa M, Bianchi G, Solinas G, Fabbri M, Laskarin G, Mantovani A (2010) Engagement of the mannose receptor by tumoral mucins activates an immune suppressive phenotype in human tumor-associated macrophages. Clin Dev Immunol 2010:547179PubMedGoogle Scholar
  8. Allen IC, TeKippe EM, Woodford RM, Uronis JM, Holl EK, Rogers AB, Herfarth HH, Jobin C, Ting JP (2010) The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. J Exp Med 207(5):1045–1056PubMedGoogle Scholar
  9. Anz D, Koelzer VH, Moder S, Thaler R, Schwerd T, Lahl K, Sparwasser T, Besch R, Poeck H, Hornung V, Hartmann G, Rothenfusser S, Bourquin C, Endres S (2010) Immunostimulatory RNA blocks suppression by regulatory T cells. J Immunol 184(2):939–946PubMedGoogle Scholar
  10. Arai Y, Hirose N, Nakazawa S, Yamamura K, Shimizu K, Takayama M, Ebihara Y, Osono Y, Homma S (2001) Lipoprotein metabolism in Japanese centenarians: effects of apolipoprotein E polymorphism and nutritional status. J Am Geriatr Soc 49(11):1434–1441PubMedGoogle Scholar
  11. Arnold CR, Wolf J, Brunner S, Herndler-Brandstetter D, Grubeck-Loebenstein B (2011) Gain and loss of T cell subsets in old age–age-related reshaping of the T cell repertoire. J Clin Immunol 31(2):137–146PubMedGoogle Scholar
  12. Arroyo DS, Soria JA, Gaviglio EA, Garcia-Keller C, Cancela LM, Rodriguez-Galan MC, Wang JM, Iribarren P (2013) Toll-like receptor 2 ligands promote microglial cell death by inducing autophagy. FASEB J 27(1):299–312PubMedGoogle Scholar
  13. Atianand MK, Fitzgerald KA (2013) Molecular basis of DNA recognition in the immune system. J Immunol 190(5):1911–1918PubMedGoogle Scholar
  14. Balistreri CR, Candore G, Colonna-Romano G, Lio D, Caruso M, Hoffmann E, Franceschi C, Caruso C (2004) Role of toll-like receptor 4 in acute myocardial infarction and longevity. JAMA 292(19):2339–2340PubMedGoogle Scholar
  15. Balistreri CR, Candore G, Mirabile M, Lio D, Caimi G, Incalcaterra E, Caruso M, Hoffmann E, Caruso C (2008a) TLR2 and age-related diseases: potential effects of Arg753Gln and Arg677Trp polymorphisms in acute myocardial infarction. Rejuvenation Res 11(2):293–296PubMedGoogle Scholar
  16. Balistreri CR, Grimaldi MP, Chiappelli M, Licastro F, Castiglia L, Listi F, Vasto S, Lio D, Caruso C, Candore G (2008b) Association between the polymorphisms of TLR4 and CD14 genes and Alzheimer’s disease. Curr Pharm Des 14(26):2672–2677PubMedGoogle Scholar
  17. Balkwill F, Coussens LM (2004) Cancer: an inflammatory link. Nature 431(7007):405–406PubMedGoogle Scholar
  18. Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357(9255):539–545PubMedGoogle Scholar
  19. Barnholtz-Sloan JS, Shetty PB, Guan X, Nyante SJ, Luo J, Brennan DJ, Millikan RC (2010) FGFR2 and other loci identified in genome-wide association studies are associated with breast cancer in African-American and younger women. Carcinogenesis 31(8):1417–1423PubMedGoogle Scholar
  20. Basith S, Manavalan B, Yoo TH, Kim SG, Choi S (2012) Roles of toll-like receptors in cancer: a double-edged sword for defense and offense. Arch Pharm Res 35(8):1297–1316PubMedGoogle Scholar
  21. Bauer AK, Dixon D, DeGraff LM, Cho HY, Walker CR, Malkinson AM, Kleeberger SR (2005) Toll-like receptor 4 in butylated hydroxytoluene-induced mouse pulmonary inflammation and tumorigenesis. J Natl Cancer Inst 97(23):1778–1781PubMedGoogle Scholar
  22. Bauer C, Duewell P, Mayer C, Lehr HA, Fitzgerald KA, Dauer M, Tschopp J, Endres S, Latz E, Schnurr M (2010) Colitis induced in mice with dextran sulfate sodium (DSS) is mediated by the NLRP3 inflammasome. Gut 59(9):1192–1199PubMedGoogle Scholar
  23. Belderbos ME, van Bleek GM, Levy O, Blanken MO, Houben ML, Schuijff L, Kimpen JL, Bont L (2009) Skewed pattern of toll-like receptor 4-mediated cytokine production in human neonatal blood: low LPS-induced IL-12p70 and high IL-10 persist throughout the first month of life. Clin Immunol 133(2):228–237PubMedGoogle Scholar
  24. Berger R, Fiegl H, Goebel G, Obexer P, Ausserlechner M, Doppler W, Hauser-Kronberger C, Reitsamer R, Egle D, Reimer D, Muller-Holzner E, Jones A, Widschwendter M (2010) Toll-like receptor 9 expression in breast and ovarian cancer is associated with poorly differentiated tumors. Cancer Sci 101(4):1059–1066PubMedGoogle Scholar
  25. Bersani I, Speer CP, Kunzmann S (2012) Surfactant proteins A and D in pulmonary diseases of preterm infants. Expert Rev Anti Infect Ther 10(5):573–584PubMedGoogle Scholar
  26. Bes-Houtmann S, Roche R, Hoareau L, Gonthier MP, Festy F, Caillens H, Gasque P, Lefebvre d’Hellencourt C, Cesari M (2007) Presence of functional TLR2 and TLR4 on human adipocytes. Histochem Cell Biol 127(2):131–137PubMedGoogle Scholar
  27. Biswas M, Kumar SR, Allen A, Yong W, Nimmanapalli R, Samal SK, Elankumaran S (2012) Cell-type-specific innate immune response to oncolytic Newcastle disease virus. Viral Immunol 25(4):268–276PubMedGoogle Scholar
  28. Blasius AL, Beutler B (2010) Intracellular toll-like receptors. Immunity 32(3):305–315PubMedGoogle Scholar
  29. Boehmer ED, Goral J, Faunce DE, Kovacs EJ (2004) Age-dependent decrease in toll-like receptor 4-mediated proinflammatory cytokine production and mitogen-activated protein kinase expression. J Leukoc Biol 75(2):342–349PubMedGoogle Scholar
  30. Boehmer ED, Meehan MJ, Cutro BT, Kovacs EJ (2005) Aging negatively skews macrophage. Mech Ageing Dev 126(12):1305–1313PubMedGoogle Scholar
  31. Bomfim GF, Dos Santos RA, Oliveira MA, Giachini FR, Akamine EH, Tostes RC, Fortes ZB, Webb RC, Carvalho MH (2012) Toll-like receptor 4 contributes to blood pressure regulation and vascular contraction in spontaneously hypertensive rats. Clin Sci 122(11):535–543PubMedGoogle Scholar
  32. Boraska Jelavic T, Barisic M, Drmic Hofman I, Boraska V, Vrdoljak E, Peruzovic M, Hozo I, Puljiz Z, Terzic J (2006) Microsatellite GT polymorphism in the toll-like receptor 2 is associated with colorectal cancer. Clin Genet 70(2):156–160PubMedGoogle Scholar
  33. Bortoluci KR, Medzhitov R (2010) Control of infection by pyroptosis and autophagy: role of TLR and NLR. Cell Mol Life Sci 67(10):1643–1651PubMedGoogle Scholar
  34. Brignole C, Marimpietri D, Di Paolo D, Perri P, Morandi F, Pastorino F, Zorzoli A, Pagnan G, Loi M, Caffa I, Erminio G, Haupt R, Gambini C, Pistoia V, Ponzoni M (2010) Therapeutic targeting of TLR9 inhibits cell growth and induces apoptosis in neuroblastoma. Cancer Res 70(23):9816–9826PubMedGoogle Scholar
  35. Bruunsgaard H, Andersen-Ranberg K, Jeune B, Pedersen AN, Skinhoj P, Pedersen BK (1999) A high plasma concentration of TNF-alpha is associated with dementia in centenarians. J Gerontol A Biol Sci Med Sci 54(7):M357–M364PubMedGoogle Scholar
  36. Bsibsi M, Ravid R, Gveric D, van Noort JM (2002) Broad expression of toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 61(11):1013–1021PubMedGoogle Scholar
  37. Bsibsi M, Persoon-Deen C, Verwer RW, Meeuwsen S, Ravid R, Van Noort JM (2006) Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators. Glia 53(7):688–695PubMedGoogle Scholar
  38. Bunt SK, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S (2006) Inflammation induces myeloid-derived suppressor cells that facilitate tumor progression. J Immunol 176(1):284–290PubMedGoogle Scholar
  39. Bunt SK, Yang L, Sinha P, Clements VK, Leips J, Ostrand-Rosenberg S (2007) Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res 67(20):10019–10026PubMedGoogle Scholar
  40. Burl S, Adetifa UJ, Cox M, Touray E, Ota MO, Marchant A, Whittle H, McShane H, Rowland-Jones SL, Flanagan KL (2010) Delaying bacillus Calmette-Guerin vaccination from birth to 4 1/2 months of age reduces postvaccination Th1 and IL-17 responses but leads to comparable mycobacterial responses at 9 months of age. J Immunol 185(4):2620–2628PubMedGoogle Scholar
  41. Burl S, Townend J, Njie-Jobe J, Cox M, Adetifa UJ, Touray E, Philbin VJ, Mancuso C, Kampmann B, Whittle H, Jaye A, Flanagan KL, Levy O (2011) Age-dependent maturation of toll-like receptor-mediated cytokine responses in Gambian infants. PLoS One 6(4):e18185PubMedGoogle Scholar
  42. Canaday DH, Amponsah NA, Jones L, Tisch DJ, Hornick TR, Ramachandra L (2010) Influenza-induced production of interferon-alpha is defective in geriatric individuals. J Clin Immunol 30(3):373–383PubMedGoogle Scholar
  43. Cani PD, Delzenne NM (2009) Interplay between obesity and associated metabolic disorders: new insights into the gut microbiota. Curr Opin Pharmacol 9(6):737–743PubMedGoogle Scholar
  44. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R (2007) Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 56(7):1761–1772PubMedGoogle Scholar
  45. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R (2008) Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 57(6):1470–1481PubMedGoogle Scholar
  46. Caricilli AM, Nascimento PH, Pauli JR, Tsukumo DM, Velloso LA, Carvalheira JB, Saad MJ (2008) Inhibition of toll-like receptor 2 expression improves insulin sensitivity and signaling in muscle and white adipose tissue of mice fed a high-fat diet. J Endocrinol 199(3):399–406PubMedGoogle Scholar
  47. Caricilli AM, Picardi PK, de Abreu LL, Ueno M, Prada PO, Ropelle ER, Hirabara SM, Castoldi A, Vieira P, Camara NO, Curi R, Carvalheira JB, Saad MJ (2011) Gut microbiota is a key modulator of insulin resistance in TLR 2 knockout mice. PLoS Biol 9(12):e1001212PubMedGoogle Scholar
  48. Carvalho BM, Guadagnini D, Tsukumo DM, Schenka AA, Latuf-Filho P, Vassallo J, Dias JC, Kubota LT, Carvalheira JB, Saad MJ (2012) Modulation of gut microbiota by antibiotics improves insulin signalling in high-fat fed mice. Diabetologia 55(10):2823–2834PubMedGoogle Scholar
  49. Casanova JL, Abel L, Quintana-Murci L (2011) Human TLRs and IL-1Rs in host defense: natural insights from evolutionary, epidemiological, and clinical genetics. Annu Rev Immunol 29:447–491PubMedGoogle Scholar
  50. Cedzynski M, Swierzko AS, Kilpatrick DC (2012) Factors of the lectin pathway of complement activation and their clinical associations in neonates. J Biomed Biotechnol 2012:363246PubMedGoogle Scholar
  51. Cerhan JR, Ansell SM, Fredericksen ZS, Kay NE, Liebow M, Call TG, Dogan A, Cunningham JM, Wang AH, Liu-Mares W, Macon WR, Jelinek D, Witzig TE, Habermann TM, Slager SL (2007) Genetic variation in 1253 immune and inflammation genes and risk of non-Hodgkin lymphoma. Blood 110(13):4455–4463PubMedGoogle Scholar
  52. Chadwick W, Brenneman R, Martin B, Maudsley S (2010) Complex and multidimensional lipid raft alterations in a murine model of Alzheimer’s disease. Int J Alzheimer’s Dis 2010:604792Google Scholar
  53. Chang S, Dolganiuc A, Szabo G (2007) Toll-like receptors 1 and 6 are involved in TLR2-mediated macrophage activation by hepatitis C virus core and NS3 proteins. J Leukoc Biol 82(3):479–487PubMedGoogle Scholar
  54. Charrier E, Cordeiro P, Cordeau M, Dardari R, Michaud A, Harnois M, Merindol N, Herblot S, Duval M (2012) Post-transcriptional down-regulation of toll-like receptor signaling pathway in umbilical cord blood plasmacytoid dendritic cells. Cell Immunol 276(1–2):114–121PubMedGoogle Scholar
  55. Chelvarajan RL, Collins SM, Van Willigen JM, Bondada S (2005) The unresponsiveness of aged mice to polysaccharide antigens is a result of a defect in macrophage function. J Leukoc Biol 77(4):503–512PubMedGoogle Scholar
  56. Chelvarajan RL, Liu Y, Popa D, Getchell ML, Getchell TV, Stromberg AJ, Bondada S (2006) Molecular basis of age-associated cytokine dysregulation in LPS-stimulated macrophages. J Leukoc Biol 79(6):1314–1327PubMedGoogle Scholar
  57. Chen J, Smith LE (2012) Protective inflammasome activation in AMD. Nat Med 18(5):658–660PubMedGoogle Scholar
  58. Chen IF, Ou-Yang F, Hung JY, Liu JC, Wang H, Wang SC, Hou MF, Hortobagyi GN, Hung MC (2006a) AIM2 suppresses human breast cancer cell proliferation in vitro and mammary tumor growth in a mouse model. Mol Cancer Ther 5(1):1–7PubMedGoogle Scholar
  59. Chen K, Iribarren P, Hu J, Chen J, Gong W, Cho EH, Lockett S, Dunlop NM, Wang JM (2006b) Activation of toll-like receptor 2 on microglia promotes cell uptake of Alzheimer disease-associated amyloid beta peptide. J Biol Chem 281(6):3651–3659PubMedGoogle Scholar
  60. Chen K, Li F, Li J, Cai H, Strom S, Bisello A, Kelley DE, Friedman-Einat M, Skibinski GA, McCrory MA, Szalai AJ, Zhao AZ (2006c) Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nat Med 12(4):425–432PubMedGoogle Scholar
  61. Chen R, Alvero AB, Silasi DA, Kelly MG, Fest S, Visintin I, Leiser A, Schwartz PE, Rutherford T, Mor G (2008) Regulation of IKKbeta by miR-199a affects NF-kappaB activity in ovarian cancer cells. Oncogene 27(34):4712–4723PubMedGoogle Scholar
  62. Chen GY, Liu M, Wang F, Bertin J, Nunez G (2011) A functional role for Nlrp6 in intestinal inflammation and tumorigenesis. J Immunol 186(12):7187–7194PubMedGoogle Scholar
  63. Chen LC, Wang LJ, Tsang NM, Ojcius DM, Chen CC, Ouyang CN, Hsueh C, Liang Y, Chang KP, Chen CC, Chang YS (2012) Tumour inflammasome-derived IL-1beta recruits neutrophils and improves local recurrence-free survival in EBV-induced nasopharyngeal carcinoma. EMBO Mol Med 4(12):1276–1293PubMedGoogle Scholar
  64. Cherfils-Vicini J, Platonova S, Gillard M, Laurans L, Validire P, Caliandro R, Magdeleinat P, Mami-Chouaib F, Dieu-Nosjean MC, Fridman WH, Damotte D, Sautes-Fridman C, Cremer I (2010) Triggering of TLR7 and TLR8 expressed by human lung cancer cells induces cell survival and chemoresistance. J Clin Invest 120(4):1285–1297PubMedGoogle Scholar
  65. Chew V, Chen J, Lee D, Loh E, Lee J, Lim KH, Weber A, Slankamenac K, Poon RT, Yang H, Ooi LL, Toh HC, Heikenwalder M, Ng IO, Nardin A, Abastado JP (2012) Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma. Gut 61(3):427–438PubMedGoogle Scholar
  66. Choubey D, Walter S, Geng Y, Xin H (2000) Cytoplasmic localization of the interferon-inducible protein that is encoded by the AIM2 (absent in melanoma) gene from the 200-gene family. FEBS Lett 474(1):38–42PubMedGoogle Scholar
  67. Choubey D, Deka R, Ho SM (2008) Interferon-inducible IFI16 protein in human cancers and autoimmune diseases. Front Biosci 13:598–608PubMedGoogle Scholar
  68. Chow MT, Sceneay J, Paget C, Wong CS, Duret H, Tschopp J, Moller A, Smyth MJ (2012) NLRP3 suppresses NK cell-mediated responses to carcinogen-induced tumors and metastases. Cancer Res 72(22):5721–5732PubMedGoogle Scholar
  69. Chung HY, Cesari M, Anton S, Marzetti E, Giovannini S, Seo AY, Carter C, Yu BP, Leeuwenburgh C (2009) Molecular inflammation: underpinnings of aging and age-related diseases. Ageing Res Rev 8(1):18–30PubMedGoogle Scholar
  70. Chung H, Watanabe T, Kudo M, Chiba T (2010) Hepatitis C virus core protein induces homotolerance and cross-tolerance to toll-like receptor ligands by activation of toll-like receptor 2. J Infect Dis 202(6):853–861PubMedGoogle Scholar
  71. Chung H, Watanabe T, Kudo M, Chiba T (2011) Correlation between hyporesponsiveness to toll-like receptor ligands and liver dysfunction in patients with chronic hepatitis C virus infection. J Viral Hepat 18(10):e561–e567PubMedGoogle Scholar
  72. Clark AS, West K, Streicher S, Dennis PA (2002) Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 1(9):707–717PubMedGoogle Scholar
  73. Cohen PA, Ko JS, Storkus WJ, Spencer CD, Bradley JM, Gorman JE, McCurry DB, Zorro-Manrique S, Dominguez AL, Pathangey LB, Rayman PA, Rini BI, Gendler SJ, Finke JH (2012) Myeloid-derived suppressor cells adhere to physiologic STAT3- vs STAT5-dependent hematopoietic programming, establishing diverse tumor-mediated mechanisms of immunologic escape. Immunol Invest 41(6–7):680–710PubMedGoogle Scholar
  74. Cole JE, Navin TJ, Cross AJ, Goddard ME, Alexopoulou L, Mitra AT, Davies AH, Flavell RA, Feldmann M, Monaco C (2011) Unexpected protective role for toll-like receptor 3 in the arterial wall. Proc Natl Acad Sci U S A 108(6):2372–2377PubMedGoogle Scholar
  75. Coley FC (1894) A pseudo-hypertrophic family. Br Med J 1(1730):399–400PubMedGoogle Scholar
  76. Combrinck MI, Perry VH, Cunningham C (2002) Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease. Neuroscience 112(1):7–11PubMedGoogle Scholar
  77. Corbett NP, Blimkie D, Ho KC, Cai B, Sutherland DP, Kallos A, Crabtree J, Rein-Weston A, Lavoie PM, Turvey SE, Hawkins NR, Self SG, Wilson CB, Hajjar AM, Fortuno ES III, Kollmann TR (2010) Ontogeny of toll-like receptor mediated cytokine responses of human blood mononuclear cells. PLoS One 5(11):e15041PubMedGoogle Scholar
  78. Corsini E, Vismara L, Lucchi L, Viviani B, Govoni S, Galli CL, Marinovich M, Racchi M (2006) High interleukin-10 production is associated with low antibody response to influenza vaccination in the elderly. J Leukoc Biol 80(2):376–382PubMedGoogle Scholar
  79. Creely SJ, McTernan PG, Kusminski CM, Fisher fM, Da Silva NF, Khanolkar M, Evans M, Harte AL, Kumar S (2007) Lipopolysaccharide activates an innate immune system response in human adipose tissue in obesity and type 2 diabetes. Am J Physiol Endocrinol Metab 292(3):E740–E747PubMedGoogle Scholar
  80. Cribbs DH, Berchtold NC, Perreau V, Coleman PD, Rogers J, Tenner AJ, Cotman CW (2012) Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study. J Neuroinflammation 9:179PubMedGoogle Scholar
  81. Cunningham C, Wilcockson DC, Campion S, Lunnon K, Perry VH (2005) Central and systemic endotoxin challenges exacerbate the local inflammatory response and increase neuronal death during chronic neurodegeneration. J Neurosci 25(40):9275–9284PubMedGoogle Scholar
  82. D’Souza G, Kreimer AR, Viscidi R, Pawlita M, Fakhry C, Koch WM, Westra WH, Gillison ML (2007) Case–control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 356(19):1944–1956PubMedGoogle Scholar
  83. Dang Y, Wagner WM, Gad E, Rastetter L, Berger CM, Holt GE, Disis ML (2012) Dendritic cell-activating vaccine adjuvants differ in the ability to elicit antitumor immunity due to an adjuvant-specific induction of immunosuppressive cells. Clin Cancer Res 18(11):3122–3131PubMedGoogle Scholar
  84. Dangaj D, Abbott KL, Mookerjee A, Zhao A, Kirby PS, Sandaltzopoulos R, Powell DJ Jr, Lamaziere A, Siegel DL, Wolf C, Scholler N (2011) Mannose receptor (MR) engagement by mesothelin GPI anchor polarizes tumor-associated macrophages and is blocked by anti-MR human recombinant antibody. PLoS One 6(12):e28386PubMedGoogle Scholar
  85. Dasari P, Zola H, Nicholson IC (2011) Expression of toll-like receptors by neonatal leukocytes. Pediatr Allergy Immunol 22(2):221–228PubMedGoogle Scholar
  86. Dasu MR, Jialal I (2011) Free fatty acids in the presence of high glucose amplify monocyte inflammation via toll-like receptors. Am J Physiol Endocrinol Metab 300(1):E145–E154PubMedGoogle Scholar
  87. Dasu MR, Devaraj S, Zhao L, Hwang DH, Jialal I (2008) High glucose induces toll-like receptor expression in human monocytes: mechanism of activation. Diabetes 57(11):3090–3098PubMedGoogle Scholar
  88. Dasu MR, Devaraj S, Park S, Jialal I (2010) Increased toll-like receptor (TLR) activation and TLR ligands in recently diagnosed type 2 diabetic subjects. Diabetes Care 33(4):861–868PubMedGoogle Scholar
  89. Dasu MR, Ramirez S, Isseroff RR (2012) Toll-like receptors and diabetes: a therapeutic perspective. Clin Sci 122(5):203–214PubMedGoogle Scholar
  90. Davis JE, Gabler NK, Walker-Daniels J, Spurlock ME (2008) Tlr-4 deficiency selectively protects against obesity induced by diets high in saturated fat. Obesity 16(6):1248–1255PubMedGoogle Scholar
  91. Davis JE, Braucher DR, Walker-Daniels J, Spurlock ME (2011) Absence of Tlr2 protects against high-fat diet-induced inflammation and results in greater insulin-stimulated glucose transport in cultured adipocytes. J Nutr Biochem 22(2):136–141PubMedGoogle Scholar
  92. De Cesare M, Calcaterra C, Pratesi G, Gatti L, Zunino F, Menard S, Balsari A (2008) Eradication of ovarian tumor xenografts by locoregional administration of targeted immunotherapy. Clin Cancer Res 14(17):5512–5518PubMedGoogle Scholar
  93. De Nardo D, Latz E (2011) NLRP3 inflammasomes link inflammation and metabolic disease. Trends Immunol 32(8):373–379PubMedGoogle Scholar
  94. de Oliveira JG, Silva AE (2012) Polymorphisms of the TLR2 and TLR4 genes are associated with risk of gastric cancer in a Brazilian population. World J Gastroenterol 18(11):1235–1242PubMedGoogle Scholar
  95. de Rivero Vaccari JP, Lotocki G, Alonso OF, Bramlett HM, Dietrich WD, Keane RW (2009) Therapeutic neutralization of the NLRP1 inflammasome reduces the innate immune response and improves histopathology after traumatic brain injury. J Cereb Blood Flow Metab 29(7):1251–1261PubMedGoogle Scholar
  96. Delgado MA, Deretic V (2009) Toll-like receptors in control of immunological autophagy. Cell DeathDiffer 16(7):976–983Google Scholar
  97. Della BS, Bierti L, Presicce P, Arienti R, Valenti M, Saresella M, Vergani C, Villa ML (2007) Peripheral blood dendritic cells and monocytes are differently regulated in the elderly. Clin Immunol 122(2):220–228Google Scholar
  98. Deretic V (2012) Autophagy as an innate immunity paradigm: expanding the scope and repertoire of pattern recognition receptors. Curr Opin Immunol 24(1):21–31PubMedGoogle Scholar
  99. DeYoung KL, Ray ME, Su YA, Anzick SL, Johnstone RW, Trapani JA, Meltzer PS, Trent JM (1997) Cloning a novel member of the human interferon-inducible gene family associated with control of tumorigenicity in a model of human melanoma. Oncogene 15(4):453–457PubMedGoogle Scholar
  100. Diebold SS, Kaisho T, Hemmi H, Akira S, Sousa R (2004) Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science 303(5663):1529–1531PubMedGoogle Scholar
  101. Diego VP, Curran JE, Charlesworth J, Peralta JM, Voruganti VS, Cole SA, Dyer TD, Johnson MP, Moses EK, Goring HH, Williams JT, Comuzzie AG, Almasy L, Blangero J, Williams-Blangero S (2012) Systems genetics of the nuclear factor-kappaB signal transduction network. I. Detection of several quantitative trait loci potentially relevant to aging. Mech Ageing Dev 133(1):11–19PubMedGoogle Scholar
  102. Dixit VD (2012) Impact of immune-metabolic interactions on age-related thymic demise and T cell senescence. Semin Immunol 24(5):321–330PubMedGoogle Scholar
  103. Dixit E, Kagan JC (2013) Intracellular pathogen detection by RIG-I-like receptors. Adv Immunol 117:99–125PubMedGoogle Scholar
  104. Doan HQ, Bowen KA, Jackson LA, Evers BM (2009) Toll-like receptor 4 activation increases Akt phosphorylation in colon cancer cells. Anticancer Res 29(7):2473–2478PubMedGoogle Scholar
  105. Dolganiuc A, Chang S, Kodys K, Mandrekar P, Bakis G, Cormier M, Szabo G (2006) Hepatitis C virus (HCV) core protein-induced, monocyte-mediated mechanisms of reduced IFN-alpha and plasmacytoid dendritic cell loss in chronic HCV infection. J Immunol 177(10):6758–6768PubMedGoogle Scholar
  106. Dong B, Qi D, Yang L, Huang Y, Xiao X, Tai N, Wen L, Wong FS (2012) TLR4 regulates cardiac lipid accumulation and diabetic heart disease in the nonobese diabetic mouse model of type 1 diabetes. Am J Physiol Heart Circ Physiol 303(6):H732–H742PubMedGoogle Scholar
  107. Dostert C, Ludigs K, Guarda G (2013) Innate and adaptive effects of inflammasomes on T cell responses. Curr Opin Immunol 25(3):359–365PubMedGoogle Scholar
  108. Doyle SL, Campbell M, Ozaki E, Salomon RG, Mori A, Kenna PF, Farrar GJ, Kiang AS, Humphries MM, Lavelle EC, O’Neill LA, Hollyfield JG, Humphries P (2012) NLRP3 has a protective role in age-related macular degeneration through the induction of IL-18 by drusen components. Nat Med 18(5):791–798PubMedGoogle Scholar
  109. Droemann D, Albrecht D, Gerdes J, Ulmer AJ, Branscheid D, Vollmer E, Dalhoff K, Zabel P, Goldmann T (2005) Human lung cancer cells express functionally active toll-like receptor 9. Respir Res 6:1PubMedGoogle Scholar
  110. Du J, Huo J, Shi J, Yuan Z, Zhang C, Fu W, Jiang H, Yi Q, Hou J (2011) Polymorphisms of nuclear factor-kappaB family genes are associated with development of multiple myeloma and treatment outcome in patients receiving bortezomib-based regimens. Haematologica 96(5):729–737PubMedGoogle Scholar
  111. Duan X, Ponomareva L, Veeranki S, Choubey D (2011a) IFI16 induction by glucose restriction in human fibroblasts contributes to autophagy through activation of the ATM/AMPK/p53 pathway. PLoS One 6(5):e19532PubMedGoogle Scholar
  112. Duan X, Ponomareva L, Veeranki S, Panchanathan R, Dickerson E, Choubey D (2011b) Differential roles for the interferon-inducible IFI16 and AIM2 innate immune sensors for cytosolic DNA in cellular senescence of human fibroblasts. Mol Cancer Res 9(5):589–602PubMedGoogle Scholar
  113. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464(7293):1357–1361PubMedGoogle Scholar
  114. Dupaul-Chicoine J, Yeretssian G, Doiron K, Bergstrom KS, McIntire CR, LeBlanc PM, Meunier C, Turbide C, Gros P, Beauchemin N, Vallance BA, Saleh M (2010) Control of intestinal homeostasis, colitis, and colitis-associated colorectal cancer by the inflammatory caspases. Immunity 32(3):367–378PubMedGoogle Scholar
  115. Dzopalic T, Rajkovic I, Dragicevic A, Colic M (2012) The response of human dendritic cells to co-ligation of pattern-recognition receptors. Immunol Res 52(1–2):20–33PubMedGoogle Scholar
  116. Dzumhur A, Zibar L, Wagner J, Simundic T, Dembic Z, Barbic J (2012) Association studies of gene polymorphisms in toll-like receptors 2 and 4 in Croatian patients with acute myocardial infarction. Scand J Immunol 75(5):517–523PubMedGoogle Scholar
  117. Edfeldt K, Bennet AM, Eriksson P, Frostegard J, Wiman B, Hamsten A, Hansson GK, de Faire U, Yan ZQ (2004) Association of hypo-responsive toll-like receptor 4 variants with risk of myocardial infarction. Eur Heart J 25(16):1447–1453PubMedGoogle Scholar
  118. Egen JG, Kuhns MS, Allison JP (2002) CTLA-4: new insights into its biological function and use in tumor immunotherapy. Nat Immunol 3(7):611–618PubMedGoogle Scholar
  119. Ehses JA, Meier DT, Wueest S, Rytka J, Boller S, Wielinga PY, Schraenen A, Lemaire K, Debray S, Van Lommel L, Pospisilik JA, Tschopp O, Schultze SM, Malipiero U, Esterbauer H, Ellingsgaard H, Rutti S, Schuit FC, Lutz TA, Boni-Schnetzler M, Konrad D, Donath MY (2010) Toll-like receptor 2-deficient mice are protected from insulin resistance and beta cell dysfunction induced by a high-fat diet. Diabetologia 53(8):1795–1806PubMedGoogle Scholar
  120. Eisenbarth SC, Colegio OR, O’Connor W, Sutterwala FS, Flavell RA (2008) Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature 453(7198):1122–1126PubMedGoogle Scholar
  121. El MR, El GM, Myer R, High KP (2009) Aging-dependent upregulation of IL-23p19 gene expression in dendritic cells is associated with differential transcription factor binding and histone modifications. Aging Cell 8(5):553–565Google Scholar
  122. Elankumaran S, Chavan V, Qiao D, Shobana R, Moorkanat G, Biswas M, Samal SK (2010) Type I interferon-sensitive recombinant newcastle disease virus for oncolytic virotherapy. J Virol 84(8):3835–3844PubMedGoogle Scholar
  123. Elinav E, Strowig T, Henao-Mejia J, Flavell RA (2011a) Regulation of the antimicrobial response by NLR proteins. Immunity 34(5):665–679PubMedGoogle Scholar
  124. Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ, Peaper DR, Bertin J, Eisenbarth SC, Gordon JI, Flavell RA (2011b) NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145(5):745–757PubMedGoogle Scholar
  125. Erridge C (2009) The roles of toll-like receptors in atherosclerosis. J Innate Immun 1(4):340–349PubMedGoogle Scholar
  126. Erridge C, Samani NJ (2009) Saturated fatty acids do not directly stimulate toll-like receptor signaling. Arterioscler Thromb Vasc Biol 29(11):1944–1949PubMedGoogle Scholar
  127. Esplin BL, Shimazu T, Welner RS, Garrett KP, Nie L, Zhang Q, Humphrey MB, Yang Q, Borghesi LA, Kincade PW (2011) Chronic exposure to a TLR ligand injures hematopoietic stem cells. J Immunol 186(9):5367–5375PubMedGoogle Scholar
  128. Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, Lovat F, Fadda P, Mao C, Nuovo GJ, Zanesi N, Crawford M, Ozer GH, Wernicke D, Alder H, Caligiuri MA, Nana-Sinkam P, Perrotti D, Croce CM (2012) MicroRNAs bind to toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A 109(31):E2110–E2116PubMedGoogle Scholar
  129. Fabelo N, Martin V, Marin R, Santpere G, Aso E, Ferrer I, Diaz M (2012) Evidence for premature lipid raft aging in APP/PS1 double-transgenic mice, a model of familial Alzheimer disease. J Neuropathol Exp Neurol 71(10):868–881PubMedGoogle Scholar
  130. Favre J, Musette P, Douin-Echinard V, Laude K, Henry JP, Arnal JF, Thuillez C, Richard V (2007) Toll-like receptors 2-deficient mice are protected against postischemic coronary endothelial dysfunction. Arterioscler Thromb Vasc Biol 27(5):1064–1071PubMedGoogle Scholar
  131. Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES (2009) AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature 458(7237):509–513PubMedGoogle Scholar
  132. Fernandez-Velasco M, Prieto P, Terron V, Benito G, Flores JM, Delgado C, Zaragoza C, Lavin B, Gomez-Parrizas M, Lopez-Collazo E, Martin-Sanz P, Bosca L (2012) NOD1 activation induces cardiac dysfunction and modulates cardiac fibrosis and cardiomyocyte apoptosis. PLoS One 7(9):e45260PubMedGoogle Scholar
  133. Ferreira AV, Mario EG, Porto LC, Andrade SP, Botion LM (2011) High-carbohydrate diet selectively induces tumor necrosis factor-alpha production in mice liver. Inflammation 34(2):139–145PubMedGoogle Scholar
  134. Field R, Campion S, Warren C, Murray C, Cunningham C (2010) Systemic challenge with the TLR3 agonist poly I:C induces amplified IFNalpha/beta and IL-1beta responses in the diseased brain and exacerbates chronic neurodegeneration. Brain Behav Immun 24(6):996–1007PubMedGoogle Scholar
  135. Fischer H, Ellstrom P, Ekstrom K, Gustafsson L, Gustafsson M, Svanborg C (2007) Ceramide as a TLR4 agonist; a putative signalling intermediate between sphingolipid receptors for microbial ligands and TLR4. Cell Microbiol 9(5):1239–1251PubMedGoogle Scholar
  136. Fortin CF, Larbi A, Lesur O, Douziech N, Fulop T Jr (2006) Impairment of SHP-1 down-regulation in the lipid rafts of human neutrophils under GM-CSF stimulation contributes to their age-related, altered functions. J Leukoc Biol 79(5):1061–1072PubMedGoogle Scholar
  137. Fortin CF, Lesur O, Fulop T Jr (2007a) Effects of aging on triggering receptor expressed on myeloid cells (TREM)-1-induced PMN functions. FEBS Lett 581(6):1173–1178PubMedGoogle Scholar
  138. Fortin CF, Lesur O, Fulop T Jr (2007b) Effects of TREM-1 activation in human neutrophils: activation of signaling pathways, recruitment into lipid rafts and association with TLR4. Int Immunol 19(1):41–50PubMedGoogle Scholar
  139. Fournier P, Arnold A, Wilden H, Schirrmacher V (2012a) Newcastle disease virus induces pro-inflammatory conditions and type I interferon for counter-acting Treg activity. Int J Oncol 40(3):840–850PubMedGoogle Scholar
  140. Fournier P, Wilden H, Schirrmacher V (2012b) Importance of retinoic acid-inducible gene I and of receptor for type I interferon for cellular resistance to infection by Newcastle disease virus. Int J Oncol 40(1):287–298PubMedGoogle Scholar
  141. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128(1):92–105PubMedGoogle Scholar
  142. Franchini M, Monnais E, Seboek D, Radimerski T, Zini E, Kaufmann K, Lutz T, Reusch C, Ackermann M, Muller B, Linscheid P (2010) Insulin resistance and increased lipolysis in bone marrow derived adipocytes stimulated with agonists of toll-like receptors. Horm Metab Res 42(10):703–709PubMedGoogle Scholar
  143. Frank S, Copanaki E, Burbach GJ, Muller UC, Deller T (2009) Differential regulation of toll-like receptor mRNAs in amyloid plaque-associated brain tissue of aged APP23 transgenic mice. Neurosci Lett 453(1):41–44PubMedGoogle Scholar
  144. Frasca D, Blomberg BB (2011) Aging affects human B cell responses. J Clin Immunol 31(3):430–435PubMedGoogle Scholar
  145. Frederich RC, Hamann A, Anderson S, Lollmann B, Lowell BB, Flier JS (1995) Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat Med 1(12):1311–1314PubMedGoogle Scholar
  146. Frenkel D, Maron R, Burt DS, Weiner HL (2005) Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears beta-amyloid in a mouse model of Alzheimer disease. J Clin Invest 115(9):2423–2433PubMedGoogle Scholar
  147. Frenkel D, Puckett L, Petrovic S, Xia W, Chen G, Vega J, Dembinsky-Vaknin A, Shen J, Plante M, Burt DS, Weiner HL (2008) A nasal proteosome adjuvant activates microglia and prevents amyloid deposition. Ann Neurol 63(5):591–601PubMedGoogle Scholar
  148. Friedman JM (2009) Obesity: causes and control of excess body fat. Nature 459(7245):340–342PubMedGoogle Scholar
  149. Fukata M, Chen A, Vamadevan AS, Cohen J, Breglio K, Krishnareddy S, Hsu D, Xu R, Harpaz N, Dannenberg AJ, Subbaramaiah K, Cooper HS, Itzkowitz SH, Abreu MT (2007) Toll-like receptor-4 promotes the development of colitis-associated colorectal tumors. Gastroenterology 133(6):1869–1881PubMedGoogle Scholar
  150. Fulop T, Larbi A, Douziech N, Fortin C, Guerard KP, Lesur O, Khalil A, Dupuis G (2004) Signal transduction and functional changes in neutrophils with aging. Aging Cell 3(4):217–226PubMedGoogle Scholar
  151. Garaude J, Blander JM (2012) Attacking tumor cells with a dual ligand for innate immune receptors. Oncotarget 3(4):361–362PubMedGoogle Scholar
  152. Garay RP, Viens P, Bauer J, Normier G, Bardou M, Jeannin JF, Chiavaroli C (2007) Cancer relapse under chemotherapy: why TLR2/4 receptor agonists can help. Eur J Pharmacol 563(1–3):1–17PubMedGoogle Scholar
  153. Garcia-Vallejo JJ, van Kooyk Y (2009) Endogenous ligands for C-type lectin receptors: the true regulators of immune homeostasis. Immunol Rev 230(1):22–37PubMedGoogle Scholar
  154. Garg NJ (2011) Inflammasomes in cardiovascular diseases. Am J Cardiovasc Dis 1(3):244–254PubMedGoogle Scholar
  155. Geijtenbeek TB, Gringhuis SI (2009) Signalling through C-type lectin receptors: shaping immune responses. Nat Rev Immunol 9(7):465–479PubMedGoogle Scholar
  156. GeurtsvanKessel CH, Lambrecht BN (2008) Division of labor between dendritic cell subsets of the lung. Mucosal Immunol 1(6):442–450PubMedGoogle Scholar
  157. Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, Vermaelen K, Panaretakis T, Mignot G, Ullrich E, Perfettini JL, Schlemmer F, Tasdemir E, Uhl M, Genin P, Civas A, Ryffel B, Kanellopoulos J, Tschopp J, Andre F, Lidereau R, McLaughlin NM, Haynes NM, Smyth MJ, Kroemer G, Zitvogel L (2009) Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med 15(10):1170–1178PubMedGoogle Scholar
  158. Giacconi R, Caruso C, Lio D, Muti E, Cipriano C, Costarelli L, Saba V, Gasparini N, Malavolta M, Mocchegiani E (2007) CD14 C (−260)T polymorphism, atherosclerosis, elderly: role of cytokines and metallothioneins. Int J Cardiol 120(1):45–51PubMedGoogle Scholar
  159. Gibbings DJ, Ciaudo C, Erhardt M, Voinnet O (2009) Multivesicular bodies associate with components of miRNA effector complexes and modulate miRNA activity. Nat Cell Biol 11(9):1143–1149PubMedGoogle Scholar
  160. Glenn JV, Mahaffy H, Wu K, Smith G, Nagai R, Simpson DA, Boulton ME, Stitt AW (2009) Advanced glycation end product (AGE) accumulation on Bruch’s membrane: links to age-related RPE dysfunction. Invest Ophthalmol Vis Sci 50(1):441–451PubMedGoogle Scholar
  161. Godbout JP, Johnson RW (2004) Interleukin-6 in the aging brain. J Neuroimmunol 147(1–2):141–144PubMedGoogle Scholar
  162. Gold MC, Donnelly E, Cook MS, Leclair CM, Lewinsohn DA (2006) Purified neonatal plasmacytoid dendritic cells overcome intrinsic maturation defect with TLR agonist stimulation. Pediatr Res 60(1):34–37PubMedGoogle Scholar
  163. Gondois-Rey F, Dental C, Halfon P, Baumert TF, Olive D, Hirsch I (2009) Hepatitis C virus is a weak inducer of interferon alpha in plasmacytoid dendritic cells in comparison with influenza and human herpesvirus type-1. PLoS One 4(2):e4319PubMedGoogle Scholar
  164. Gonzalez-Navajas JM, Lee J, David M, Raz E (2012) Immunomodulatory functions of type I interferons. Nat Rev Immunol 12(2):125–135PubMedGoogle Scholar
  165. Gonzalez-Reyes S, Fernandez JM, Gonzalez LO, Aguirre A, Suarez A, Gonzalez JM, Escaff S, Vizoso FJ (2011) Study of TLR3, TLR4, and TLR9 in prostate carcinomas and their association with biochemical recurrence. Cancer Immun Immunother 60(2):217–226Google Scholar
  166. Goossens GH, Blaak EE, Theunissen R, Duijvestijn AM, Clement K, Tervaert JW, Thewissen MM (2012) Expression of NLRP3 inflammasome and T cell population markers in adipose tissue are associated with insulin resistance and impaired glucose metabolism in humans. Mol Immunol 50(3):142–149PubMedGoogle Scholar
  167. Gorden KK, Qiu XX, Binsfeld CC, Vasilakos JP, Alkan SS (2006) Cutting edge: activation of murine TLR8 by a combination of imidazoquinoline immune response modifiers and polyT oligodeoxynucleotides. J Immunol 177(10):6584–6587PubMedGoogle Scholar
  168. Goriely S, Vincart B, Stordeur P, Vekemans J, Willems F, Goldman M, De WD (2001) Deficient IL-12(p35) gene expression by dendritic cells derived from neonatal monocytes. J Immunol 166(3):2141–2146PubMedGoogle Scholar
  169. Gorina R, Font-Nieves M, Marquez-Kisinousky L, Santalucia T, Planas AM (2011) Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFkappaB signaling, MAPK, and Jak1/Stat1 pathways. Glia 59(2):242–255PubMedGoogle Scholar
  170. Goto Y, Arigami T, Kitago M, Nguyen SL, Narita N, Ferrone S, Morton DL, Irie RF, Hoon DS (2008) Activation of toll-like receptors 2, 3, and 4 on human melanoma cells induces inflammatory factors. Mol Cancer Ther 7(11):3642–3653PubMedGoogle Scholar
  171. Gris D, Ye Z, Iocca HA, Wen H, Craven RR, Gris P, Huang M, Schneider M, Miller SD, Ting JP (2010) NLRP3 plays a critical role in the development of experimental autoimmune encephalomyelitis by mediating Th1 and Th17 responses. J Immunol 185(2):974–981PubMedGoogle Scholar
  172. Gugliesi F, Mondini M, Ravera R, Robotti A, de Andrea M, Gribaudo G, Gariglio M, Landolfo S (2005) Up-regulation of the interferon-inducible IFI16 gene by oxidative stress triggers p53 transcriptional activity in endothelial cells. J Leukoc Biol 77(5):820–829PubMedGoogle Scholar
  173. Guha M (2012) Anticancer TLR agonists on the ropes. Nat Rev Drug Discov 11(7):503–505PubMedGoogle Scholar
  174. Ha T, Hu Y, Liu L, Lu C, McMullen JR, Kelley J, Kao RL, Williams DL, Gao X, Li C (2010) TLR2 ligands induce cardioprotection against ischaemia/reperfusion injury through a PI3K/Akt-dependent mechanism. Cardiovasc Res 87(4):694–703PubMedGoogle Scholar
  175. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF (2001) An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 20(6):705–732PubMedGoogle Scholar
  176. Halle A, Hornung V, Petzold GC, Stewart CR, Monks BG, Reinheckel T, Fitzgerald KA, Latz E, Moore KJ, Golenbock DT (2008) The NALP3 inflammasome is involved in the innate immune response to amyloid-beta. Nat Immunol 9(8):857–865PubMedGoogle Scholar
  177. Hao Y, O’Neill P, Naradikian MS, Scholz JL, Cancro MP (2011) A B-cell subset uniquely responsive to innate stimuli accumulates in aged mice. Blood 118(5):1294–1304PubMedGoogle Scholar
  178. Hardison SE, Brown GD (2012) C-type lectin receptors orchestrate antifungal immunity. Nat Immunol 13(9):817–822PubMedGoogle Scholar
  179. Hardy OT, Kim A, Ciccarelli C, Hayman LL, Wiecha J (2013) Increased toll-like receptor (TLR) mRNA expression in monocytes is a feature of metabolic syndrome in adolescents. Pediatric obesity 8(1):e19–e23PubMedGoogle Scholar
  180. Harmey JH, Bucana CD, Lu W, Byrne AM, McDonnell S, Lynch C, Bouchier-Hayes D, Dong Z (2002) Lipopolysaccharide-induced metastatic growth is associated with increased angiogenesis, vascular permeability and tumor cell invasion. Int J Cancer 101(5):415–422PubMedGoogle Scholar
  181. He W, Liu Q, Wang L, Chen W, Li N, Cao X (2007) TLR4 signaling promotes immune escape of human lung cancer cells by inducing immunosuppressive cytokines and apoptosis resistance. Mol Immunol 44(11):2850–2859PubMedGoogle Scholar
  182. He S, Chu J, Wu LC, Mao H, Peng Y, Alvarez-Breckenridge CA, Hughes T, Wei M, Zhang J, Yuan S, Sandhu S, Vasu S, Benson DM Jr, Hofmeister CC, He X, Ghoshal K, Devine SM, Caligiuri MA, Yu J (2013) MicroRNAs activate natural killer cells through toll-like receptor signaling. Blood 121(23):4663–4671PubMedGoogle Scholar
  183. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493(7434):674–678PubMedGoogle Scholar
  184. Herber DL, Mercer M, Roth LM, Symmonds K, Maloney J, Wilson N, Freeman MJ, Morgan D, Gordon MN (2007) Microglial activation is required for Abeta clearance after intracranial injection of lipopolysaccharide in APP transgenic mice. J Neuroimmune Pharmacol 2(2):222–231PubMedGoogle Scholar
  185. Himes RW, Smith CW (2010) Tlr2 is critical for diet-induced metabolic syndrome in a murine model. FASEB J 24(3):731–739PubMedGoogle Scholar
  186. Hinojosa E, Boyd AR, Orihuela CJ (2009) Age-associated inflammation and toll-like receptor dysfunction prime the lungs for pneumococcal pneumonia. J Infect Dis 200(4):546–554PubMedGoogle Scholar
  187. Hoebe K, Du X, Georgel P, Janssen E, Tabeta K, Kim SO, Goode J, Lin P, Mann N, Mudd S, Crozat K, Sovath S, Han J, Beutler B (2003) Identification of Lps2 as a key transducer of MyD88-independent TIR signalling. Nature 424(6950):743–748PubMedGoogle Scholar
  188. Hoffmann O, Braun JS, Becker D, Halle A, Freyer D, Dagand E, Lehnardt S, Weber JR (2007) TLR2 mediates neuroinflammation and neuronal damage. J Immunol 178(10):6476–6481PubMedGoogle Scholar
  189. Holloway JW, Yang IA, Ye S (2005) Variation in the toll-like receptor 4 gene and susceptibility to myocardial infarction. Pharmacogenet Genomics 15(1):15–21PubMedGoogle Scholar
  190. Hommelberg PP, Plat J, Langen RC, Schols AM, Mensink RP (2009) Fatty acid-induced NF-kappaB activation and insulin resistance in skeletal muscle are chain length dependent. Am J Physiol Endocrinol Metab 296(1):E114–E120PubMedGoogle Scholar
  191. Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G, Caffrey DR, Latz E, Fitzgerald KA (2009) AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458(7237):514–518PubMedGoogle Scholar
  192. Hosoi T, Yokoyama S, Matsuo S, Akira S, Ozawa K (2010) Myeloid differentiation factor 88 (MyD88)-deficiency increases risk of diabetes in mice. PLoS One 5(9)Google Scholar
  193. Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444(7121):860–867PubMedGoogle Scholar
  194. Hsu RY, Chan CH, Spicer JD, Rousseau MC, Giannias B, Rousseau S, Ferri LE (2011) LPS-induced TLR4 signaling in human colorectal cancer cells increases beta1 integrin-mediated cell adhesion and liver metastasis. Cancer Res 71(5):1989–1998PubMedGoogle Scholar
  195. Hu B, Elinav E, Huber S, Booth CJ, Strowig T, Jin C, Eisenbarth SC, Flavell RA (2010) Inflammation-induced tumorigenesis in the colon is regulated by caspase-1 and NLRC4. Proc Natl Acad Sci USA 107(50):21635–21640PubMedGoogle Scholar
  196. Hu J, He Y, Yan M, Zhu C, Ye W, Zhu H, Chen W, Zhang C, Zhang Z (2013) Dose dependent activation of retinoic acid-inducible gene-I promotes both proliferation and apoptosis signals in human head and neck squamous cell carcinoma. PLoS One 8(3):e58273PubMedGoogle Scholar
  197. Hua D, Liu MY, Cheng ZD, Qin XJ, Zhang HM, Chen Y, Qin GJ, Liang G, Li JN, Han XF, Liu DX (2009) Small interfering RNA-directed targeting of toll-like receptor 4 inhibits human prostate cancer cell invasion, survival, and tumorigenicity. Mol Immunol 46(15):2876–2884PubMedGoogle Scholar
  198. Huang B, Zhao J, Li H, He KL, Chen Y, Chen SH, Mayer L, Unkeless JC, Xiong H (2005) Toll-like receptors on tumor cells facilitate evasion of immune surveillance. Cancer Res 65(12):5009–5014PubMedGoogle Scholar
  199. Huang B, Zhao J, Shen S, Li H, He KL, Shen GX, Mayer L, Unkeless J, Li D, Yuan Y, Zhang GM, Xiong H, Feng ZH (2007) Listeria monocytogenes promotes tumor growth via tumor cell toll-like receptor 2 signaling. Cancer Res 67(9):4346–4352PubMedGoogle Scholar
  200. Huang CC, Liu K, Pope RM, Du P, Lin S, Rajamannan NM, Huang QQ, Jafari N, Burke GL, Post W, Watson KE, Johnson C, Daviglus ML, Lloyd-Jones DM (2011) Activated TLR signaling in atherosclerosis among women with lower Framingham risk score: the multi-ethnic study of atherosclerosis. PLoS One 6(6):e21067PubMedGoogle Scholar
  201. Huang CY, Chen JJ, Shen KY, Chang LS, Yeh YC, Chen IH, Chong P, Liu SJ, Leng CH (2012a) Recombinant lipidated HPV E7 induces a Th-1-biased immune response and protective immunity against cervical cancer in a mouse model. PLoS One 7(7):e40970PubMedGoogle Scholar
  202. Huang Y, Cai B, Xu M, Qiu Z, Tao Y, Zhang Y, Wang J, Xu Y, Zhou Y, Yang J, Han X, Gao Q (2012b) Gene silencing of toll-like receptor 2 inhibits proliferation of human liver cancer cells and secretion of inflammatory cytokines. PLoS One 7(7):e38890PubMedGoogle Scholar
  203. Huleatt JW, Nakaar V, Desai P, Huang Y, Hewitt D, Jacobs A, Tang J, McDonald W, Song L, Evans RK, Umlauf S, Tussey L, Powell TJ (2008) Potent immunogenicity and efficacy of a universal influenza vaccine candidate comprising a recombinant fusion protein linking influenza M2e to the TLR5 ligand flagellin. Vaccine 26(2):201–214PubMedGoogle Scholar
  204. Hutton MJ, Soukhatcheva G, Johnson JD, Verchere CB (2010) Role of the TLR signaling molecule TRIF in beta-cell function and glucose homeostasis. Islets 2(2):104–111PubMedGoogle Scholar
  205. Ilvesaro JM, Merrell MA, Swain TM, Davidson J, Zayzafoon M, Harris KW, Selander KS (2007) Toll like receptor-9 agonists stimulate prostate cancer invasion in vitro. Prostate 67(7):774–781PubMedGoogle Scholar
  206. Ilvesaro JM, Merrell MA, Li L, Wakchoure S, Graves D, Brooks S, Rahko E, Jukkola-Vuorinen A, Vuopala KS, Harris KW, Selander KS (2008) Toll-like receptor 9 mediates CpG oligonucleotide-induced cellular invasion. Mol Cancer Res 6(10):1534–1543PubMedGoogle Scholar
  207. Imran M, Waheed Y, Manzoor S, Bilal M, Ashraf W, Ali M, Ashraf M (2012) Interaction of Hepatitis C virus proteins with pattern recognition receptors. Virol J 9:126PubMedGoogle Scholar
  208. in t’ Veld BA, Ruitenberg A, Hofman A, Launer LJ, van Duijn CM, Stijnen T, Breteler MM, Stricker BH (2001) Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease. N Engl J Med 345(21):1515–1521PubMedGoogle Scholar
  209. Into T, Inomata M, Takayama E, Takigawa T (2012) Autophagy in regulation of Toll-like receptor signaling. Cell Signal 24(6):1150–1162PubMedGoogle Scholar
  210. Ioannou S, Voulgarelis M (2010) Toll-like receptors, tissue injury, and tumourigenesis. Mediators Inflamm 2010Google Scholar
  211. Iribarren P, Chen K, Hu J, Gong W, Cho EH, Lockett S, Uranchimeg B, Wang JM (2005) CpG-containing oligodeoxynucleotide promotes microglial cell uptake of amyloid beta 1–42 peptide by up-regulating the expression of the G-protein- coupled receptor mFPR2. FASEB J 19(14):2032–2034PubMedGoogle Scholar
  212. Ishii KJ, Kawakami K, Gursel I, Conover J, Joshi BH, Klinman DM, Puri RK (2003) Antitumor therapy with bacterial DNA and toxin: complete regression of established tumor induced by liposomal CpG oligodeoxynucleotides plus interleukin-13 cytotoxin. Clin Cancer Res 9(17):6516–6522PubMedGoogle Scholar
  213. Iwasaki A, Medzhitov R (2010) Regulation of adaptive immunity by the innate immune system. Science 327(5963):291–295PubMedGoogle Scholar
  214. Iyer SS, Pulskens WP, Sadler JJ, Butter LM, Teske GJ, Ulland TK, Eisenbarth SC, Florquin S, Flavell RA, Leemans JC, Sutterwala FS (2009) Necrotic cells trigger a sterile inflammatory response through the Nlrp3 inflammasome. Proc Natl Acad Sci U S A 106(48):20388–20393PubMedGoogle Scholar
  215. Janeway CA Jr (1989) Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol 54(Pt 1):1–13PubMedGoogle Scholar
  216. Janeway CA Jr, Medzhitov R (2002) Innate immune recognition. Annu Rev Immunol 20:197–216PubMedGoogle Scholar
  217. Jang HJ, Kim HS, Hwang DH, Quon MJ, Kim JA (2013) Toll-like receptor 2 mediates high-fat diet-induced impairment of vasodilator actions of insulin. Am J Physiol Endocrinol Metab 304(10):E1077–E1088PubMedGoogle Scholar
  218. Jego G, Bataille R, Geffroy-Luseau A, Descamps G, Pellat-Deceunynck C (2006) Pathogen-associated molecular patterns are growth and survival factors for human myeloma cells through toll-like receptors. Leukemia 20(6):1130–1137PubMedGoogle Scholar
  219. Jha S, Srivastava SY, Brickey WJ, Iocca H, Toews A, Morrison JP, Chen VS, Gris D, Matsushima GK, Ting JP (2010) The inflammasome sensor, NLRP3, regulates CNS inflammation and demyelination via caspase-1 and interleukin-18. J Neurosci 30(47):15811–15820PubMedGoogle Scholar
  220. Jialal I, Huet BA, Kaur H, Chien A, Devaraj S (2012) Increased toll-like receptor activity in patients with metabolic syndrome. Diabetes Care 35(4):900–904PubMedGoogle Scholar
  221. Jiang H, Van DV, Satwani P, Baxi LV, Cairo MS (2004) Differential gene expression patterns by oligonucleotide microarray of basal versus lipopolysaccharide-activated monocytes from cord blood versus adult peripheral blood. J Immunol 172(10):5870–5879PubMedGoogle Scholar
  222. Jiang Z, Georgel P, Du X, Shamel L, Sovath S, Mudd S, Huber M, Kalis C, Keck S, Galanos C, Freudenberg M, Beutler B (2005) CD14 is required for MyD88-independent LPS signaling. Nat Immunol 6(6):565–570PubMedGoogle Scholar
  223. Jing Y, Shaheen E, Drake RR, Chen N, Gravenstein S, Deng Y (2009) Aging is associated with a numerical and functional decline in plasmacytoid dendritic cells, whereas myeloid dendritic cells are relatively unaltered in human peripheral blood. Hum Immunol 70(10):777–784PubMedGoogle Scholar
  224. Johansen T, Lamark T (2011) Selective autophagy mediated by autophagic adapter proteins. Autophagy 7(3):279–296PubMedGoogle Scholar
  225. Johnson BD, Kip KE, Marroquin OC, Ridker PM, Kelsey SF, Shaw LJ, Pepine CJ, Sharaf B, Bairey Merz CN, Sopko G, Olson MB, Reis SE (2004) Serum amyloid A as a predictor of coronary artery disease and cardiovascular outcome in women: the National Heart, Lung, and Blood Institute-Sponsored Women’s Ischemia Syndrome Evaluation (WISE). Circulation 109(6):726–732PubMedGoogle Scholar
  226. Johnson KE, Chikoti L, Chandran B (2013) Herpes simplex virus 1 infection induces activation and subsequent inhibition of the IFI16 and NLRP3 inflammasomes. J Virol 87(9):5005–5018PubMedGoogle Scholar
  227. Johnstone RW, Wei W, Greenway A, Trapani JA (2000) Functional interaction between p53 and the interferon-inducible nucleoprotein IFI 16. Oncogene 19(52):6033–6042PubMedGoogle Scholar
  228. Jones SC, Brahmakshatriya V, Huston G, Dibble J, Swain SL (2010) TLR-activated dendritic cells enhance the response of aged naive CD4 T cells via an IL-6-dependent mechanism. J Immunol 185(11):6783–6794PubMedGoogle Scholar
  229. Jounai N, Takeshita F, Kobiyama K, Sawano A, Miyawaki A, Xin KQ, Ishii KJ, Kawai T, Akira S, Suzuki K, Okuda K (2007) The Atg5 Atg12 conjugate associates with innate antiviral immune responses. Proc Natl Acad Sci U S A 104(35):14050–14055PubMedGoogle Scholar
  230. Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES (2012) Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem 287(43):36617–36622PubMedGoogle Scholar
  231. Junjie X, Songyao J, Minmin S, Yanyan S, Baiyong S, Xiaxing D, Jiabin J, Xi Z, Hao C (2012) The association between toll-like receptor 2 single-nucleotide polymorphisms and hepatocellular carcinoma susceptibility. BMC Cancer 12:57PubMedGoogle Scholar
  232. Kadl A, Sharma PR, Chen W, Agrawal R, Meher AK, Rudraiah S, Grubbs N, Sharma R, Leitinger N (2011) Oxidized phospholipid-induced inflammation is mediated by toll-like receptor 2. Free Radic Biol Med 51(10):1903–1909PubMedGoogle Scholar
  233. Kagan JC, Iwasaki A (2012) Phagosome as the organelle linking innate and adaptive immunity. Traffic 9999(9999)Google Scholar
  234. Karin M (2006) Nuclear factor-kappaB in cancer development and progression. Nature 441(7092):431–436PubMedGoogle Scholar
  235. Katsargyris A, Tsiodras S, Theocharis S, Giaginis K, Vasileiou I, Bakoyiannis C, Georgopoulos S, Bastounis E, Klonaris C (2011) Toll-like receptor 4 immunohistochemical expression is enhanced in macrophages of symptomatic carotid atherosclerotic plaques. Cerebrovasc Dis 31(1):29–36PubMedGoogle Scholar
  236. Kauppinen A, Niskanen H, Suuronen T, Kinnunen K, Salminen A, Kaarniranta K (2012) Oxidative stress activates NLRP3 inflammasomes in ARPE-19 cells–implications for age-related macular degeneration (AMD). Immunol Lett 147(1–2):29–33PubMedGoogle Scholar
  237. Kawaguchi M, Takahashi M, Hata T, Kashima Y, Usui F, Morimoto H, Izawa A, Takahashi Y, Masumoto J, Koyama J, Hongo M, Noda T, Nakayama J, Sagara J, Taniguchi S, Ikeda U (2011) Inflammasome activation of cardiac fibroblasts is essential for myocardial ischemia/reperfusion injury. Circulation 123(6):594–604PubMedGoogle Scholar
  238. Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34(5):637–650PubMedGoogle Scholar
  239. Kawanishi N, Yano H, Yokogawa Y, Suzuki K (2010) Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet-induced obese mice. Exerc Immunol Rev 16:105–118PubMedGoogle Scholar
  240. Kelly MG, Alvero AB, Chen R, Silasi DA, Abrahams VM, Chan S, Visintin I, Rutherford T, Mor G (2006) TLR-4 signaling promotes tumor growth and paclitaxel chemoresistance in ovarian cancer. Cancer Res 66(7):3859–3868PubMedGoogle Scholar
  241. Kerur N, Veettil MV, Sharma-Walia N, Bottero V, Sadagopan S, Otageri P, Chandran B (2011) IFI16 acts as a nuclear pathogen sensor to induce the inflammasome in response to Kaposi Sarcoma-associated herpesvirus infection. Cell Host Microbe 9(5):363–375PubMedGoogle Scholar
  242. Kierdorf K, Fritz G (2013) RAGE regulation and signaling in inflammation and beyond. J Leukoc Biol 94(1):55–68PubMedGoogle Scholar
  243. Kigerl KA, Lai W, Rivest S, Hart RP, Satoskar AR, Popovich PG (2007) Toll-like receptor (TLR)-2 and TLR-4 regulate inflammation, gliosis, and myelin sparing after spinal cord injury. J Neurochem 102(1):37–50PubMedGoogle Scholar
  244. Killeen SD, Wang JH, Andrews EJ, Redmond HP (2009) Bacterial endotoxin enhances colorectal cancer cell adhesion and invasion through TLR-4 and NF-kappaB-dependent activation of the urokinase plasminogen activator system. Br J Cancer 100(10):1589–1602PubMedGoogle Scholar
  245. Kim F, Pham M, Luttrell I, Bannerman DD, Tupper J, Thaler J, Hawn TR, Raines EW, Schwartz MW (2007a) Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res 100(11):1589–1596PubMedGoogle Scholar
  246. Kim HS, Han MS, Chung KW, Kim S, Kim E, Kim MJ, Jang E, Lee HA, Youn J, Akira S, Lee MS (2007b) Toll-like receptor 2 senses beta-cell death and contributes to the initiation of autoimmune diabetes. Immunity 27(2):321–333PubMedGoogle Scholar
  247. Kim WY, Lee JW, Choi JJ, Choi CH, Kim TJ, Kim BG, Song SY, Bae DS (2008) Increased expression of toll-like receptor 5 during progression of cervical neoplasia. Int J Gynecol Cancer 18(2):300–305PubMedGoogle Scholar
  248. Kim S, Takahashi H, Lin WW, Descargues P, Grivennikov S, Kim Y, Luo JL, Karin M (2009a) Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 457(7225):102–106PubMedGoogle Scholar
  249. Kim YS, Park ZY, Kim SY, Jeong E, Lee JY (2009b) Alteration of toll-like receptor 4 activation by 4-hydroxy-2-nonenal mediated by the suppression of receptor homodimerization. Chem Biol Interact 182(1):59–66PubMedGoogle Scholar
  250. Kim KA, Gu W, Lee IA, Joh EH, Kim DH (2012) High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway. PLoS One 7(10):e47713PubMedGoogle Scholar
  251. Kim MJ, Choi NY, Koo JE, Kim SY, Joung SM, Jeong E, Lee JY (2013) Suppression of toll-like receptor 4 activation by endogenous oxidized phosphatidylcholine, KOdiA-PC by inhibiting LPS binding to MD2. Inflamm Res 62(6):571–580PubMedGoogle Scholar
  252. Kleinridders A, Schenten D, Konner AC, Belgardt BF, Mauer J, Okamura T, Wunderlich FT, Medzhitov R, Bruning JC (2009) MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab 10(4):249–259PubMedGoogle Scholar
  253. Knapp S, Matt U, Leitinger N, van der Poll T (2007) Oxidized phospholipids inhibit phagocytosis and impair outcome in gram-negative sepsis in vivo. J Immunol 178(2):993–1001PubMedGoogle Scholar
  254. Koliaraki V, Kollias G (2011) A new role for myeloid HO-1 in the innate to adaptive crosstalk and immune homeostasis. Adv Exp Med Biol 780:101–111PubMedGoogle Scholar
  255. Kollmann TR, Levy O, Montgomery RR, Goriely S (2012) Innate immune function by toll-like receptors: distinct responses in newborns and the elderly. Immunity 37(5):771–783PubMedGoogle Scholar
  256. Kondo Y, Nagai K, Nakahata S, Saito Y, Ichikawa T, Suekane A, Taki T, Iwakawa R, Enari M, Taniwaki M, Yokota J, Sakoda S, Morishita K (2012) Overexpression of the DNA sensor proteins, absent in melanoma 2 and interferon-inducible 16, contributes to tumorigenesis of oral squamous cell carcinoma with p53 inactivation. Cancer Sci 103(4):782–790PubMedGoogle Scholar
  257. Kong KF, Delroux K, Wang X, Qian F, Arjona A, Malawista SE, Fikrig E, Montgomery RR (2008) Dysregulation of TLR3 impairs the innate immune response to West Nile virus in the elderly. J Virol 82(15):7613–7623PubMedGoogle Scholar
  258. Kong X, Thimmulappa R, Kombairaju P, Biswal S (2010) NADPH oxidase-dependent reactive oxygen species mediate amplified TLR4 signaling and sepsis-induced mortality in Nrf2-deficient mice. J Immunol 185(1):569–577PubMedGoogle Scholar
  259. Konner AC, Bruning JC (2011) Toll-like receptors: linking inflammation to metabolism. Trends Endocrinol Metab 22(1):16–23PubMedGoogle Scholar
  260. Kopp A, Buechler C, Neumeier M, Weigert J, Aslanidis C, Scholmerich J, Schaffler A (2009) Innate immunity and adipocyte function: ligand-specific activation of multiple toll-like receptors modulates cytokine, adipokine, and chemokine secretion in adipocytes. Obesity 17(4):648–656PubMedGoogle Scholar
  261. Kopp A, Buechler C, Bala M, Neumeier M, Scholmerich J, Schaffler A (2010) Toll-like receptor ligands cause proinflammatory and prodiabetic activation of adipocytes via phosphorylation of extracellular signal-regulated kinase and c-Jun N-terminal kinase but not interferon regulatory factor-3. Endocrinology 151(3):1097–1108PubMedGoogle Scholar
  262. Kotas ME, Jurczak MJ, Annicelli C, Gillum MP, Cline GW, Shulman GI, Medzhitov R (2013) Role of caspase-1 in regulation of triglyceride metabolism. Proc Natl Acad Sci U S A 110(12):4810–4815PubMedGoogle Scholar
  263. Kovacs EJ, Palmer JL, Fortin CF, Fulop T Jr, Goldstein DR, Linton PJ (2009) Aging and innate immunity in the mouse: impact of intrinsic and extrinsic factors. Trends Immunol 30(7):319–324PubMedGoogle Scholar
  264. Krieg AM (2008) Toll-like receptor 9 (TLR9) agonists in the treatment of cancer. Oncogene 27(2):161–167PubMedGoogle Scholar
  265. Kundu SD, Lee C, Billips BK, Habermacher GM, Zhang Q, Liu V, Wong LY, Klumpp DJ, Thumbikat P (2008) The toll-like receptor pathway: a novel mechanism of infection-induced carcinogenesis of prostate epithelial cells. Prostate 68(2):223–229PubMedGoogle Scholar
  266. Kunzli BM, Bernlochner MI, Rath S, Kaser S, Csizmadia E, Enjyoji K, Cowan P, d’Apice A, Dwyer K, Rosenberg R, Perren A, Friess H, Maurer CA, Robson SC (2011) Impact of CD39 and purinergic signalling on the growth and metastasis of colorectal cancer. Purinergic Signal 7(2):231–241PubMedGoogle Scholar
  267. Kuo LH, Tsai PJ, Jiang MJ, Chuang YL, Yu L, Lai KT, Tsai YS (2011) Toll-like receptor 2 deficiency improves insulin sensitivity and hepatic insulin signalling in the mouse. Diabetologia 54(1):168–179PubMedGoogle Scholar
  268. Kutikhin AG (2011a) Association of polymorphisms in TLR genes and in genes of the toll-like receptor signaling pathway with cancer risk. Hum Immunol 72(11):1095–1116PubMedGoogle Scholar
  269. Kutikhin AG (2011b) Impact of toll-like receptor 4 polymorphisms on risk of cancer. Hum Immunol 72(2):193–206PubMedGoogle Scholar
  270. Kutikhin AG, Yuzhalin AE (2012a) C-type lectin receptors and RIG-I-like receptors: new points on the oncogenomics map. Cancer Manage Res 4:39–53Google Scholar
  271. Kutikhin AG, Yuzhalin AE (2012b) Inherited variation in pattern recognition receptors and cancer: dangerous liaisons? Cancer Manage Res 4:31–38Google Scholar
  272. Lagos D, Vart RJ, Gratrix F, Westrop SJ, Emuss V, Wong PP, Robey R, Imami N, Bower M, Gotch F, Boshoff C (2008) Toll-like receptor 4 mediates innate immunity to Kaposi sarcoma herpesvirus. Cell Host Microbe 4(5):470–483PubMedGoogle Scholar
  273. Lambrecht BN, Hammad H (2012) The airway epithelium in asthma. Nat Med 18(5):684–692PubMedGoogle Scholar
  274. Lawrie CH, Gal S, Dunlop HM, Pushkaran B, Liggins AP, Pulford K, Banham AH, Pezzella F, Boultwood J, Wainscoat JS, Hatton CS, Harris AL (2008) Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol 141(5):672–675PubMedGoogle Scholar
  275. Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271(5256):1734–1736PubMedGoogle Scholar
  276. LeBouder E, Rey-Nores JE, Raby AC, Affolter M, Vidal K, Thornton CA, Labeta MO (2006) Modulation of neonatal microbial recognition: TLR-mediated innate immune responses are specifically and differentially modulated by human milk. J Immunol 176(6):3742–3752PubMedGoogle Scholar
  277. Lee JY, Sohn KH, Rhee SH, Hwang D (2001) Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through toll-like receptor 4. J Biol Chem 276(20):16683–16689PubMedGoogle Scholar
  278. Lee JW, Choi JJ, Seo ES, Kim MJ, Kim WY, Choi CH, Kim TJ, Kim BG, Song SY, Bae DS (2007) Increased toll-like receptor 9 expression in cervical neoplasia. Mol Carcinog 46(11):941–947PubMedGoogle Scholar
  279. Lee JY, Park AK, Lee KM, Park SK, Han S, Han W, Noh DY, Yoo KY, Kim H, Chanock SJ, Rothman N, Kang D (2009) Candidate gene approach evaluates association between innate immunity genes and breast cancer risk in Korean women. Carcinogenesis 30(9):1528–1531PubMedGoogle Scholar
  280. Lee J, Giordano S, Zhang J (2012) Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling. Biochem J 441(2):523–540PubMedGoogle Scholar
  281. Lefebvre JS, Maue AC, Eaton SM, Lanthier PA, Tighe M, Haynes L (2012) The aged microenvironment contributes to the age-related functional defects of CD4 T cells in mice. Aging Cell 11(5):732–740PubMedGoogle Scholar
  282. Lehnardt S, Lachance C, Patrizi S, Lefebvre S, Follett PL, Jensen FE, Rosenberg PA, Volpe JJ, Vartanian T (2002) The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci 22(7):2478–2486PubMedGoogle Scholar
  283. Lehnardt S, Massillon L, Follett P, Jensen FE, Ratan R, Rosenberg PA, Volpe JJ, Vartanian T (2003) Activation of innate immunity in the CNS triggers neurodegeneration through a toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A 100(14):8514–8519PubMedGoogle Scholar
  284. Lemke G, Rothlin CV (2008) Immunobiology of the TAM receptors. Nat Rev Immunol 8(5):327–336PubMedGoogle Scholar
  285. Letiembre M, Hao W, Liu Y, Walter S, Mihaljevic I, Rivest S, Hartmann T, Fassbender K (2007) Innate immune receptor expression in normal brain aging. Neuroscience 146(1):248–254PubMedGoogle Scholar
  286. Letiembre M, Liu Y, Walter S, Hao W, Pfander T, Wrede A, Schulz-Schaeffer W, Fassbender K (2009) Screening of innate immune receptors in neurodegenerative diseases: a similar pattern. Neurobiol Aging 30(5):759–768PubMedGoogle Scholar
  287. Levy O (2005) Innate immunity of the human newborn: distinct cytokine responses to LPS and other toll-like receptor agonists. J Endotoxin Res 11(2):113–116PubMedGoogle Scholar
  288. Levy O (2007) Innate immunity of the newborn: basic mechanisms and clinical correlates. Nat Rev Immunol 7(5):379–390PubMedGoogle Scholar
  289. Levy O, Zarember KA, Roy RM, Cywes C, Godowski PJ, Wessels MR (2004) Selective impairment of TLR-mediated innate immunity in human newborns: neonatal blood plasma reduces monocyte TNF-alpha induction by bacterial lipopeptides, lipopolysaccharide, and imiquimod, but preserves the response to R-848. J Immunol 173(7):4627–4634PubMedGoogle Scholar
  290. Levy O, Coughlin M, Cronstein BN, Roy RM, Desai A, Wessels MR (2006) The adenosine system selectively inhibits TLR-mediated TNF-alpha production in the human newborn. J Immunol 177(3):1956–1966PubMedGoogle Scholar
  291. Levy E, Xanthou G, Petrakou E, Zacharioudaki V, Tsatsanis C, Fotopoulos S, Xanthou M (2009) Distinct roles of TLR4 and CD14 in LPS-induced inflammatory responses of neonates. Pediatr Res 66(2):179–184PubMedGoogle Scholar
  292. Li J, Song W, Czerwinski DK, Varghese B, Uematsu S, Akira S, Krieg AM, Levy R (2007a) Lymphoma immunotherapy with CpG oligodeoxynucleotides requires TLR9 either in the host or in the tumor itself. J Immunol 179(4):2493–2500PubMedGoogle Scholar
  293. Li Y, Chu N, Hu A, Gran B, Rostami A, Zhang GX (2007b) Increased IL-23p19 expression in multiple sclerosis lesions and its induction in microglia. Brain 130(Pt 2):490–501PubMedGoogle Scholar
  294. Li XD, Chiu YH, Ismail AS, Behrendt CL, Wight-Carter M, Hooper LV, Chen ZJ (2011) Mitochondrial antiviral signaling protein (MAVS) monitors commensal bacteria and induces an immune response that prevents experimental colitis. Proc Natl Acad Sci U S A 108(42):17390–17395PubMedGoogle Scholar
  295. Li K, Li NL, Wei D, Pfeffer SR, Fan M, Pfeffer LM (2012a) Activation of chemokine and inflammatory cytokine response in hepatitis C virus-infected hepatocytes depends on toll-like receptor 3 sensing of hepatitis C virus double-stranded RNA intermediates. Hepatology 55(3):666–675PubMedGoogle Scholar
  296. Li Q, Li X, Guo Z, Xu F, Xia J, Liu Z, Ren T (2012b) MicroRNA-574-5p was pivotal for TLR9 signaling enhanced tumor progression via down-regulating checkpoint suppressor 1 in human lung cancer. PLoS One 7(11):e48278PubMedGoogle Scholar
  297. Liao JB (2006) Viruses and human cancer. Yale J Biol Med 79(3–4):115–122PubMedGoogle Scholar
  298. Lifshitz V, Weiss R, Benromano T, Kfir E, Blumenfeld-Katzir T, Tempel-Brami C, Assaf Y, Xia W, Wyss-Coray T, Weiner HL, Frenkel D (2012) Immunotherapy of cerebrovascular amyloidosis in a transgenic mouse model. Neurobiol Aging 33(2):432 e431–432 e413Google Scholar
  299. Lin L, Park S, Lakatta EG (2009) RAGE signaling in inflammation and arterial aging. Front Biosci 14:1403–1413Google Scholar
  300. Lin H, Hua F, Hu ZW (2012) Autophagic flux, supported by toll-like receptor 2 activity, defends against the carcinogenesis of hepatocellular carcinoma. Autophagy 8(12):1859–1861PubMedGoogle Scholar
  301. Lin H, Yan J, Wang Z, Hua F, Yu J, Sun W, Li K, Liu H, Yang H, Lv Q, Xue J, Hu ZW (2013a) Loss of immunity-supported senescence enhances susceptibility to hepatocellular carcinogenesis and progression in toll-like receptor 2-deficient mice. Hepatology 57(1):171–182PubMedGoogle Scholar
  302. Lin T, Walker GB, Kurji K, Fang E, Law G, Prasad SS, Kojic L, Cao S, White V, Cui JZ, Matsubara JA (2013b) Parainflammation associated with advanced glycation endproduct stimulation of RPE in vitro: implications for age-related degenerative diseases of the eye. Cytokine 62(3):369–381PubMedGoogle Scholar
  303. Lisciandro JG, Prescott SL, Nadal-Sims MG, Devitt CJ, Pomat W, Siba PM, Tulic MC, Holt PG, Strickland D, van den Biggelaar AH (2012) Ontogeny of toll-like and NOD-like receptor-mediated innate immune responses in Papua New Guinean infants. PLoSOne 7(5):e36793Google Scholar
  304. Liu HM, Gale M (2010) Hepatitis C virus evasion from RIG-I-dependent hepatic innate immunity. Gastroenterol Res Pract 2010:548390PubMedGoogle Scholar
  305. Liu X, Xu Q, Chen W, Cao H, Zheng R, Li G (2009) Hepatitis B virus DNA-induced carcinogenesis of human normal liver cells by virtue of nonmethylated CpG DNA. Oncol Rep 21(4):941–947PubMedGoogle Scholar
  306. Liu J, Radler D, Illi S, Klucker E, Turan E, Von Mutius ME, Kabesch M, Schaub B (2011) TLR2 polymorphisms influence neonatal regulatory T cells depending on maternal atopy. Allergy 66(8):1020–1029PubMedGoogle Scholar
  307. Liu ML, Scalia R, Mehta JL, Williams KJ (2012) Cholesterol-induced membrane microvesicles as novel carriers of damage-associated molecular patterns: mechanisms of formation, action, and detoxification. Arterioscler Thromb Vasc Biol 32(9):2113–2121PubMedGoogle Scholar
  308. Lokeshwar VB, Cerwinka WH, Isoyama T, Lokeshwar BL (2005) HYAL1 hyaluronidase in prostate cancer: a tumor promoter and suppressor. Cancer Res 65(17):7782–7789PubMedGoogle Scholar
  309. Long TM, Chakrabarti A, Ezelle HJ, Brennan-Laun SE, Raufman JP, Polyakova I, Silverman RH, Hassel BA (2013) RNase-L deficiency exacerbates experimental colitis and colitis-associated cancer. Inflamm Bowel Dis 19(6):1295–1305PubMedGoogle Scholar
  310. Longobardo MT, Cefalu AB, Pezzino F, Noto D, Emmanuele G, Barbagallo CM, Fiore B, Monastero R, Castello A, Molini V, Notarbartolo A, Travali S, Averna MR (2003) The C(−260)>T gene polymorphism in the promoter of the CD14 monocyte receptor gene is not associated with acute myocardial infarction. Clin Exp Med 3(3):161–165PubMedGoogle Scholar
  311. Lowe EL, Crother TR, Rabizadeh S, Hu B, Wang H, Chen S, Shimada K, Wong MH, Michelsen KS, Arditi M (2010) Toll-like receptor 2 signaling protects mice from tumor development in a mouse model of colitis-induced cancer. PLoS One 5(9):e13027PubMedGoogle Scholar
  312. Lu H, Wagner WM, Gad E, Yang Y, Duan H, Amon LM, Van Denend N, Larson ER, Chang A, Tufvesson H, Disis ML (2010) Treatment failure of a TLR-7 agonist occurs due to self-regulation of acute inflammation and can be overcome by IL-10 blockade. J Immunol 184(9):5360–5367PubMedGoogle Scholar
  313. Lu S, Bevier M, Huhn S, Sainz J, Lascorz J, Pardini B, Naccarati A, Vodickova L, Novotny J, Hemminki K, Vodicka P, Forsti A (2013) Genetic variants in C-type lectin genes are associated with colorectal cancer susceptibility and clinical outcome. Int J Cancer. May 3 doi: 10.1002/ijc.28251. [Epub ahead of print]
  314. Luo JL, Maeda S, Hsu LC, Yagita H, Karin M (2004) Inhibition of NF-kappaB in cancer cells converts inflammation- induced tumor growth mediated by TNFalpha to TRAIL-mediated tumor regression. Cancer Cell 6(3):297–305PubMedGoogle Scholar
  315. Lust JA, Lacy MQ, Zeldenrust SR, Dispenzieri A, Gertz MA, Witzig TE, Kumar S, Hayman SR, Russell SJ, Buadi FK, Geyer SM, Campbell ME, Kyle RA, Rajkumar SV, Greipp PR, Kline MP, Xiong Y, Moon-Tasson LL, Donovan KA (2009) Induction of a chronic disease state in patients with smoldering or indolent multiple myeloma by targeting interleukin 1{beta}-induced interleukin 6 production and the myeloma proliferative component. Mayo Clin Proc 84(2):114–122PubMedGoogle Scholar
  316. Ma Y, Aymeric L, Locher C, Mattarollo SR, Delahaye NF, Pereira P, Boucontet L, Apetoh L, Ghiringhelli F, Casares N, Lasarte JJ, Matsuzaki G, Ikuta K, Ryffel B, Benlagha K, Tesniere A, Ibrahim N, Dechanet-Merville J, Chaput N, Smyth MJ, Kroemer G, Zitvogel L (2011) Contribution of IL-17-producing gamma delta T cells to the efficacy of anticancer chemotherapy. J Exp Med 208(3):491–503PubMedGoogle Scholar
  317. Malathi K, Dong B, Gale M Jr, Silverman RH (2007) Small self-RNA generated by RNase L amplifies antiviral innate immunity. Nature 448(7155):816–819PubMedGoogle Scholar
  318. Manicassamy S, Pulendran B (2009) Modulation of adaptive immunity with toll-like receptors. Semin Immunol 21(4):185–193PubMedGoogle Scholar
  319. Marker T, Sell H, Zillessen P, Glode A, Kriebel J, Ouwens DM, Pattyn P, Ruige J, Famulla S, Roden M, Eckel J, Habich C (2012) Heat shock protein 60 as a mediator of adipose tissue inflammation and insulin resistance. Diabetes 61(3):615–625PubMedGoogle Scholar
  320. Marshall NA, Galvin KC, Corcoran AM, Boon L, Higgs R, Mills KH (2012) Immunotherapy with PI3K inhibitor and toll-like receptor agonist induces IFN-gamma+IL-17+ polyfunctional T cells that mediate rejection of murine tumors. Cancer Res 72(3):581–591PubMedGoogle Scholar
  321. Marta M, Andersson A, Isaksson M, Kampe O, Lobell A (2008) Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis. Eur J Immunol 38(2):565–575PubMedGoogle Scholar
  322. Martin V, Fabelo N, Santpere G, Puig B, Marin R, Ferrer I, Diaz M (2010) Lipid alterations in lipid rafts from Alzheimer’s disease human brain cortex. Alzheimer’s Dis 19(2):489–502Google Scholar
  323. Martinez-Vicente M, Cuervo AM (2007) Autophagy and neurodegeneration: when the cleaning crew goes on strike. Lancet Neurol 6(4):352–361PubMedGoogle Scholar
  324. Martino G, Pluchino S (2007) Neural stem cells: guardians of the brain. Nat Cell Biol 9(9):1031–1034PubMedGoogle Scholar
  325. Martins I, Tesniere A, Kepp O, Michaud M, Schlemmer F, Senovilla L, Seror C, Metivier D, Perfettini JL, Zitvogel L, Kroemer G (2009) Chemotherapy induces ATP release from tumor cells. Cell Cycle 8(22):3723–3728PubMedGoogle Scholar
  326. Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, Becker C, Franchi L, Yoshihara E, Chen Z, Mullooly N, Mielke LA, Harris J, Coll RC, Mills KH, Mok KH, Newsholme P, Nunez G, Yodoi J, Kahn SE, Lavelle EC, O’Neill LA (2010) Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1beta in type 2 diabetes. Nat Immunol 11(10):897–904PubMedGoogle Scholar
  327. Matijevic T, Pavelic J (2011) The dual role of TLR3 in metastatic cell line. Clin Exp Metastasis 28(7):701–712PubMedGoogle Scholar
  328. Matijevic T, Marjanovic M, Pavelic J (2009) Functionally active toll-like receptor 3 on human primary and metastatic cancer cells. Scand J Immunol 70(1):18–24PubMedGoogle Scholar
  329. Mattson MP (2004) Pathways towards and away from Alzheimer’s disease. Nature 430(7000):631–639PubMedGoogle Scholar
  330. Maue AC, Eaton SM, Lanthier PA, Sweet KB, Blumerman SL, Haynes L (2009) Proinflammatory adjuvants enhance the cognate helper activity of aged CD4 T cells. J Immunol 182(10):6129–6135PubMedGoogle Scholar
  331. Mawhinney LJ, de Rivero Vaccari JP, Dale GA, Keane RW, Bramlett HM (2011) Heightened inflammasome activation is linked to age-related cognitive impairment in Fischer 344 rats. BMC Neurosci 12:123PubMedGoogle Scholar
  332. Medzhitov R (2009) Approaching the asymptote: 20 years later. Immunity 30(6):766–775PubMedGoogle Scholar
  333. Menu P, Pellegrin M, Aubert JF, Bouzourene K, Tardivel A, Mazzolai L, Tschopp J (2011) Atherosclerosis in ApoE-deficient mice progresses independently of the NLRP3 inflammasome. Cell Death Dis 2:e137PubMedGoogle Scholar
  334. Merrell MA, Ilvesaro JM, Lehtonen N, Sorsa T, Gehrs B, Rosenthal E, Chen D, Shackley B, Harris KW, Selander KS (2006) Toll-like receptor 9 agonists promote cellular invasion by increasing matrix metalloproteinase activity. Mol Cancer Res 4(7):437–447PubMedGoogle Scholar
  335. Mezzaroma E, Toldo S, Farkas D, Seropian IM, Van Tassell BW, Salloum FN, Kannan HR, Menna AC, Voelkel NF, Abbate A (2011) The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse. Proc Natl Acad Sci U S A 108(49):19725–19730PubMedGoogle Scholar
  336. Miao EA, Leaf IA, Treuting PM, Mao DP, Dors M, Sarkar A, Warren SE, Wewers MD, Aderem A (2010) Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat Immunol 11(12):1136–1142PubMedGoogle Scholar
  337. Michaud M, Martins I, Sukkurwala AQ, Adjemian S, Ma Y, Pellegatti P, Shen S, Kepp O, Scoazec M, Mignot G, Rello-Varona S, Tailler M, Menger L, Vacchelli E, Galluzzi L, Ghiringhelli F, di Virgilio F, Zitvogel L, Kroemer G (2011) Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334(6062):1573–1577PubMedGoogle Scholar
  338. Michelsen KS, Wong MH, Shah PK, Zhang W, Yano J, Doherty TM, Akira S, Rajavashisth TB, Arditi M (2004) Lack of toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proc Natl Acad Sci U S A 101(29):10679–10684PubMedGoogle Scholar
  339. Miller YI, Choi SH, Wiesner P, Fang L, Harkewicz R, Hartvigsen K, Boullier A, Gonen A, Diehl CJ, Que X, Montano E, Shaw PX, Tsimikas S, Binder CJ, Witztum JL (2011) Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ Res 108(2):235–248PubMedGoogle Scholar
  340. Miller YI, Choi SH, Wiesner P, Bae YS (2012) The SYK side of TLR4: signalling mechanisms in response to LPS and minimally oxidized LDL. Br J Pharmacol 167(5):990–999PubMedGoogle Scholar
  341. Minoretti P, Gazzaruso C, Vito CD, Emanuele E, Bianchi M, Coen E, Reino M, Geroldi D (2006) Effect of the functional toll-like receptor 4 Asp299Gly polymorphism on susceptibility to late-onset alzheimer’s disease. Neurosci Lett 391(3):147–149PubMedGoogle Scholar
  342. Mistry AM, Swick AG, Romsos DR (1997) Leptin rapidly lowers food intake and elevates metabolic rates in lean and ob/ob mice. J Nutr 127(10):2065–2072PubMedGoogle Scholar
  343. Mitchell PS, Parkin RK, Kroh EM, Fritz BR, Wyman SK, Pogosova-Agadjanyan EL, Peterson A, Noteboom J, O’Briant KC, Allen A, Lin DW, Urban N, Drescher CW, Knudsen BS, Stirewalt DL, Gentleman R, Vessella RL, Nelson PS, Martin DB, Tewari M (2008) Circulating microRNAs as stable blood-based markers for cancer detection. Proc Natl Acad Sci U S A 105(30):10513–10518PubMedGoogle Scholar
  344. Moghimpour Bijani F, Vallejo JG, Rezaei N (2012) Toll-like receptor signaling pathways in cardiovascular diseases: challenges and opportunities. Int Rev Immunol 31(5):379–395PubMedGoogle Scholar
  345. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, Marks JS (2003) Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001. JAMA 289(1):76–79PubMedGoogle Scholar
  346. Mollaki V, Georgiadis T, Tassidou A, Ioannou M, Daniil Z, Koutsokera A, Papathanassiou AA, Zintzaras E, Vassilopoulos G (2009) Polymorphisms and haplotypes in TLR9 and MYD88 are associated with the development of Hodgkin’s lymphoma: a candidate-gene association study. J Hum Genet 54(11):655–659PubMedGoogle Scholar
  347. Monroy CM, Cortes AC, Lopez MS, D’Amelio AM Jr, Etzel CJ, Younes A, Strom SS, El-Zein RA (2011) Hodgkin disease risk: role of genetic polymorphisms and gene-gene interactions in inflammation pathway genes. Mol Carcinog 50(1):36–46PubMedGoogle Scholar
  348. Morales A, Eidinger D, Bruce AW (1976) Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol 116(2):180–183PubMedGoogle Scholar
  349. Moumad K, Lascorz J, Bevier M, Khyatti M, Ennaji MM, Benider A, Huhn S, Lu S, Chouchane L, Corbex M, Hemminki K, Forsti A (2013) Genetic polymorphisms in host innate immune sensor genes and the risk of nasopharyngeal carcinoma in north Africa. G3 3(6):971–977PubMedGoogle Scholar
  350. Mullins RF, Russell SR, Anderson DH, Hageman GS (2000) Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J 14(7):835–846PubMedGoogle Scholar
  351. Nakahira K, Haspel JA, Rathinam VA, Lee SJ, Dolinay T, Lam HC, Englert JA, Rabinovitch M, Cernadas M, Kim HP, Fitzgerald KA, Ryter SW, Choi AM (2011) Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat Immunol 12(3):222–230PubMedGoogle Scholar
  352. Nebel A, Flachsbart F, Schafer A, Nothnagel M, Nikolaus S, Mokhtari NE, Schreiber S (2007) Role of the toll-like receptor 4 polymorphism Asp299Gly in longevity and myocardial infarction in German men. Mech Ageing Dev 128(5–6):409–411PubMedGoogle Scholar
  353. Netea MG, Wijmenga C, O’Neill LA (2012) Genetic variation in toll-like receptors and disease susceptibility. Nat Immunol 13(6):535–542PubMedGoogle Scholar
  354. Ng LK, Rich AM, Hussaini HM, Thomson WM, Fisher AL, Horne LS, Seymour GJ (2011) Toll-like receptor 2 is present in the microenvironment of oral squamous cell carcinoma. Br J Cancer 104(3):460–463PubMedGoogle Scholar
  355. Nguyen MT, Favelyukis S, Nguyen AK, Reichart D, Scott PA, Jenn A, Liu-Bryan R, Glass CK, Neels JG, Olefsky JM (2007) A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem 282(48):35279–35292PubMedGoogle Scholar
  356. Nguyen M, Leuridan E, Zhang T, De WD, Willems F, Van DP, Goldman M, Goriely S (2010) Acquisition of adult-like TLR4 and TLR9 responses during the first year of life. PLoS One 5(4):e10407PubMedGoogle Scholar
  357. Niemi K, Teirila L, Lappalainen J, Rajamaki K, Baumann MH, Oorni K, Wolff H, Kovanen PT, Matikainen S, Eklund KK (2011) Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. J Immunol 186(11):6119–6128PubMedGoogle Scholar
  358. Nieters A, Beckmann L, Deeg E, Becker N (2006) Gene polymorphisms in toll-like receptors, interleukin-10, and interleukin-10 receptor alpha and lymphoma risk. Genes Immun 7(8):615–624PubMedGoogle Scholar
  359. Nijnik A, Woodbine L, Marchetti C, Dawson S, Lambe T, Liu C, Rodrigues NP, Crockford TL, Cabuy E, Vindigni A, Enver T, Bell JI, Slijepcevic P, Goodnow CC, Jeggo PA, Cornall RJ (2007) DNA repair is limiting for haematopoietic stem cells during ageing. Nature 447(7145):686–690PubMedGoogle Scholar
  360. Nischalke HD, Coenen M, Berger C, Aldenhoff K, Muller T, Berg T, Kramer B, Korner C, Odenthal M, Schulze F, Grunhage F, Nattermann J, Sauerbruch T, Spengler U (2012) The toll-like receptor 2 (TLR2) -196 to −174 del/ins polymorphism affects viral loads and susceptibility to hepatocellular carcinoma in chronic hepatitis C. Int J Cancer 130(6):1470–1475PubMedGoogle Scholar
  361. Nixon RA, Yang DS (2011) Autophagy failure in Alzheimer’s disease–locating the primary defect. Neurobiol Dis 43(1):38–45PubMedGoogle Scholar
  362. Nogueira-Machado JA, Volpe CM, Veloso CA, Chaves MM (2011) HMGB1, TLR and RAGE: a functional tripod that leads to diabetic inflammation. Expert Opin Ther Targets 15(8):1023–1035PubMedGoogle Scholar
  363. Nomi N, Kodama S, Suzuki M (2010) Toll-like receptor 3 signaling induces apoptosis in human head and neck cancer via survivin associated pathway. Oncol Rep 24(1):225–231PubMedGoogle Scholar
  364. Normand S, Delanoye-Crespin A, Bressenot A, Huot L, Grandjean T, Peyrin-Biroulet L, Lemoine Y, Hot D, Chamaillard M (2011) Nod-like receptor pyrin domain-containing protein 6 (NLRP6) controls epithelial self-renewal and colorectal carcinogenesis upon injury. Proc Natl Acad Sci U S A 108(23):9601–9606PubMedGoogle Scholar
  365. Nyugen J, Agrawal S, Gollapudi S, Gupta S (2010) Impaired functions of peripheral blood monocyte subpopulations in aged humans. J Clin Immunol 30(6):806–813PubMedGoogle Scholar
  366. O’Neill LA, Golenbock D, Bowie AG (2013) The history of toll-like receptors - redefining innate immunity. Nat Rev Immunol 13(6):453–460PubMedGoogle Scholar
  367. Obici S, Zhang BB, Karkanias G, Rossetti L (2002) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8(12):1376–1382PubMedGoogle Scholar
  368. Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, Oyabu J, Murakawa T, Nakayama H, Nishida K, Akira S, Yamamoto A, Komuro I, Otsu K (2012) Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure. Nature 485(7397):251–255PubMedGoogle Scholar
  369. Okun E, Griffioen KJ, Lathia JD, Tang SC, Mattson MP, Arumugam TV (2009) Toll-like receptors in neurodegeneration. Brain Res Rev 59(2):278–292PubMedGoogle Scholar
  370. Okun E, Griffioen K, Barak B, Roberts NJ, Castro K, Pita MA, Cheng A, Mughal MR, Wan R, Ashery U, Mattson MP (2010) Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis. Proc Natl Acad Sci U S A 107(35):15625–15630PubMedGoogle Scholar
  371. Okun E, Griffioen KJ, Mattson MP (2011) Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci 34(5):269–281PubMedGoogle Scholar
  372. Oliveira AG, Carvalho BM, Tobar N, Ropelle ER, Pauli JR, Bagarolli RA, Guadagnini D, Carvalheira JB, Saad MJ (2011) Physical exercise reduces circulating lipopolysaccharide and TLR4 activation and improves insulin signaling in tissues of DIO rats. Diabetes 60(3):784–796PubMedGoogle Scholar
  373. Olivieri F, Antonicelli R, Cardelli M, Marchegiani F, Cavallone L, Mocchegiani E, Franceschi C (2006) Genetic polymorphisms of inflammatory cytokines and myocardial infarction in the elderly. Mech Ageing Dev 127(6):552–559PubMedGoogle Scholar
  374. Palin K, Bluthe RM, McCusker RH, Levade T, Moos F, Dantzer R, Kelley KW (2009) The type 1 TNF receptor and its associated adapter protein, FAN, are required for TNFalpha-induced sickness behavior. Psychopharmacology 201(4):549–556PubMedGoogle Scholar
  375. Palm NW, Medzhitov R (2009) Immunostimulatory activity of haptenated proteins. Proc Natl Acad Sci U S A 106(12):4782–4787PubMedGoogle Scholar
  376. Panda A, Arjona A, Sapey E, Bai F, Fikrig E, Montgomery RR, Lord JM, Shaw AC (2009) Human innate immunosenescence: causes and consequences for immunity in old age. Trends Immunol 30(7):325–333PubMedGoogle Scholar
  377. Panda A, Qian F, Mohanty S, Van DD, Newman FK, Zhang L, Chen S, Towle V, Belshe RB, Fikrig E, Allore HG, Montgomery RR, Shaw AC (2010) Age-associated decrease in TLR function in primary human dendritic cells predicts influenza vaccine response. J Immunol 184(5):2518–2527PubMedGoogle Scholar
  378. Pandey S, Mittal RD, Srivastava M, Srivastava K, Singh S, Srivastava S, Mittal B (2009) Impact of toll-like receptors [TLR] 2 (−196 to −174 del) and TLR 4 (Asp299Gly, Thr399Ile) in cervical cancer susceptibility in North Indian women. Gynecol Oncol 114(3):501–505PubMedGoogle Scholar
  379. Park JH, Yoon HE, Kim DJ, Kim SA, Ahn SG, Yoon JH (2011) Toll-like receptor 5 activation promotes migration and invasion of salivary gland adenocarcinoma. J Oral Pathol Med 40(2):187–193PubMedGoogle Scholar
  380. Pasare C, Medzhitov R (2005) Control of B-cell responses by toll-like receptors. Nature 438(7066):364–368PubMedGoogle Scholar
  381. Patel MR, Kratzke RA (2013) Oncolytic virus therapy for cancer: the first wave of translational clinical trials. Transl Res 161(4):355–364PubMedGoogle Scholar
  382. Paul-Clark MJ, McMaster SK, Sorrentino R, Sriskandan S, Bailey LK, Moreno L, Ryffel B, Quesniaux VF, Mitchell JA (2009) Toll-like receptor 2 is essential for the sensing of oxidants during inflammation. Am J Respir Crit Care Med 179(4):299–306PubMedGoogle Scholar
  383. Peng G, Guo Z, Kiniwa Y, Voo KS, Peng W, Fu T, Wang DY, Li Y, Wang HY, Wang RF (2005) Toll-like receptor 8-mediated reversal of CD4+ regulatory T cell function. Science 309(5739):1380–1384PubMedGoogle Scholar
  384. Peters T, Weiss JM, Sindrilaru A, Wang H, Oreshkova T, Wlaschek M, Maity P, Reimann J, Scharffetter-Kochanek K (2009) Reactive oxygen intermediate-induced pathomechanisms contribute to immunosenescence, chronic inflammation and autoimmunity. Mech Ageing Dev 130(9):564–587PubMedGoogle Scholar
  385. Pikarsky E, Ben-Neriah Y (2006) NF-kappaB inhibition: a double-edged sword in cancer? Eur J Cancer 42(6):779–784PubMedGoogle Scholar
  386. Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y (2004) NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431(7007):461–466PubMedGoogle Scholar
  387. Pimentel-Nunes P, Afonso L, Lopes P, Roncon-Albuquerque R Jr, Goncalves N, Henrique R, Moreira-Dias L, Leite-Moreira AF, Dinis-Ribeiro M (2011) Increased expression of toll-like receptors (TLR) 2, 4 and 5 in gastric dysplasia. Pathology Oncol Res 17(3):677–683Google Scholar
  388. Pimentel-Nunes P, Goncalves N, Boal-Carvalho I, Afonso L, Lopes P, Roncon-Albuquerque R Jr, Henrique R, Moreira-Dias L, Leite-Moreira AF, Dinis-Ribeiro M (2013) Helicobacter pylori induces increased expression of toll-like receptors and decreased Toll-interacting protein in gastric mucosa that persists throughout gastric carcinogenesis. Helicobacter 18(1):22–32PubMedGoogle Scholar
  389. Plum L, Belgardt BF, Bruning JC (2006) Central insulin action in energy and glucose homeostasis. J Clin Invest 116(7):1761–1766PubMedGoogle Scholar
  390. Poggi M, Bastelica D, Gual P, Iglesias MA, Gremeaux T, Knauf C, Peiretti F, Verdier M, Juhan-Vague I, Tanti JF, Burcelin R, Alessi MC (2007) C3H/HeJ mice carrying a toll-like receptor 4 mutation are protected against the development of insulin resistance in white adipose tissue in response to a high-fat diet. Diabetologia 50(6):1267–1276PubMedGoogle Scholar
  391. Pontillo A, Catamo E, Arosio B, Mari D, Crovella S (2012) NALP1/NLRP1 genetic variants are associated with Alzheimer disease. Alzheimer Dis Assoc Disord 26(3):277–281PubMedGoogle Scholar
  392. Prakash S, Agrawal S, Cao JN, Gupta S, Agrawal A (2012) Impaired secretion of interferons by dendritic cells from aged subjects to influenza: role of histone modifications. Age (Dordr) Sep 25. [Epub ahead of print]Google Scholar
  393. Purdue MP, Lan Q, Wang SS, Kricker A, Menashe I, Zheng TZ, Hartge P, Grulich AE, Zhang Y, Morton LM, Vajdic CM, Holford TR, Severson RK, Leaderer BP, Cerhan JR, Yeager M, Cozen W, Jacobs K, Davis S, Rothman N, Chanock SJ, Chatterjee N, Armstrong BK (2009) A pooled investigation of toll-like receptor gene variants and risk of non-Hodgkin lymphoma. Carcinogenesis 30(2):275–281PubMedGoogle Scholar
  394. Qian F, Wang X, Zhang L, Lin A, Zhao H, Fikrig E, Montgomery RR (2011) Impaired interferon signaling in dendritic cells from older donors infected in vitro with West Nile virus. J Infect Dis 203(10):1415–1424PubMedGoogle Scholar
  395. Qian F, Wang X, Zhang L, Chen S, Piecychna M, Allore H, Bockenstedt L, Malawista S, Bucala R, Shaw AC, Fikrig E, Montgomery RR (2012) Age-associated elevation in TLR5 leads to increased inflammatory responses in the elderly. Aging Cell 11(1):104–110PubMedGoogle Scholar
  396. Qian F, Bolen CR, Jing C, Wang X, Zheng W, Zhao H, Fikrig E, Bruce RD, Kleinstein SH, Montgomery RR (2013) Impaired toll-like receptor 3-mediated immune responses from macrophages of patients chronically infected with hepatitis C virus. Clin Vaccine Immunol 20(2):146–155PubMedGoogle Scholar
  397. Rajamaki K, Lappalainen J, Oorni K, Valimaki E, Matikainen S, Kovanen PT, Eklund KK (2010) Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One 5(7):e11765PubMedGoogle Scholar
  398. Rajaraman P, Brenner AV, Butler MA, Wang SS, Pfeiffer RM, Ruder AM, Linet MS, Yeager M, Wang Z, Orr N, Fine HA, Kwon D, Thomas G, Rothman N, Inskip PD, Chanock SJ (2009) Common variation in genes related to innate immunity and risk of adult glioma. Cancer Epidemiol Biomarkers Prev 18(5):1651–1658PubMedGoogle Scholar
  399. Rajaraman P, Brenner AV, Neta G, Pfeiffer R, Wang SS, Yeager M, Thomas G, Fine HA, Linet MS, Rothman N, Chanock SJ, Inskip PD (2010) Risk of meningioma and common variation in genes related to innate immunity. Cancer Epidemiol Biomarkers Prev 19(5):1356–1361PubMedGoogle Scholar
  400. Rakoff-Nahoum S, Medzhitov R (2007) Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 317(5834):124–127PubMedGoogle Scholar
  401. Rathinam VA, Fitzgerald KA (2011) Cytosolic surveillance and antiviral immunity. Curr Opin Virol 1(6):455–462PubMedGoogle Scholar
  402. Rathinam VA, Jiang Z, Waggoner SN, Sharma S, Cole LE, Waggoner L, Vanaja SK, Monks BG, Ganesan S, Latz E, Hornung V, Vogel SN, Szomolanyi-Tsuda E, Fitzgerald KA (2010) The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses. Nat Immunol 11(5):395–402PubMedGoogle Scholar
  403. Ray ME, Su YA, Meltzer PS, Trent JM (1996) Isolation and characterization of genes associated with chromosome-6 mediated tumor suppression in human malignant melanoma. Oncogene 12(12):2527–2533PubMedGoogle Scholar
  404. Raynor J, Lages CS, Shehata H, Hildeman DA, Chougnet CA (2012) Homeostasis and function of regulatory T cells in aging. Curr Opin Immunol 24(4):482–487PubMedGoogle Scholar
  405. Reed-Geaghan EG, Savage JC, Hise AG, Landreth GE (2009) CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta}-stimulated microglial activation. J Neurosci 29(38):11982–11992PubMedGoogle Scholar
  406. Reed-Geaghan EG, Reed QW, Cramer PE, Landreth GE (2010) Deletion of CD14 attenuates Alzheimer’s disease pathology by influencing the brain’s inflammatory milieu. J Neurosci 30(46):15369–15373PubMedGoogle Scholar
  407. Ren T, Wen ZK, Liu ZM, Qian C, Liang YJ, Jin ML, Cai YY, Xu L (2008) Targeting toll-like receptor 9 with CpG oligodeoxynucleotides enhances anti-tumor responses of peripheral blood mononuclear cells from human lung cancer patients. Cancer Invest 26(5):448–455PubMedGoogle Scholar
  408. Ren T, Xu L, Jiao S, Wang Y, Cai Y, Liang Y, Zhou Y, Zhou H, Wen Z (2009) TLR9 signaling promotes tumor progression of human lung cancer cell in vivo. Pathol Oncol Res 15(4):623–630PubMedGoogle Scholar
  409. Renshaw M, Rockwell J, Engleman C, Gewirtz A, Katz J, Sambhara S (2002) Cutting edge: impaired toll-like receptor expression and function in aging. J Immunol 169(9):4697–4701PubMedGoogle Scholar
  410. Reyna SM, Ghosh S, Tantiwong P, Meka CS, Eagan P, Jenkinson CP, Cersosimo E, Defronzo RA, Coletta DK, Sriwijitkamol A, Musi N (2008) Elevated toll-like receptor 4 expression and signaling in muscle from insulin-resistant subjects. Diabetes 57(10):2595–2602PubMedGoogle Scholar
  411. Reynolds CM, McGillicuddy FC, Harford KA, Finucane OM, Mills KH, Roche HM (2012) Dietary saturated fatty acids prime the NLRP3 inflammasome via TLR4 in dendritic cells-implications for diet-induced insulin resistance. Mol Nutr Food Res 56(8):1212–1222PubMedGoogle Scholar
  412. Rietschel ET, Brade H, Brade L, Brandenburg K, Schade U, Seydel U, Zahringer U, Galanos C, Luderitz O, Westphal O et al (1987) Lipid A, the endotoxic center of bacterial lipopolysaccharides: relation of chemical structure to biological activity. Prog Clin Biol Res 231:25–53PubMedGoogle Scholar
  413. Rolls A, Shechter R, London A, Ziv Y, Ronen A, Levy R, Schwartz M (2007) Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol 9(9):1081–1088PubMedGoogle Scholar
  414. Roncon-Albuquerque R Jr, Moreira-Rodrigues M, Faria B, Ferreira AP, Cerqueira C, Lourenco AP, Pestana M, von Hafe P, Leite-Moreira AF (2008) Attenuation of the cardiovascular and metabolic complications of obesity in CD14 knockout mice. Life Sci 83(13–14):502–510PubMedGoogle Scholar
  415. Rosenbaum JT (2012) Eyeing macular degeneration–few inflammatory remarks. N Engl J Med 367(8):768–770PubMedGoogle Scholar
  416. Roth GA, Moser B, Roth-Walter F, Giacona MB, Harja E, Papapanou PN, Schmidt AM, Lalla E (2007) Infection with a periodontal pathogen increases mononuclear cell adhesion to human aortic endothelial cells. Atherosclerosis 190(2):271–281PubMedGoogle Scholar
  417. Russell SJ, Peng KW, Bell JC (2012) Oncolytic virotherapy. Nat Biotechnol 30(7):658–670PubMedGoogle Scholar
  418. Saberi M, Woods NB, de Luca C, Schenk S, Lu JC, Bandyopadhyay G, Verma IM, Olefsky JM (2009) Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab 10(5):419–429PubMedGoogle Scholar
  419. Sadeghi K, Berger A, Langgartner M, Prusa AR, Hayde M, Herkner K, Pollak A, Spittler A, Forster-Waldl E (2007) Immaturity of infection control in preterm and term newborns is associated with impaired toll-like receptor signaling. J Infect Dis 195(2):296–302PubMedGoogle Scholar
  420. Saitoh T, Fujita N, Jang MH, Uematsu S, Yang BG, Satoh T, Omori H, Noda T, Yamamoto N, Komatsu M, Tanaka K, Kawai T, Tsujimura T, Takeuchi O, Yoshimori T, Akira S (2008) Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature 456(7219):264–268PubMedGoogle Scholar
  421. Salagianni M, Galani IE, Lundberg AM, Davos CH, Varela A, Gavriil A, Lyytikainen LP, Lehtimaki T, Sigala F, Folkersen L, Gorgoulis V, Lenglet S, Montecucco F, Mach F, Hedin U, Hansson GK, Monaco C, Andreakos E (2012) Toll-like receptor 7 protects from atherosclerosis by constraining “inflammatory” macrophage activation. Circulation 126(8):952–962PubMedGoogle Scholar
  422. Salaun B, Coste I, Rissoan MC, Lebecque SJ, Renno T (2006) TLR3 can directly trigger apoptosis in human cancer cells. J Immunol 176(8):4894–4901PubMedGoogle Scholar
  423. Salminen A, Ojala J, Suuronen T, Kaarniranta K, Kauppinen A (2008) Amyloid-beta oligomers set fire to inflammasomes and induce Alzheimer’s pathology. J Cell Mol Med 12(6A):2255–2262PubMedGoogle Scholar
  424. Salminen A, Kaarniranta K, Kauppinen A (2012) Inflammaging: disturbed interplay between autophagy and inflammasomes. Aging (AlbanyNY) 4(3):166–175Google Scholar
  425. Sandanger O, Ranheim T, Vinge LE, Bliksoen M, Alfsnes K, Finsen AV, Dahl CP, Askevold ET, Florholmen G, Christensen G, Fitzgerald KA, Lien E, Valen G, Espevik T, Aukrust P, Yndestad A (2013) The NLRP3 inflammasome is up-regulated in cardiac fibroblasts and mediates myocardial ischaemia-reperfusion injury. Cardiovasc Res 99(1):164–174PubMedGoogle Scholar
  426. Sandoval D, Cota D, Seeley RJ (2008) The integrative role of CNS fuel-sensing mechanisms in energy balance and glucose regulation. Annu Rev Physiol 70:513–535PubMedGoogle Scholar
  427. Schaefer L, Babelova A, Kiss E, Hausser HJ, Baliova M, Krzyzankova M, Marsche G, Young MF, Mihalik D, Gotte M, Malle E, Schaefer RM, Grone HJ (2005) The matrix component biglycan is proinflammatory and signals through toll-like receptors 4 and 2 in macrophages. J Clin Invest 115(8):2223–2233PubMedGoogle Scholar
  428. Schaeffler A, Gross P, Buettner R, Bollheimer C, Buechler C, Neumeier M, Kopp A, Schoelmerich J, Falk W (2009) Fatty acid-induced induction of toll-like receptor-4/nuclear factor-kappaB pathway in adipocytes links nutritional signalling with innate immunity. Immunology 126(2):233–245PubMedGoogle Scholar
  429. Scheibner KA, Lutz MA, Boodoo S, Fenton MJ, Powell JD, Horton MR (2006) Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J Immunol 177(2):1272–1281PubMedGoogle Scholar
  430. Schindowski K, Frohlich L, Maurer K, Muller WE, Eckert A (2002) Age-related impairment of human T lymphocytes’ activation: specific differences between CD4(+) and CD8(+) subsets. Mech Ageing Dev 123(4):375–390PubMedGoogle Scholar
  431. Schlapbach LJ, Mattmann M, Thiel S, Boillat C, Otth M, Nelle M, Wagner B, Jensenius JC, Aebi C (2010) Differential role of the lectin pathway of complement activation in susceptibility to neonatal sepsis. Clin Infect Dis 51(2):153–162PubMedGoogle Scholar
  432. Schneider-Ohrum K, Giles BM, Weirback HK, Williams BL, DeAlmeida DR, Ross TM (2011) Adjuvants that stimulate TLR3 or NLPR3 pathways enhance the efficiency of influenza virus-like particle vaccines in aged mice. Vaccine 29(48):9081–9092PubMedGoogle Scholar
  433. Scholtes VP, Versteeg D, de Vries JP, Hoefer IE, Schoneveld AH, Stella PR, Doevendans PA, van Keulen KJ, de Kleijn DP, Moll FL, Pasterkamp G (2011) Toll-like receptor 2 and 4 stimulation elicits an enhanced inflammatory response in human obese patients with atherosclerosis. Clin Sci 121(5):205–214PubMedGoogle Scholar
  434. Schon MP, Schon M (2008) TLR7 and TLR8 as targets in cancer therapy. Oncogene 27(2):190–199PubMedGoogle Scholar
  435. Schwartz EA, Zhang WY, Karnik SK, Borwege S, Anand VR, Laine PS, Su Y, Reaven PD (2010) Nutrient modification of the innate immune response: a novel mechanism by which saturated fatty acids greatly amplify monocyte inflammation. Arterioscler Thromb Vasc Biol 30(4):802–808PubMedGoogle Scholar
  436. Sen G, Chen Q, Snapper CM (2006) Immunization of aged mice with a pneumococcal conjugate vaccine combined with an unmethylated CpG-containing oligodeoxynucleotide restores defective immunoglobulin G antipolysaccharide responses and specific CD4 + −T-cell priming to young adult levels. Infect Immun 74(4):2177–2186PubMedGoogle Scholar
  437. Senn JJ (2006) Toll-like receptor-2 is essential for the development of palmitate-induced insulin resistance in myotubes. J Biol Chem 281(37):26865–26875PubMedGoogle Scholar
  438. Seya T, Azuma M, Matsumoto M (2013) Targeting TLR3 with no RIG-I/MDA5 activation is effective in immunotherapy for cancer. Expert Opin Ther Targets 17(5):533–544PubMedGoogle Scholar
  439. Sharma S, Dominguez AL, Hoelzinger DB, Lustgarten J (2008) CpG-ODN but not other TLR-ligands restore the antitumor responses in old mice: the implications for vaccinations in the aged. Cancer Immunol Immunother 57(4):549–561PubMedGoogle Scholar
  440. Sharma MD, Hou DY, Baban B, Koni PA, He Y, Chandler PR, Blazar BR, Mellor AL, Munn DH (2010) Reprogrammed foxp3(+) regulatory T cells provide essential help to support cross-presentation and CD8(+) T cell priming in naive mice. Immunity 33(6):942–954PubMedGoogle Scholar
  441. Shaw AC, Panda A, Joshi SR, Qian F, Allore HG, Montgomery RR (2011) Dysregulation of human toll-like receptor function in aging. Ageing Res Rev 10(3):346–353PubMedGoogle Scholar
  442. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS (2006) TLR4 links innate immunity and fatty acid-induced insulin resistance. J Clin Invest 116(11):3015–3025PubMedGoogle Scholar
  443. Shi CS, Shenderov K, Huang NN, Kabat J, Abu-Asab M, Fitzgerald KA, Sher A, Kehrl JH (2012) Activation of autophagy by inflammatory signals limits IL-1beta production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol 13(3):255–263PubMedGoogle Scholar
  444. Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, Ramanujan VK, Wolf AJ, Vergnes L, Ojcius DM, Rentsendorj A, Vargas M, Guerrero C, Wang Y, Fitzgerald KA, Underhill DM, Town T, Arditi M (2012) Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity 36(3):401–414PubMedGoogle Scholar
  445. Shojaei H, Oberg HH, Juricke M, Marischen L, Kunz M, Mundhenke C, Gieseler F, Kabelitz D, Wesch D (2009) Toll-like receptors 3 and 7 agonists enhance tumor cell lysis by human gammadelta T cells. Cancer Res 69(22):8710–8717PubMedGoogle Scholar
  446. Siegemund S, Sauer K (2012) Balancing pro- and anti-inflammatory TLR4 signaling. Nat Immunol 13(11):1031–1033PubMedGoogle Scholar
  447. Siegmund B, Lehr HA, Fantuzzi G, Dinarello CA (2001) IL-1 beta -converting enzyme (caspase-1) in intestinal inflammation. Proc Natl Acad Sci U S A 98(23):13249–13254PubMedGoogle Scholar
  448. Simons MP, O’Donnell MA, Griffith TS (2008) Role of neutrophils in BCG immunotherapy for bladder cancer. Urol Oncol 26(4):341–345PubMedGoogle Scholar
  449. Skountzou I, Martin Mdel P, Wang B, Ye L, Koutsonanos D, Weldon W, Jacob J, Compans RW (2010) Salmonella flagellins are potent adjuvants for intranasally administered whole inactivated influenza vaccine. Vaccine 28(24):4103–4112PubMedGoogle Scholar
  450. Sloane JA, Batt C, Ma Y, Harris ZM, Trapp B, Vartanian T (2010) Hyaluronan blocks oligodendrocyte progenitor maturation and remyelination through TLR2. Proc Natl Acad Sci U S A 107(25):11555–11560PubMedGoogle Scholar
  451. Sluyter R, Dalitz JG, Wiley JS (2004a) P2X7 receptor polymorphism impairs extracellular adenosine 5’-triphosphate-induced interleukin-18 release from human monocytes. Genes Immun 5(7):588–591PubMedGoogle Scholar
  452. Sluyter R, Shemon AN, Wiley JS (2004b) Glu496 to Ala polymorphism in the P2X7 receptor impairs ATP-induced IL-1 beta release from human monocytes. J Immunol 172(6):3399–3405PubMedGoogle Scholar
  453. Soares JB, Pimentel-Nunes P, Afonso L, Rolanda C, Lopes P, Roncon-Albuquerque R Jr, Goncalves N, Boal-Carvalho I, Pardal F, Lopes S, Macedo G, Lara-Santos L, Henrique R, Moreira-Dias L, Goncalves R, Dinis-Ribeiro M, Leite-Moreira AF (2012) Increased hepatic expression of TLR2 and TLR4 in the hepatic inflammation-fibrosis-carcinoma sequence. Innate Immun 18(5):700–708PubMedGoogle Scholar
  454. Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T (2012) Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol 24(5):331–341PubMedGoogle Scholar
  455. Song X, Krelin Y, Dvorkin T, Bjorkdahl O, Segal S, Dinarello CA, Voronov E, Apte RN (2005) CD11b+/Gr-1+ immature myeloid cells mediate suppression of T cells in mice bearing tumors of IL-1beta-secreting cells. J Immunol 175(12):8200–8208PubMedGoogle Scholar
  456. Song MJ, Kim KH, Yoon JM, Kim JB (2006) Activation of toll-like receptor 4 is associated with insulin resistance in adipocytes. Biochem Biophys Res Commun 346(3):739–745PubMedGoogle Scholar
  457. Song LL, Alimirah F, Panchanathan R, Xin H, Choubey D (2008) Expression of an IFN-inducible cellular senescence gene, IFI16, is up-regulated by p53. Mol Cancer Res 6(11):1732–1741PubMedGoogle Scholar
  458. Song LL, Ponomareva L, Shen H, Duan X, Alimirah F, Choubey D (2010) Interferon-inducible IFI16, a negative regulator of cell growth, down-regulates expression of human telomerase reverse transcriptase (hTERT) gene. PLoS One 5(1):e8569PubMedGoogle Scholar
  459. Song M, Jin J, Lim JE, Kou J, Pattanayak A, Rehman JA, Kim HD, Tahara K, Lalonde R, Fukuchi K (2011) TLR4 mutation reduces microglial activation, increases Abeta deposits and exacerbates cognitive deficits in a mouse model of Alzheimer’s disease. J Neuroinflammation 8:92PubMedGoogle Scholar
  460. Sotomayor EM, Borrello I, Tubb E, Allison JP, Levitsky HI (1999) In vivo blockade of CTLA-4 enhances the priming of responsive T cells but fails to prevent the induction of tumor antigen-specific tolerance. Proc Natl Acad Sci U S A 96(20):11476–11481PubMedGoogle Scholar
  461. Spaner DE, Shi Y, White D, Shaha S, He L, Masellis A, Wong K, Gorczynski R (2010) A phase I/II trial of TLR-7 agonist immunotherapy in chronic lymphocytic leukemia. Leukemia 24(1):222–226PubMedGoogle Scholar
  462. Spirig R, Tsui J, Shaw S (2012) The emerging role of TLR and innate immunity in cardiovascular disease. Cardiol Res Prac 2012:181394Google Scholar
  463. Sridharan A, Esposo M, Kaushal K, Tay J, Osann K, Agrawal S, Gupta S, Agrawal A (2011) Age-associated impaired plasmacytoid dendritic cell functions lead to decreased CD4 and CD8 T cell immunity. Age 33(3):363–376PubMedGoogle Scholar
  464. Srivastava K, Srivastava A, Kumar A, Mittal B (2010) Significant association between toll-like receptor gene polymorphisms and gallbladder cancer. Liver Int 30(7):1067–1072PubMedGoogle Scholar
  465. Stagg J, Smyth MJ (2010) Extracellular adenosine triphosphate and adenosine in cancer. Oncogene 29(39):5346–5358PubMedGoogle Scholar
  466. Stewart WF, Kawas C, Corrada M, Metter EJ (1997) Risk of Alzheimer’s disease and duration of NSAID use. Neurology 48(3):626–632PubMedGoogle Scholar
  467. Stienstra R, Joosten LA, Koenen T, van Tits B, van Diepen JA, van den Berg SA, Rensen PC, Voshol PJ, Fantuzzi G, Hijmans A, Kersten S, Muller M, van den Berg WB, van Rooijen N, Wabitsch M, Kullberg BJ, van der Meer JW, Kanneganti T, Tack CJ, Netea MG (2010) The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity. Cell Metab 12(6):593–605PubMedGoogle Scholar
  468. Stienstra R, van Diepen JA, Tack CJ, Zaki MH, van de Veerdonk FL, Perera D, Neale GA, Hooiveld GJ, Hijmans A, Vroegrijk I, van den Berg S, Romijn J, Rensen PC, Joosten LA, Netea MG, Kanneganti TD (2011) Inflammasome is a central player in the induction of obesity and insulin resistance. Proc Natl Acad Sci U S A 108(37):15324–15329PubMedGoogle Scholar
  469. Stout-Delgado HW, Yang X, Walker WE, Tesar BM, Goldstein DR (2008) Aging impairs IFN regulatory factor 7 up-regulation in plasmacytoid dendritic cells during TLR9 activation. J Immunol 181(10):6747–6756PubMedGoogle Scholar
  470. Stout-Delgado HW, Du W, Shirali AC, Booth CJ, Goldstein DR (2009) Aging promotes neutrophil-induced mortality by augmenting IL-17 production during viral infection. Cell Host Microbe 6(5):446–456PubMedGoogle Scholar
  471. Stout-Delgado HW, Vaughan SE, Shirali AC, Jaramillo RJ, Harrod KS (2012) Impaired NLRP3 inflammasome function in elderly mice during influenza infection is rescued by treatment with nigericin. J Immunol 188(6):2815–2824PubMedGoogle Scholar
  472. Sun Z, Luo Q, Ye D, Chen W, Chen F (2012) Role of toll-like receptor 4 on the immune escape of human oral squamous cell carcinoma and resistance of cisplatin-induced apoptosis. Mol Cancer 11:33PubMedGoogle Scholar
  473. Sutton CE, Lalor SJ, Sweeney CM, Brereton CF, Lavelle EC, Mills KH (2009) Interleukin-1 and IL-23 induce innate IL-17 production from gammadelta T cells, amplifying Th17 responses and autoimmunity. Immunity 31(2):331–341PubMedGoogle Scholar
  474. Szajnik M, Szczepanski MJ, Czystowska M, Elishaev E, Mandapathil M, Nowak-Markwitz E, Spaczynski M, Whiteside TL (2009) TLR4 signaling induced by lipopolysaccharide or paclitaxel regulates tumor survival and chemoresistance in ovarian cancer. Oncogene 28(49):4353–4363PubMedGoogle Scholar
  475. Szczepanski M, Stelmachowska M, Stryczynski L, Golusinski W, Samara H, Mozer-Lisewska I, Zeromski J (2007) Assessment of expression of toll-like receptors 2, 3 and 4 in laryngeal carcinoma. Eur Arch Otorhinolaryngol 264(5):525–530PubMedGoogle Scholar
  476. Szczepanski MJ, Czystowska M, Szajnik M, Harasymczuk M, Boyiadzis M, Kruk-Zagajewska A, Szyfter W, Zeromski J, Whiteside TL (2009) Triggering of toll-like receptor 4 expressed on human head and neck squamous cell carcinoma promotes tumor development and protects the tumor from immune attack. Cancer Res 69(7):3105–3113PubMedGoogle Scholar
  477. Tahara K, Kim HD, Jin JJ, Maxwell JA, Li L, Fukuchi K (2006) Role of toll-like receptor signalling in Abeta uptake and clearance. Brain 129(Pt 11):3006–3019PubMedGoogle Scholar
  478. Tahara T, Arisawa T, Wang F, Shibata T, Nakamura M, Sakata M, Hirata I, Nakano H (2007) Toll-like receptor 2–196 to 174del polymorphism influences the susceptibility of Japanese people to gastric cancer. Cancer Sci 98(11):1790–1794PubMedGoogle Scholar
  479. Tal MC, Sasai M, Lee HK, Yordy B, Shadel GS, Iwasaki A (2009) Absence of autophagy results in reactive oxygen species-dependent amplification of RLR signaling. Proc Natl Acad Sci USA 106(8):2770–2775PubMedGoogle Scholar
  480. Tan L, Schedl P, Song HJ, Garza D, Konsolaki M (2008) The Toll–>NFkappaB signaling pathway mediates the neuropathological effects of the human Alzheimer’s Abeta42 polypeptide in Drosophila. PLoS One 3(12):e3966PubMedGoogle Scholar
  481. Tanaka S, Ide M, Shibutani T, Ohtaki H, Numazawa S, Shioda S, Yoshida T (2006) Lipopolysaccharide-induced microglial activation induces learning and memory deficits without neuronal cell death in rats. J Neurosci Res 83(4):557–566PubMedGoogle Scholar
  482. Tanaka T, Oh-Hashi K, Shitara H, Hirata Y, Kiuchi K (2008) NF-kappaB independent signaling pathway is responsible for LPS-induced GDNF gene expression in primary rat glial cultures. Neurosci Lett 431(3):262–267PubMedGoogle Scholar
  483. Tanaka J, Sugimoto K, Shiraki K, Tameda M, Kusagawa S, Nojiri K, Beppu T, Yoneda K, Yamamoto N, Uchida K, Kojima T, Takei Y (2010) Functional cell surface expression of toll-like receptor 9 promotes cell proliferation and survival in human hepatocellular carcinomas. Int J Oncol 37(4):805–814PubMedGoogle Scholar
  484. Tang SC, Arumugam TV, Xu X, Cheng A, Mughal MR, Jo DG, Lathia JD, Siler DA, Chigurupati S, Ouyang X, Magnus T, Camandola S, Mattson MP (2007) Pivotal role for neuronal toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci U S A 104(34):13798–13803PubMedGoogle Scholar
  485. Tang SC, Lathia JD, Selvaraj PK, Jo DG, Mughal MR, Cheng A, Siler DA, Markesbery WR, Arumugam TV, Mattson MP (2008) Toll-like receptor-4 mediates neuronal apoptosis induced by amyloid beta-peptide and the membrane lipid peroxidation product 4-hydroxynonenal. Exp Neurol 213(1):114–121PubMedGoogle Scholar
  486. Tarallo V, Hirano Y, Gelfand BD, Dridi S, Kerur N, Kim Y, Cho WG, Kaneko H, Fowler BJ, Bogdanovich S, Albuquerque RJ, Hauswirth WW, Chiodo VA, Kugel JF, Goodrich JA, Ponicsan SL, Chaudhuri G, Murphy MP, Dunaief JL, Ambati BK, Ogura Y, Yoo JW, Lee DK, Provost P, Hinton DR, Nunez G, Baffi JZ, Kleinman ME, Ambati J (2012) DICER1 loss and Alu RNA induce age-related macular degeneration via the NLRP3 inflammasome and MyD88. Cell 149(4):847–859PubMedGoogle Scholar
  487. Tauber SC, Ebert S, Weishaupt JH, Reich A, Nau R, Gerber J (2009) Stimulation of toll-like receptor 9 by chronic intraventricular unmethylated cytosine-guanine DNA infusion causes neuroinflammation and impaired spatial memory. J Neuropathol Exp Neurol 68(10):1116–1124PubMedGoogle Scholar
  488. Tesar BM, Walker WE, Unternaehrer J, Joshi NS, Chandele A, Haynes L, Kaech S, Goldstein DR (2006) Murine [corrected] myeloid dendritic cell-dependent toll-like receptor immunity is preserved with aging. Aging Cell 5(6):473–486PubMedGoogle Scholar
  489. Ting JP, Lovering RC, Alnemri ES, Bertin J, Boss JM, Davis BK, Flavell RA, Girardin SE, Godzik A, Harton JA, Hoffman HM, Hugot JP, Inohara N, Mackenzie A, Maltais LJ, Nunez G, Ogura Y, Otten LA, Philpott D, Reed JC, Reith W, Schreiber S, Steimle V, Ward PA (2008) The NLR gene family: a standard nomenclature. Immunity 28(3):285–287PubMedGoogle Scholar
  490. Tomita T, Kanai T, Fujii T, Nemoto Y, Okamoto R, Tsuchiya K, Totsuka T, Sakamoto N, Akira S, Watanabe M (2008) MyD88-dependent pathway in T cells directly modulates the expansion of colitogenic CD4+ T cells in chronic colitis. J Immunol 180(8):5291–5299PubMedGoogle Scholar
  491. Touil T, Fitzgerald D, Zhang GX, Rostami A, Gran B (2006) Cutting Edge: TLR3 stimulation suppresses experimental autoimmune encephalomyelitis by inducing endogenous IFN-beta. J Immunol 177(11):7505–7509PubMedGoogle Scholar
  492. Tripathy D, Mohanty P, Dhindsa S, Syed T, Ghanim H, Aljada A, Dandona P (2003) Elevation of free fatty acids induces inflammation and impairs vascular reactivity in healthy subjects. Diabetes 52(12):2882–2887PubMedGoogle Scholar
  493. Tseng WA, Thein T, Kinnunen K, Lashkari K, Gregory MS, D’Amore PA, Ksander BR (2013) NLRP3 inflammasome activation in retinal pigment epithelial cells by lysosomal destabilization: implications for age-related macular degeneration. Invest Ophthalmol Vis Sci 54(1):110–120PubMedGoogle Scholar
  494. Tsukumo DM, Carvalho-Filho MA, Carvalheira JB, Prada PO, Hirabara SM, Schenka AA, Araujo EP, Vassallo J, Curi R, Velloso LA, Saad MJ (2007) Loss-of-function mutation in toll-like receptor 4 prevents diet-induced obesity and insulin resistance. Diabetes 56(8):1986–1998PubMedGoogle Scholar
  495. Tu S, Bhagat G, Cui G, Takaishi S, Kurt-Jones EA, Rickman B, Betz KS, Penz-Oesterreicher M, Bjorkdahl O, Fox JG, Wang TC (2008) Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 14(5):408–419PubMedGoogle Scholar
  496. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI (2006) An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444(7122):1027–1031PubMedGoogle Scholar
  497. Tzima S, Victoratos P, Kranidioti K, Alexiou M, Kollias G (2009) Myeloid heme oxygenase-1 regulates innate immunity and autoimmunity by modulating IFN-beta production. J Exp Med 206(5):1167–1179PubMedGoogle Scholar
  498. Unterholzner L, Keating SE, Baran M, Horan KA, Jensen SB, Sharma S, Sirois CM, Jin T, Latz E, Xiao TS, Fitzgerald KA, Paludan SR, Bowie AG (2010) IFI16 is an innate immune sensor for intracellular DNA. Nat Immunol 11(11):997–1004PubMedGoogle Scholar
  499. Upham JW, Lee PT, Holt BJ, Heaton T, Prescott SL, Sharp MJ, Sly PD, Holt PG (2002) Development of interleukin-12-producing capacity throughout childhood. Infect Immun 70(12):6583–6588PubMedGoogle Scholar
  500. Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS (1997) Protection from obesity-induced insulin resistance in mice lacking TNF-alpha function. Nature 389(6651):610–614PubMedGoogle Scholar
  501. Vaknin I, Blinder L, Wang L, Gazit R, Shapira E, Genina O, Pines M, Pikarsky E, Baniyash M (2008) A common pathway mediated through toll-like receptors leads to T- and natural killer-cell immunosuppression. Blood 111(3):1437–1447PubMedGoogle Scholar
  502. Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO (2007) Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol 9(6):654–659PubMedGoogle Scholar
  503. van Deventer HW, Burgents JE, Wu QP, Woodford RM, Brickey WJ, Allen IC, McElvania-TeKippe E, Serody JS, Ting JP (2010) The inflammasome component NLRP3 impairs antitumor vaccine by enhancing the accumulation of tumor-associated myeloid-derived suppressor cells. Cancer Res 70(24):10161–10169PubMedGoogle Scholar
  504. van Diepen JA, Stienstra R, Vroegrijk IO, van den Berg SA, Salvatori D, Hooiveld GJ, Kersten S, Tack CJ, Netea MG, Smit JW, Joosten LA, Havekes LM, van Dijk KW, Rensen PC (2013) Caspase-1 deficiency in mice reduces intestinal triglyceride absorption and hepatic triglyceride secretion. J Lipid Res 54(2):448–456PubMedGoogle Scholar
  505. Van DD, Shaw AC (2007) Toll-like receptors in older adults. J Am Geriatr Soc 55(9):1438–1444Google Scholar
  506. Van DD, Allore HG, Mohanty S, Ginter S, Newman FK, Belshe RB, Medzhitov R, Shaw AC (2007a) Prevaccine determination of the expression of costimulatory B7 molecules in activated monocytes predicts influenza vaccine responses in young and older adults. JInfect Dis 195(11):1590–1597Google Scholar
  507. Van DD, Mohanty S, Thomas V, Ginter S, Montgomery RR, Fikrig E, Allore HG, Medzhitov R, Shaw AC (2007b) Age-associated defect in human TLR-1/2 function. J Immunol 178(2):970–975Google Scholar
  508. Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD (2011) The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17(2):179–188PubMedGoogle Scholar
  509. Veeranki S, Duan X, Panchanathan R, Liu H, Choubey D (2011) IFI16 protein mediates the anti-inflammatory actions of the type-I interferons through suppression of activation of caspase-1 by inflammasomes. PLoS One 6(10):e27040PubMedGoogle Scholar
  510. Vincent IE, Zannetti C, Lucifora J, Norder H, Protzer U, Hainaut P, Zoulim F, Tommasino M, Trepo C, Hasan U, Chemin I (2011) Hepatitis B virus impairs TLR9 expression and function in plasmacytoid dendritic cells. PLoS One 6(10):e26315PubMedGoogle Scholar
  511. Vollmar P, Kullmann JS, Thilo B, Claussen MC, Rothhammer V, Jacobi H, Sellner J, Nessler S, Korn T, Hemmer B (2010) Active immunization with amyloid-beta 1–42 impairs memory performance through TLR2/4-dependent activation of the innate immune system. J Immunol 185(10):6338–6347PubMedGoogle Scholar
  512. Voronov E, Shouval DS, Krelin Y, Cagnano E, Benharroch D, Iwakura Y, Dinarello CA, Apte RN (2003) IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci U S A 100(5):2645–2650PubMedGoogle Scholar
  513. Walker VP, Zhang X, Rastegar I, Liu PT, Hollis BW, Adams JS, Modlin RL (2011) Cord blood vitamin D status impacts innate immune responses. J Clin Endocrinol Metab 96(6):1835–1843PubMedGoogle Scholar
  514. Walter S, Letiembre M, Liu Y, Heine H, Penke B, Hao W, Bode B, Manietta N, Walter J, Schulz-Schuffer W, Fassbender K (2007) Role of the toll-like receptor 4 in neuroinflammation in Alzheimer’s disease. Cell Physiol Biochem 20(6):947–956PubMedGoogle Scholar
  515. Wang JH, Manning BJ, Wu QD, Blankson S, Bouchier-Hayes D, Redmond HP (2003) Endotoxin/lipopolysaccharide activates NF-kappa B and enhances tumor cell adhesion and invasion through a beta 1 integrin-dependent mechanism. J Immunol 170(2):795–804PubMedGoogle Scholar
  516. Wang H, Rayburn ER, Wang W, Kandimalla ER, Agrawal S, Zhang R (2006a) Chemotherapy and chemosensitization of non-small cell lung cancer with a novel immunomodulatory oligonucleotide targeting toll-like receptor 9. Mol Cancer Ther 5(6):1585–1592PubMedGoogle Scholar
  517. Wang H, Rayburn ER, Wang W, Kandimalla ER, Agrawal S, Zhang R (2006b) Immunomodulatory oligonucleotides as novel therapy for breast cancer: pharmacokinetics, in vitro and in vivo anticancer activity, and potentiation of antibody therapy. Mol Cancer Ther 5(8):2106–2114PubMedGoogle Scholar
  518. Wang Y, Zhang HX, Sun YP, Liu ZX, Liu XS, Wang L, Lu SY, Kong H, Liu QL, Li XH, Lu ZY, Chen SJ, Chen Z, Bao SS, Dai W, Wang ZG (2007) Rig-I−/− mice develop colitis associated with downregulation of G alpha i2. Cell Res 17(10):858–868PubMedGoogle Scholar
  519. Wang N, Liang Y, Devaraj S, Wang J, Lemon SM, Li K (2009a) Toll-like receptor 3 mediates establishment of an antiviral state against hepatitis C virus in hepatoma cells. J Virol 83(19):9824–9834PubMedGoogle Scholar
  520. Wang SS, Bratti MC, Rodriguez AC, Herrero R, Burk RD, Porras C, Gonzalez P, Sherman ME, Wacholder S, Lan ZE, Schiffman M, Chanock SJ, Hildesheim A (2009b) Common variants in immune and DNA repair genes and risk for human papillomavirus persistence and progression to cervical cancer. J Infect Dis 199(1):20–30PubMedGoogle Scholar
  521. Wang SS, Purdue MP, Cerhan JR, Zheng T, Menashe I, Armstrong BK, Lan Q, Hartge P, Kricker A, Zhang Y, Morton LM, Vajdic CM, Holford TR, Severson RK, Grulich A, Leaderer BP, Davis S, Cozen W, Yeager M, Chanock SJ, Chatterjee N, Rothman N (2009c) Common gene variants in the tumor necrosis factor (TNF) and TNF receptor superfamilies and NF-kB transcription factors and non-Hodgkin lymphoma risk. PLoS One 4(4):e5360PubMedGoogle Scholar
  522. Wang LZ, Yu JT, Miao D, Wu ZC, Zong Y, Wen CQ, Tan L (2011) Genetic association of TLR4/11367 polymorphism with late-onset alzheimer’s disease in a Han Chinese population. Brain Res 1381:202–207PubMedGoogle Scholar
  523. Wang C, Fei G, Liu Z, Li Q, Xu Z, Ren T (2012) HMGB1 was a pivotal synergistic effecor for CpG oligonucleotide to enhance the progression of human lung cancer cells. Cancer Biol Ther 13(9):727–736PubMedGoogle Scholar
  524. Wang Y, Li J, Wang X, Ye L, Zhou Y, Thomas RM, Ho W (2013a) Hepatitis C virus impairs TLR3 signaling and inhibits IFN-lambda 1 expression in human hepatoma cell line. Innate Immun. Mar 25. [Epub ahead of print]Google Scholar
  525. Wang Z, Lin H, Hua F, Hu ZW (2013b) Repairing DNA damage by XRCC6/KU70 reverses TLR4-deficiency-worsened HCC development via restoring senescence and autophagic flux. Autophagy 9(6):925–927PubMedGoogle Scholar
  526. Wang Z, Yan J, Lin H, Hua F, Wang X, Liu H, Lv X, Yu J, Mi S, Wang J, Hu ZW (2013c) Toll-like receptor 4 activity protects against hepatocellular tumorigenesis and progression by regulating expression of DNA repair protein Ku70 in mice. Hepatology 57(5):1869–1881PubMedGoogle Scholar
  527. Watson MB, Costello DA, Carney DG, McQuillan K, Lynch MA (2010) SIGIRR modulates the inflammatory response in the brain. Brain Behav Immun 24(6):985–995PubMedGoogle Scholar
  528. Weiner HL, Frenkel D (2006) Immunology and immunotherapy of Alzheimer’s disease. Nat Rev Immunol 6(5):404–416PubMedGoogle Scholar
  529. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr (2003) Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 112(12):1796–1808PubMedGoogle Scholar
  530. Weismann D, Binder CJ (2012) The innate immune response to products of phospholipid peroxidation. Biochim Biophys Acta 1818(10):2465–2475PubMedGoogle Scholar
  531. Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP (2011) Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 12(5):408–415PubMedGoogle Scholar
  532. Wen H, Ting JP, O’Neill LA (2012) A role for the NLRP3 inflammasome in metabolic diseases–did Warburg miss inflammation? Nat Immunol 13(4):352–357PubMedGoogle Scholar
  533. West XZ, Malinin NL, Merkulova AA, Tischenko M, Kerr BA, Borden EC, Podrez EA, Salomon RG, Byzova TV (2010) Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature 467(7318):972–976PubMedGoogle Scholar
  534. West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, Walsh MC, Choi Y, Shadel GS, Ghosh S (2011) TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 472(7344):476–480PubMedGoogle Scholar
  535. Willingham SB, Ting JP (2008) NLRs and the dangers of pollution and aging. Nat Immunol 9(8):831–833PubMedGoogle Scholar
  536. Winter RN, Kramer A, Borkowski A, Kyprianou N (2001) Loss of caspase-1 and caspase-3 protein expression in human prostate cancer. Cancer Res 61(3):1227–1232PubMedGoogle Scholar
  537. Woerner SM, Kloor M, Schwitalle Y, Youmans H, Doeberitz M, Gebert J, Dihlmann S (2007) The putative tumor suppressor AIM2 is frequently affected by different genetic alterations in microsatellite unstable colon cancers. Genes Chromosomes Cancer 46(12):1080–1089PubMedGoogle Scholar
  538. Wolchok JD, Hodi FS, Weber JS, Allison JP, Urba WJ, Robert C, O’Day SJ, Hoos A, Humphrey R, Berman DM, Lonberg N, Korman AJ (2013) Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma. Ann N Y Acad Sci 1291(1):1–13PubMedGoogle Scholar
  539. Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC (1990) CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249(4975):1431–1433PubMedGoogle Scholar
  540. Xie W, Wang Y, Huang Y, Yang H, Wang J, Hu Z (2009) Toll-like receptor 2 mediates invasion via activating NF-kappaB in MDA-MB-231 breast cancer cells. Biochem Biophys Res Commun 379(4):1027–1032PubMedGoogle Scholar
  541. Xie W, Huang Y, Xie W, Guo A, Wu W (2010) Bacteria peptidoglycan promoted breast cancer cell invasiveness and adhesiveness by targeting toll-like receptor 2 in the cancer cells. PLoS One 5(5):e10850PubMedGoogle Scholar
  542. Xin H, Curry J, Johnstone RW, Nickoloff BJ, Choubey D (2003) Role of IFI 16, a member of the interferon-inducible p200-protein family, in prostate epithelial cellular senescence. Oncogene 22(31):4831–4840PubMedGoogle Scholar
  543. Xin H, Pereira-Smith OM, Choubey D (2004) Role of IFI 16 in cellular senescence of human fibroblasts. Oncogene 23(37):6209–6217PubMedGoogle Scholar
  544. Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J Clin Invest 112(12):1821–1830PubMedGoogle Scholar
  545. Xu Y, Zhao Y, Huang H, Chen G, Wu X, Wang Y, Chang W, Zhu Z, Feng Y, Wu D (2010) Expression and function of toll-like receptors in multiple myeloma patients: toll-like receptor ligands promote multiple myeloma cell growth and survival via activation of nuclear factor-kappaB. Br J Haematol 150(5):543–553PubMedGoogle Scholar
  546. Xu H, Wu Q, Dang S, Jin M, Xu J, Cheng Y, Pan M, Wu Y, Zhang C, Zhang Y (2011) Alteration of CXCR7 expression mediated by TLR4 promotes tumor cell proliferation and migration in human colorectal carcinoma. PLoS One 6(12):e27399PubMedGoogle Scholar
  547. Xu N, Yao HP, Lv GC, Chen Z (2012) Downregulation of TLR7/9 leads to deficient production of IFN-alpha from plasmacytoid dendritic cells in chronic hepatitis B. Inflamm Res 61(9):997–1004PubMedGoogle Scholar
  548. Xu L, Wen Z, Zhou Y, Liu Z, Li Q, Fei G, Luo J, Ren T (2013) MicroRNA-7-regulated TLR9 signaling-enhanced growth and metastatic potential of human lung cancer cells by altering the phosphoinositide-3-kinase, regulatory subunit 3/Akt pathway. Mol Biol Cell 24(1):42–55PubMedGoogle Scholar
  549. Yamada Y, Ishibashi K, Ishibashi K, Bhutto IA, Tian J, Lutty GA, Handa JT (2006) The expression of advanced glycation endproduct receptors in rpe cells associated with basal deposits in human maculas. Exp Eye Res 82(5):840–848PubMedGoogle Scholar
  550. Yanagisawa S, Koarai A, Sugiura H, Ichikawa T, Kanda M, Tanaka R, Akamatsu K, Hirano T, Matsunaga K, Minakata Y, Ichinose M (2009) Oxidative stress augments toll-like receptor 8 mediated neutrophilic responses in healthy subjects. Respir Res 10:50PubMedGoogle Scholar
  551. Yang H, Zhou H, Feng P, Zhou X, Wen H, Xie X, Shen H, Zhu X (2010) Reduced expression of toll-like receptor 4 inhibits human breast cancer cells proliferation and inflammatory cytokines secretion. J Exp Clin Cancer Res 29:92PubMedGoogle Scholar
  552. Yao D, Brownlee M (2010) Hyperglycemia-induced reactive oxygen species increase expression of the receptor for advanced glycation end products (RAGE) and RAGE ligands. Diabetes 59(1):249–255PubMedGoogle Scholar
  553. Ye SM, Johnson RW (2001) An age-related decline in interleukin-10 may contribute to the increased expression of interleukin-6 in brain of aged mice. Neuroimmunomodulation 9(4):183–192PubMedGoogle Scholar
  554. Yerkovich ST, Wikstrom ME, Suriyaarachchi D, Prescott SL, Upham JW, Holt PG (2007) Postnatal development of monocyte cytokine responses to bacterial lipopolysaccharide. PediatrRes 62(5):547–552Google Scholar
  555. Yin Y, Yan Y, Jiang X, Mai J, Chen NC, Wang H, Yang XF (2009) Inflammasomes are differentially expressed in cardiovascular and other tissues. Int J Immunopathol Pharmacol 22(2):311–322PubMedGoogle Scholar
  556. Youm YH, Adijiang A, Vandanmagsar B, Burk D, Ravussin A, Dixit VD (2011) Elimination of the NLRP3-ASC inflammasome protects against chronic obesity-induced pancreatic damage. Endocrinology 152(11):4039–4045PubMedGoogle Scholar
  557. Youm YH, Kanneganti TD, Vandanmagsar B, Zhu X, Ravussin A, Adijiang A, Owen JS, Thomas MJ, Francis J, Parks JS, Dixit VD (2012) The Nlrp3 inflammasome promotes age-related thymic demise and immunosenescence. Cell reports 1(1):56–68PubMedGoogle Scholar
  558. Zaki MH, Boyd KL, Vogel P, Kastan MB, Lamkanfi M, Kanneganti TD (2010a) The NLRP3 inflammasome protects against loss of epithelial integrity and mortality during experimental colitis. Immunity 32(3):379–391PubMedGoogle Scholar
  559. Zaki MH, Vogel P, Body-Malapel M, Lamkanfi M, Kanneganti TD (2010b) IL-18 production downstream of the Nlrp3 inflammasome confers protection against colorectal tumor formation. J Immunol 185(8):4912–4920PubMedGoogle Scholar
  560. Zaki MH, Vogel P, Malireddi RK, Body-Malapel M, Anand PK, Bertin J, Green DR, Lamkanfi M, Kanneganti TD (2011) The NOD-like receptor NLRP12 attenuates colon inflammation and tumorigenesis. Cancer Cell 20(5):649–660PubMedGoogle Scholar
  561. Zanoni I, Ostuni R, Marek LR, Barresi S, Barbalat R, Barton GM, Granucci F, Kagan JC (2011) CD14 controls the LPS-induced endocytosis of toll-like receptor 4. Cell 147(4):868–880PubMedGoogle Scholar
  562. Zee RY, Lindpaintner K, Struk B, Hennekens CH, Ridker PM (2001) A prospective evaluation of the CD14 C(−260)T gene polymorphism and the risk of myocardial infarction. Atherosclerosis 154(3):699–702PubMedGoogle Scholar
  563. Zee RY, Hegener HH, Gould J, Ridker PM (2005) Toll-like receptor 4 Asp299Gly gene polymorphism and risk of atherothrombosis. Stroke 36(1):154–157PubMedGoogle Scholar
  564. Zhang Z, Schluesener HJ (2006) Mammalian toll-like receptors: from endogenous ligands to tissue regeneration. Cell Mol Life Sci 63(24):2901–2907PubMedGoogle Scholar
  565. Zhang CF, Cao BW, Lu ZM, Xing HP, Cui JG, Ning T, Ke Y (2004) Relationship between polymorphism of IRF-3 gene codon 427 and esophageal cancer in Anyang population of China. Beijing Da Xue Xue Bao 36(4):345–347PubMedGoogle Scholar
  566. Zhang Y, Luo F, Cai Y, Liu N, Wang L, Xu D, Chu Y (2011) TLR1/TLR2 agonist induces tumor regression by reciprocal modulation of effector and regulatory T cells. J Immunol 186(4):1963–1969PubMedGoogle Scholar
  567. Zhang K, Zhou B, Wang Y, Rao L, Zhang L (2013) The TLR4 gene polymorphisms and susceptibility to cancer: a systematic review and meta-analysis. Eur J Cancer 49(4):946–954PubMedGoogle Scholar
  568. Zhao P, Wang J, He L, Ma H, Zhang X, Zhu X, Dolence EK, Ren J, Li J (2009) Deficiency in TLR4 signal transduction ameliorates cardiac injury and cardiomyocyte contractile dysfunction during ischemia. J Cell Mol Med 13(8A):1513–1525PubMedGoogle Scholar
  569. Zheng L, Kagedal K, Dehvari N, Benedikz E, Cowburn R, Marcusson J, Terman A (2009) Oxidative stress induces macroautophagy of amyloid beta-protein and ensuing apoptosis. Free Radic Biol Med 46(3):422–429PubMedGoogle Scholar
  570. Zheng L, Terman A, Hallbeck M, Dehvari N, Cowburn RF, Benedikz E, Kagedal K, Cedazo-Minguez A, Marcusson J (2011) Macroautophagy-generated increase of lysosomal amyloid beta-protein mediates oxidant-induced apoptosis of cultured neuroblastoma cells. Autophagy 7(12):1528–1545PubMedGoogle Scholar
  571. Zheng L, Cedazo-Minguez A, Hallbeck M, Jerhammar F, Marcusson J, Terman A (2012) Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system. Transl neurodegeneration 1(1):19Google Scholar
  572. Zhou M, McFarland-Mancini MM, Funk HM, Husseinzadeh N, Mounajjed T, Drew AF (2009) Toll-like receptor expression in normal ovary and ovarian tumors. Cancer Immunol Immunother 58(9):1375–1385PubMedGoogle Scholar
  573. Zhou R, Yazdi AS, Menu P, Tschopp J (2011) A role for mitochondria in NLRP3 inflammasome activation. Nature 469(7329):221–225PubMedGoogle Scholar
  574. Zitvogel L, Kepp O, Kroemer G (2010) Decoding cell death signals in inflammation and immunity. Cell 140(6):798–804PubMedGoogle Scholar
  575. Zitvogel L, Kepp O, Kroemer G (2011) Immune parameters affecting the efficacy of chemotherapeutic regimens. Nat Rev Clin Oncol 8(3):151–160PubMedGoogle Scholar
  576. Zitvogel L, Kepp O, Galluzzi L, Kroemer G (2012) Inflammasomes in carcinogenesis and anticancer immune responses. Nat Immunol 13(4):343–351PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Meakins-Christie Laboratories, Department of MedicineResearch Institute of the McGill University Health Centre, McGill UniversityMontrealCanada
  2. 2.Meakins-Christie Laboratories, Department of Physiology, Faculty of MedicineMcGill UniversityMontrealCanada

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