Seminars in Immunopathology

, Volume 36, Issue 5, pp 595–609 | Cite as

Beyond canonical inflammasomes: emerging pathways in IL-1-mediated autoinflammatory disease

  • John R. Lukens
  • Thirumala-Devi KannegantiEmail author


In recent years, non-communicable chronic diseases that are potentiated by sterile inflammation have replaced infectious diseases as the major threat to human health. Sterile inflammation that results from aberrant tissue damage plays pivotal roles in the pathogenesis of numerous acute and chronic inflammatory diseases including atherosclerosis, type 2 diabetes, cancer, obesity, and multiple neurodegenerative diseases. The cellular events and molecular signaling pathways that govern sterile inflammation currently remain poorly defined; however, emerging data suggest central roles for IL-1 in driving autoimmune and inflammatory disease pathogenesis. Improved characterization of the immunological pathways that contribute to sterile inflammation are desperately needed to develop effective therapeutics to treat these devastating diseases. In this review, we discuss recent advances in our understanding of how IL-1 is regulated in response to tissue damage. In particular, we highlight recent studies that describe novel roles for conventional cell death molecules in the regulation of IL-1β production.


Sterile inflammation Interleukin-1 Innate immunity Inflammasome NOD-like receptor Autoinflammation 





Pathogen-associated molecular patterns


Danger-associated molecular patterns


IL-1 receptor


NOD-like receptor


AIM2-like receptor


Toll-like receptor


Central nervous system


Experimental autoimmune encephalomyelitis


Amyotrophic lateral sclerosis


Regulatory T cells


Islet amyloid polypeptide


Systemic lupus erythematosus


Receptor-interacting protein


FAS-associated death domain


TNF receptor 1


Inhibitors of apoptosis proteins


Chronic obstructive pulmonary disease


Endoplasmic reticulum



We apologize to authors whose work could not be referenced in this review due to space limitations. We thank Prajwal Gurung and Si Ming Man for their helpful discussions. This work was supported by: the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of Health, under Award Number AR056296 (T.-D.K); the National Cancer Institute, part of the National Institutes of Health, under Award Number CA163507 (T.-D.K); the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, under Award Number AI101935 (T.-D.K); and ALSAC.

Competing interests

The authors declare no competing financial interests.


  1. 1.
    Lukens JR, Gross JM, Kanneganti TD (2012) IL-1 family cytokines trigger sterile inflammatory disease. Front Immunol 3:315PubMedPubMedCentralGoogle Scholar
  2. 2.
    Simpson DM, Ross R (1972) The neutrophilic leukocyte in wound repair a study with antineutrophil serum. J Clin Invest 51(8):2009–2023PubMedPubMedCentralGoogle Scholar
  3. 3.
    Dovi JV, Szpaderska AM, DiPietro LA (2004) Neutrophil function in the healing wound: adding insult to injury? Thromb Haemost 92(2):275–280PubMedGoogle Scholar
  4. 4.
    Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Muller W, Roers A, Eming SA (2010) Differential roles of macrophages in diverse phases of skin repair. J Immunol 184(7):3964–3977PubMedGoogle Scholar
  5. 5.
    Brancato SK, Albina JE (2011) Wound macrophages as key regulators of repair: origin, phenotype, and function. Am J Pathol 178(1):19–25PubMedPubMedCentralGoogle Scholar
  6. 6.
    Rock KL, Latz E, Ontiveros F, Kono H (2010) The sterile inflammatory response. Annu Rev Immunol 28:321–342PubMedGoogle Scholar
  7. 7.
    Chen CJ, Kono H, Golenbock D, Reed G, Akira S, Rock KL (2007) Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med 13(7):851–856PubMedGoogle Scholar
  8. 8.
    Hansson GK, Hermansson A (2011) The immune system in atherosclerosis. Nat Immunol 12(3):204–212PubMedGoogle Scholar
  9. 9.
    Lucin KM, Wyss-Coray T (2009) Immune activation in brain aging and neurodegeneration: too much or too little? Neuron 64(1):110–122PubMedPubMedCentralGoogle Scholar
  10. 10.
    Kanneganti TD, Dixit VD (2012) Immunological complications of obesity. Nat Immunol 13(8):707–712PubMedGoogle Scholar
  11. 11.
    Lukens JR, Dixit VD, Kanneganti TD (2011) Inflammasome activation in obesity-related inflammatory diseases and autoimmunity. Discov Med 12(62):65–74PubMedGoogle Scholar
  12. 12.
    Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445PubMedGoogle Scholar
  13. 13.
    Osborn O, Olefsky JM (2012) The cellular and signaling networks linking the immune system and metabolism in disease. Nat Med 18(3):363–374PubMedGoogle Scholar
  14. 14.
    Kanneganti TD (2010) Central roles of NLRs and inflammasomes in viral infection. Nat Rev Immunol 10(10):688–698PubMedPubMedCentralGoogle Scholar
  15. 15.
    Lupfer C, Kanneganti TD (2012) The role of inflammasome modulation in virulence. Virulence 3(3):262–270PubMedPubMedCentralGoogle Scholar
  16. 16.
    Lamkanfi M, Vande Walle L, Kanneganti TD (2011) Deregulated inflammasome signaling in disease. Immunol Rev 243(1):163–173PubMedPubMedCentralGoogle Scholar
  17. 17.
    Liu Z, Zaki MH, Vogel P, Gurung P, Finlay BB, Deng W, Lamkanfi M, Kanneganti TD (2012) Role of inflammasomes in host defense against Citrobacter rodentium infection. J Biol Chem 287(20):16955–16964PubMedPubMedCentralGoogle Scholar
  18. 18.
    Shaw PJ, McDermott MF, Kanneganti TD (2011) Inflammasomes and autoimmunity. Trends Mol Med 17(2):57–64PubMedPubMedCentralGoogle Scholar
  19. 19.
    Dinarello CA (2011) Interleukin-1 in the pathogenesis and treatment of inflammatory diseases. Blood 117(14):3720–3732PubMedPubMedCentralGoogle Scholar
  20. 20.
    Lukens JR, Vogel P, Johnson GR, Kelliher MA, Iwakura Y, Lamkanfi M, Kanneganti TD (2013) RIP1-driven autoinflammation targets IL-1alpha independently of inflammasomes and RIP3. Nature 498(7453):224–227PubMedPubMedCentralGoogle Scholar
  21. 21.
    Orjalo AV, Bhaumik D, Gengler BK, Scott GK, Campisi J (2009) Cell surface-bound IL-1alpha is an upstream regulator of the senescence-associated IL-6/IL-8 cytokine network. Proc Natl Acad Sci U S A 106(40):17031–17036PubMedPubMedCentralGoogle Scholar
  22. 22.
    Di Paolo NC, Miao EA, Iwakura Y, Murali-Krishna K, Aderem A, Flavell RA, Papayannopoulou T, Shayakhmetov DM (2009) Virus binding to a plasma membrane receptor triggers interleukin-1 alpha-mediated proinflammatory macrophage response in vivo. Immunity 31(1):110–121PubMedPubMedCentralGoogle Scholar
  23. 23.
    Rider P, Carmi Y, Guttman O, Braiman A, Cohen I, Voronov E, White MR, Dinarello CA, Apte RN (2011) IL-1alpha and IL-1beta recruit different myeloid cells and promote different stages of sterile inflammation. J Immunol 187(9):4835–4843PubMedGoogle Scholar
  24. 24.
    Chu E, Rosenwasser LJ, Dinarello CA, Lareau M, Geha RS (1984) Role of interleukin 1 in antigen-specific T cell proliferation. J Immunol 132(3):1311–1316PubMedGoogle Scholar
  25. 25.
    Falkoff RJ, Muraguchi A, Hong JX, Butler JL, Dinarello CA, Fauci AS (1983) The effects of interleukin 1 on human B cell activation and proliferation. J Immunol 131(2):801–805PubMedGoogle Scholar
  26. 26.
    McCandless EE, Budde M, Lees JR, Dorsey D, Lyng E, Klein RS (2009) IL-1R signaling within the central nervous system regulates CXCL12 expression at the blood-brain barrier and disease severity during experimental autoimmune encephalomyelitis. J Immunol 183(1):613–620PubMedPubMedCentralGoogle Scholar
  27. 27.
    Rao DA, Eid RE, Qin L, Yi T, Kirkiles-Smith NC, Tellides G, Pober JS (2008) Interleukin (IL)-1 promotes allogeneic T cell intimal infiltration and IL-17 production in a model of human artery rejection. J Exp Med 205(13):3145–3158PubMedPubMedCentralGoogle Scholar
  28. 28.
    Nishio N, Ito S, Suzuki H, Isobe K (2009) Antibodies to wounded tissue enhance cutaneous wound healing. Immunology 128(3):369–380PubMedPubMedCentralGoogle Scholar
  29. 29.
    Lund FE (2008) Cytokine-producing B lymphocytes-key regulators of immunity. Curr Opin Immunol 20(3):332–338PubMedPubMedCentralGoogle Scholar
  30. 30.
    Kalampokis I, Yoshizaki A, Tedder TF (2013) IL-10-producing regulatory B cells (B10 cells) in autoimmune disease. Arthritis Res Ther 15(Suppl 1):S1PubMedPubMedCentralGoogle Scholar
  31. 31.
    Toulon A, Breton L, Taylor KR, Tenenhaus M, Bhavsar D, Lanigan C, Rudolph R, Jameson J, Havran WL (2009) A role for human skin-resident T cells in wound healing. J Exp Med 206(4):743–750PubMedPubMedCentralGoogle Scholar
  32. 32.
    Burzyn D, Kuswanto W, Kolodin D, Shadrach JL, Cerletti M, Jang Y, Sefik E, Tan TG, Wagers AJ, Benoist C, Mathis D (2013) A special population of regulatory T cells potentiates muscle repair. Cell 155(6):1282–1295PubMedGoogle Scholar
  33. 33.
    Sutton C, Brereton C, Keogh B, Mills KH, Lavelle EC (2006) A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis. J Exp Med 203(7):1685–1691PubMedPubMedCentralGoogle Scholar
  34. 34.
    Chung Y, Chang SH, Martinez GJ, Yang XO, Nurieva R, Kang HS, Ma L, Watowich SS, Jetten AM, Tian Q, Dong C (2009) Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30(4):576–587PubMedPubMedCentralGoogle Scholar
  35. 35.
    Matsuki T, Nakae S, Sudo K, Horai R, Iwakura Y (2006) Abnormal T cell activation caused by the imbalance of the IL-1/IL-1R antagonist system is responsible for the development of experimental autoimmune encephalomyelitis. Int Immunol 18(2):399–407PubMedGoogle Scholar
  36. 36.
    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
  37. 37.
    Lukens JR, Barr MJ, Chaplin DD, Chi H, Kanneganti TD (2012) Inflammasome-derived IL-1beta regulates the production of GM-CSF by CD4(+) T cells and gammadelta T cells. J Immunol 188(7):3107–3115PubMedPubMedCentralGoogle Scholar
  38. 38.
    Lukens JR, Gross JM, Calabrese C, Iwakura Y, Lamkanfi M, Vogel P, Kanneganti TD (2014) Critical role for inflammasome-independent IL-1beta production in osteomyelitis. Proc Natl Acad Sci U S A 111(3):1066–1071PubMedPubMedCentralGoogle Scholar
  39. 39.
    Cassel SL, Janczy JR, Bing X, Wilson SP, Olivier AK, Otero JE, Iwakura Y, Shayakhmetov DM, Bassuk AG, Abu-Amer Y, Brogden KA, Burns TL, Sutterwala FS, Ferguson PJ (2014) Inflammasome-independent IL-1beta mediates autoinflammatory disease in Pstpip2-deficient mice. Proc Natl Acad Sci U S A 111(3):1072–1077PubMedPubMedCentralGoogle Scholar
  40. 40.
    Yazdi AS, Guarda G, Riteau N, Drexler SK, Tardivel A, Couillin I, Tschopp J (2010) Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1alpha and IL-1beta. Proc Natl Acad Sci U S A 107(45):19449–19454PubMedPubMedCentralGoogle Scholar
  41. 41.
    Freigang S, Ampenberger F, Weiss A, Kanneganti TD, Iwakura Y, Hersberger M, Kopf M (2013) Fatty acid-induced mitochondrial uncoupling elicits inflammasome-independent IL-1alpha and sterile vascular inflammation in atherosclerosis. Nat Immunol 14(10):1045–1053PubMedGoogle Scholar
  42. 42.
    Barry KC, Fontana MF, Portman JL, Dugan AS, Vance RE (2013) IL-1alpha signaling initiates the inflammatory response to virulent Legionella pneumophila in vivo. J Immunol 190(12):6329–6339PubMedPubMedCentralGoogle Scholar
  43. 43.
    Cohen I, Rider P, Carmi Y, Braiman A, Dotan S, White MR, Voronov E, Martin MU, Dinarello CA, Apte RN (2010) Differential release of chromatin-bound IL-1alpha discriminates between necrotic and apoptotic cell death by the ability to induce sterile inflammation. Proc Natl Acad Sci U S A 107(6):2574–2579PubMedPubMedCentralGoogle Scholar
  44. 44.
    Berda-Haddad Y, Robert S, Salers P, Zekraoui L, Farnarier C, Dinarello CA, Dignat-George F, Kaplanski G (2011) Sterile inflammation of endothelial cell-derived apoptotic bodies is mediated by interleukin-1alpha. Proc Natl Acad Sci U S A 108(51):20684–20689PubMedPubMedCentralGoogle Scholar
  45. 45.
    Boutin H, LeFeuvre RA, Horai R, Asano M, Iwakura Y, Rothwell NJ (2001) Role of IL-1alpha and IL-1beta in ischemic brain damage. J Neurosci 21(15):5528–5534PubMedGoogle Scholar
  46. 46.
    Thornton P, McColl BW, Greenhalgh A, Denes A, Allan SM, Rothwell NJ (2010) Platelet interleukin-1alpha drives cerebrovascular inflammation. Blood 115(17):3632–3639PubMedGoogle Scholar
  47. 47.
    Luheshi NM, Kovacs KJ, Lopez-Castejon G, Brough D, Denes A (2011) Interleukin-1alpha expression precedes IL-1beta after ischemic brain injury and is localised to areas of focal neuronal loss and penumbral tissues. J Neuroinflammation 8:186PubMedPubMedCentralGoogle Scholar
  48. 48.
    Shito M, Wakabayashi G, Ueda M, Shimazu M, Shirasugi N, Endo M, Mukai M, Kitajima M (1997) Interleukin 1 receptor blockade reduces tumor necrosis factor production, tissue injury, and mortality after hepatic ischemia-reperfusion in the rat. Transplantation 63(1):143–148PubMedGoogle Scholar
  49. 49.
    Abbate A, Salloum FN, Vecile E, Das A, Hoke NN, Straino S, Biondi-Zoccai GG, Houser JE, Qureshi IZ, Ownby ED, Gustini E, Biasucci LM, Severino A, Capogrossi MC, Vetrovec GW, Crea F, Baldi A, Kukreja RC, Dobrina A (2008) Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction. Circulation 117(20):2670–2683PubMedGoogle Scholar
  50. 50.
    Pomerantz BJ, Reznikov LL, Harken AH, Dinarello CA (2001) Inhibition of caspase 1 reduces human myocardial ischemic dysfunction via inhibition of IL-18 and IL-1beta. Proc Natl Acad Sci U S A 98(5):2871–2876PubMedPubMedCentralGoogle Scholar
  51. 51.
    Green MC, Shultz LD (1975) Motheaten, an immunodeficient mutant of the mouse. I. Genetics and pathology. J Hered 66(5):250–258PubMedGoogle Scholar
  52. 52.
    Shultz LD, Coman DR, Bailey CL, Beamer WG, Sidman CL (1984) “Viable motheaten,” a new allele at the motheaten locus. I. Pathology. Am J Pathol 116(2):179–192PubMedPubMedCentralGoogle Scholar
  53. 53.
    Shultz LD, Schweitzer PA, Rajan TV, Yi T, Ihle JN, Matthews RJ, Thomas ML, Beier DR (1993) Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene. Cell 73(7):1445–1454PubMedGoogle Scholar
  54. 54.
    Tsui HW, Siminovitch KA, de Souza L, Tsui FW (1993) Motheaten and viable motheaten mice have mutations in the haematopoietic cell phosphatase gene. Nat Genet 4(2):124–129PubMedGoogle Scholar
  55. 55.
    Abram CL, Roberge GL, Pao LI, Neel BG, Lowell CA (2013) Distinct roles for neutrophils and dendritic cells in inflammation and autoimmunity in motheaten mice. Immunity 38(3):489–501PubMedPubMedCentralGoogle Scholar
  56. 56.
    Nesterovitch AB, Szanto S, Gonda A, Bardos T, Kis-Toth K, Adarichev VA, Olasz K, Ghassemi-Najad S, Hoffman MD, Tharp MD, Mikecz K, Glant TT (2011) Spontaneous insertion of a b2 element in the ptpn6 gene drives a systemic autoinflammatory disease in mice resembling neutrophilic dermatosis in humans. Am J Pathol 178(4):1701–1714PubMedPubMedCentralGoogle Scholar
  57. 57.
    Croker BA, Lawson BR, Rutschmann S, Berger M, Eidenschenk C, Blasius AL, Moresco EM, Sovath S, Cengia L, Shultz LD, Theofilopoulos AN, Pettersson S, Beutler BA (2008) Inflammation and autoimmunity caused by a SHP1 mutation depend on IL-1, MyD88, and a microbial trigger. Proc Natl Acad Sci U S A 105(39):15028–15033PubMedPubMedCentralGoogle Scholar
  58. 58.
    Schmitz J, Owyang A, Oldham E, Song Y, Murphy E, McClanahan TK, Zurawski G, Moshrefi M, Qin J, Li X, Gorman DM, Bazan JF, Kastelein RA (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23(5):479–490PubMedGoogle Scholar
  59. 59.
    Buryskova M, Pospisek M, Grothey A, Simmet T, Burysek L (2004) Intracellular interleukin-1alpha functionally interacts with histone acetyltransferase complexes. J Biol Chem 279(6):4017–4026PubMedGoogle Scholar
  60. 60.
    Werman A, Werman-Venkert R, White R, Lee JK, Werman B, Krelin Y, Voronov E, Dinarello CA, Apte RN (2004) The precursor form of IL-1alpha is an intracrine proinflammatory activator of transcription. Proc Natl Acad Sci U S A 101(8):2434–2439PubMedPubMedCentralGoogle Scholar
  61. 61.
    Andersson U, Tracey KJ (2011) HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol 29:139–162PubMedGoogle Scholar
  62. 62.
    Ali S, Mohs A, Thomas M, Klare J, Ross R, Schmitz ML, Martin MU (2011) The dual function cytokine IL-33 interacts with the transcription factor NF-kappaB to dampen NF-kappaB-stimulated gene transcription. J Immunol 187(4):1609–1616PubMedGoogle Scholar
  63. 63.
    Ravichandran KS (2010) Find-me and eat-me signals in apoptotic cell clearance: progress and conundrums. J Exp Med 207(9):1807–1817PubMedPubMedCentralGoogle Scholar
  64. 64.
    Luheshi NM, McColl BW, Brough D (2009) Nuclear retention of IL-1 alpha by necrotic cells: a mechanism to dampen sterile inflammation. Eur J Immunol 39(11):2973–2980PubMedPubMedCentralGoogle Scholar
  65. 65.
    Bauernfeind FG, Horvath G, Stutz A, Alnemri ES, MacDonald K, Speert D, Fernandes-Alnemri T, Wu J, Monks BG, Fitzgerald KA, Hornung V, Latz E (2009) Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J Immunol 183(2):787–791PubMedPubMedCentralGoogle Scholar
  66. 66.
    Kim B, Lee Y, Kim E, Kwak A, Ryoo S, Bae SH, Azam T, Kim S, Dinarello CA (2013) The interleukin-1alpha precursor is biologically active and is likely a key alarmin in the IL-1 Family of Cytokines. Front Immunol 4:391PubMedPubMedCentralGoogle Scholar
  67. 67.
    Fettelschoss A, Kistowska M, LeibundGut-Landmann S, Beer HD, Johansen P, Senti G, Contassot E, Bachmann MF, French LE, Oxenius A, Kundig TM (2011) Inflammasome activation and IL-1beta target IL-1alpha for secretion as opposed to surface expression. Proc Natl Acad Sci U S A 108(44):18055–18060PubMedPubMedCentralGoogle Scholar
  68. 68.
    Kayagaki N, Warming S, Lamkanfi M, Vande Walle L, Louie S, Dong J, Newton K, Qu Y, Liu J, Heldens S, Zhang J, Lee WP, Roose-Girma M, Dixit VM (2011) Non-canonical inflammasome activation targets caspase-11. Nature 479(7371):117–121PubMedGoogle Scholar
  69. 69.
    Kobayashi Y, Yamamoto K, Saido T, Kawasaki H, Oppenheim JJ, Matsushima K (1990) Identification of calcium-activated neutral protease as a processing enzyme of human interleukin 1 alpha. Proc Natl Acad Sci U S A 87(14):5548–5552PubMedPubMedCentralGoogle Scholar
  70. 70.
    Carruth LM, Demczuk S, Mizel SB (1991) Involvement of a calpain-like protease in the processing of the murine interleukin 1 alpha precursor. J Biol Chem 266(19):12162–12167PubMedGoogle Scholar
  71. 71.
    Gross O, Yazdi AS, Thomas CJ, Masin M, Heinz LX, Guarda G, Quadroni M, Drexler SK, Tschopp J (2012) Inflammasome activators induce interleukin-1alpha secretion via distinct pathways with differential requirement for the protease function of caspase-1. Immunity 36(3):388–400PubMedGoogle Scholar
  72. 72.
    Zheng Y, Humphry M, Maguire JJ, Bennett MR, Clarke MC (2013) Intracellular interleukin-1 receptor 2 binding prevents cleavage and activity of interleukin-1alpha, controlling necrosis-induced sterile inflammation. Immunity 38(2):285–295PubMedPubMedCentralGoogle Scholar
  73. 73.
    Kanneganti TD, Ozoren N, Body-Malapel M, Amer A, Park JH, Franchi L, Whitfield J, Barchet W, Colonna M, Vandenabeele P, Bertin J, Coyle A, Grant EP, Akira S, Nunez G (2006) Bacterial RNA and small antiviral compounds activate caspase-1 through cryopyrin/Nalp3. Nature 440(7081):233–236PubMedGoogle Scholar
  74. 74.
    Franchi L, Eigenbrod T, Nunez G (2009) Cutting edge: TNF-alpha mediates sensitization to ATP and silica via the NLRP3 inflammasome in the absence of microbial stimulation. J Immunol 183(2):792–796PubMedPubMedCentralGoogle Scholar
  75. 75.
    Van Opdenbosch N, Gurung P, Vande Walle L, Fossoul A, Kanneganti TD, Lamkanfi M (2014) Activation of the NLRP1b inflammasome independently of ASC-mediated caspase-1 autoproteolysis and speck formation. Nat Commun 5:3209PubMedPubMedCentralGoogle Scholar
  76. 76.
    Frew BC, Joag VR, Mogridge J (2012) Proteolytic processing of Nlrp1b is required for inflammasome activity. PLoS Pathog 8(4):e1002659PubMedPubMedCentralGoogle Scholar
  77. 77.
    Nour AM, Yeung YG, Santambrogio L, Boyden ED, Stanley ER, Brojatsch J (2009) Anthrax lethal toxin triggers the formation of a membrane-associated inflammasome complex in murine macrophages. Infect Immun 77(3):1262–1271PubMedGoogle Scholar
  78. 78.
    Qu Y, Misaghi S, Izrael-Tomasevic A, Newton K, Gilmour LL, Lamkanfi M, Louie S, Kayagaki N, Liu J, Komuves L, Cupp JE, Arnott D, Monack D, Dixit VM (2012) Phosphorylation of NLRC4 is critical for inflammasome activation. Nature 490(7421):539–542PubMedGoogle Scholar
  79. 79.
    Zhao Y, Yang J, Shi J, Gong YN, Lu Q, Xu H, Liu L, Shao F (2011) The NLRC4 inflammasome receptors for bacterial flagellin and type III secretion apparatus. Nature 477(7366):596–600PubMedGoogle Scholar
  80. 80.
    Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose-Girma M, Erickson S, Dixit VM (2004) Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430(6996):213–218PubMedGoogle Scholar
  81. 81.
    Miao EA, Alpuche-Aranda CM, Dors M, Clark AE, Bader MW, Miller SI, Aderem A (2006) Cytoplasmic flagellin activates caspase-1 and secretion of interleukin 1beta via Ipaf. Nat Immunol 7(6):569–575PubMedGoogle Scholar
  82. 82.
    Franchi L, Amer A, Body-Malapel M, Kanneganti TD, Ozoren N, Jagirdar R, Inohara N, Vandenabeele P, Bertin J, Coyle A, Grant EP, Nunez G (2006) Cytosolic flagellin requires Ipaf for activation of caspase-1 and interleukin 1beta in salmonella-infected macrophages. Nat Immunol 7(6):576–582PubMedGoogle Scholar
  83. 83.
    Kofoed EM, Vance RE (2011) Innate immune recognition of bacterial ligands by NAIPs determines inflammasome specificity. Nature 477(7366):592–595PubMedPubMedCentralGoogle Scholar
  84. 84.
    Ataide MA, Andrade WA, Zamboni DS, Wang D, Souza Mdo C, Franklin BS, Elian S, Martins FS, Pereira D, Reed G, Fitzgerald KA, Golenbock DT, Gazzinelli RT (2014) Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection. PLoS Pathog 10(1):e1003885PubMedPubMedCentralGoogle Scholar
  85. 85.
    Vladimer GI, Weng D, Paquette SW, Vanaja SK, Rathinam VA, Aune MH, Conlon JE, Burbage JJ, Proulx MK, Liu Q, Reed G, Mecsas JC, Iwakura Y, Bertin J, Goguen JD, Fitzgerald KA, Lien E (2012) The NLRP12 inflammasome recognizes Yersinia pestis. Immunity 37(1):96–107PubMedPubMedCentralGoogle Scholar
  86. 86.
    Khare S, Dorfleutner A, Bryan NB, Yun C, Radian AD, de Almeida L, Rojanasakul Y, Stehlik C (2012) An NLRP7-containing inflammasome mediates recognition of microbial lipopeptides in human macrophages. Immunity 36(3):464–476PubMedPubMedCentralGoogle Scholar
  87. 87.
    Anand PK, Malireddi RK, Lukens JR, Vogel P, Bertin J, Lamkanfi M, Kanneganti TD (2012) NLRP6 negatively regulates innate immunity and host defence against bacterial pathogens. Nature 488(7411):389–393PubMedPubMedCentralGoogle Scholar
  88. 88.
    Zaki MH, Man SM, Vogel P, Lamkanfi M, Kanneganti TD (2014) Salmonella exploits NLRP12-dependent innate immune signaling to suppress host defenses during infection. Proc Natl Acad Sci U S A 111(1):385–390PubMedPubMedCentralGoogle Scholar
  89. 89.
    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):649–660PubMedPubMedCentralGoogle Scholar
  90. 90.
    Allen IC, Wilson JE, Schneider M, Lich JD, Roberts RA, Arthur JC, Woodford RM, Davis BK, Uronis JM, Herfarth HH, Jobin C, Rogers AB, Ting JP (2012) NLRP12 suppresses colon inflammation and tumorigenesis through the negative regulation of noncanonical NF-kappaB signaling. Immunity 36(5):742–754PubMedPubMedCentralGoogle Scholar
  91. 91.
    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):9601–9606PubMedPubMedCentralGoogle Scholar
  92. 92.
    Elinav E, Strowig T, Kau AL, Henao-Mejia J, Thaiss CA, Booth CJ, Peaper DR, Bertin J, Eisenbarth SC, Gordon JI, Flavell RA (2011) NLRP6 inflammasome regulates colonic microbial ecology and risk for colitis. Cell 145(5):745–757PubMedPubMedCentralGoogle Scholar
  93. 93.
    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):7187–7194PubMedPubMedCentralGoogle Scholar
  94. 94.
    Hu B, Elinav E, Huber S, Strowig T, Hao L, Hafemann A, Jin C, Wunderlich C, Wunderlich T, Eisenbarth SC, Flavell RA (2013) Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer. Proc Natl Acad Sci U S A 110(24):9862–9867PubMedPubMedCentralGoogle Scholar
  95. 95.
    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):509–513PubMedPubMedCentralGoogle Scholar
  96. 96.
    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):514–518PubMedPubMedCentralGoogle Scholar
  97. 97.
    Roberts TL, Idris A, Dunn JA, Kelly GM, Burnton CM, Hodgson S, Hardy LL, Garceau V, Sweet MJ, Ross IL, Hume DA, Stacey KJ (2009) HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science 323(5917):1057–1060PubMedGoogle Scholar
  98. 98.
    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):363–375PubMedPubMedCentralGoogle Scholar
  99. 99.
    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):997–1004PubMedPubMedCentralGoogle Scholar
  100. 100.
    Tsokos GC (2011) Systemic lupus erythematosus. N Engl J Med 365(22):2110–2121PubMedGoogle Scholar
  101. 101.
    Dombrowski Y, Peric M, Koglin S, Kammerbauer C, Goss C, Anz D, Simanski M, Glaser R, Harder J, Hornung V, Gallo RL, Ruzicka T, Besch R, Schauber J (2011) Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions. Sci Transl Med 3(82):82ra38PubMedPubMedCentralGoogle Scholar
  102. 102.
    Diana J, Simoni Y, Furio L, Beaudoin L, Agerberth B, Barrat F, Lehuen A (2013) Crosstalk between neutrophils, B-1a cells and plasmacytoid dendritic cells initiates autoimmune diabetes. Nat Med 19(1):65–73PubMedGoogle Scholar
  103. 103.
    Kawane K, Ohtani M, Miwa K, Kizawa T, Kanbara Y, Yoshioka Y, Yoshikawa H, Nagata S (2006) Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature 443(7114):998–1002PubMedGoogle Scholar
  104. 104.
    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):593–605PubMedPubMedCentralGoogle Scholar
  105. 105.
    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):15324–15329PubMedPubMedCentralGoogle Scholar
  106. 106.
    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):179–188PubMedPubMedCentralGoogle Scholar
  107. 107.
    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):897–904PubMedPubMedCentralGoogle Scholar
  108. 108.
    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):408–415PubMedPubMedCentralGoogle Scholar
  109. 109.
    Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA (2012) Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482(7384):179–185PubMedPubMedCentralGoogle Scholar
  110. 110.
    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):1357–1361PubMedPubMedCentralGoogle Scholar
  111. 111.
    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):857–865PubMedPubMedCentralGoogle Scholar
  112. 112.
    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
  113. 113.
    Barnes PJ (2013) New anti-inflammatory targets for chronic obstructive pulmonary disease. Nat Rev Drug Discov 12(7):543–559PubMedGoogle Scholar
  114. 114.
    Martinon F, Petrilli V, Mayor A, Tardivel A, Tschopp J (2006) Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature 440(7081):237–241PubMedGoogle Scholar
  115. 115.
    Hornung V, Bauernfeind F, Halle A, Samstad EO, Kono H, Rock KL, Fitzgerald KA, Latz E (2008) Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization. Nat Immunol 9(8):847–856PubMedPubMedCentralGoogle Scholar
  116. 116.
    Dostert C, Petrilli V, Van Bruggen R, Steele C, Mossman BT, Tschopp J (2008) Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science 320(5876):674–677PubMedPubMedCentralGoogle Scholar
  117. 117.
    Cassel SL, Eisenbarth SC, Iyer SS, Sadler JJ, Colegio OR, Tephly LA, Carter AB, Rothman PB, Flavell RA, Sutterwala FS (2008) The Nalp3 inflammasome is essential for the development of silicosis. Proc Natl Acad Sci U S A 105(26):9035–9040PubMedPubMedCentralGoogle Scholar
  118. 118.
    Furuya T, Hayakawa H, Yamada M, Yoshimi K, Hisahara S, Miura M, Mizuno Y, Mochizuki H (2004) Caspase-11 mediates inflammatory dopaminergic cell death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. J Neurosci 24(8):1865–1872PubMedGoogle Scholar
  119. 119.
    Hisahara S, Yuan J, Momoi T, Okano H, Miura M (2001) Caspase-11 mediates oligodendrocyte cell death and pathogenesis of autoimmune-mediated demyelination. J Exp Med 193(1):111–122PubMedPubMedCentralGoogle Scholar
  120. 120.
    Gurung P, Malireddi RK, Anand PK, Demon D, Vande Walle L, Liu Z, Vogel P, Lamkanfi M, Kanneganti TD (2012) Toll or interleukin-1 receptor (TIR) domain-containing adaptor inducing interferon-beta (TRIF)-mediated caspase-11 protease production integrates Toll-like receptor 4 (TLR4) protein- and Nlrp3 inflammasome-mediated host defense against enteropathogens. J Biol Chem 287(41):34474–34483PubMedPubMedCentralGoogle Scholar
  121. 121.
    Rathinam VA, Vanaja SK, Waggoner L, Sokolovska A, Becker C, Stuart LM, Leong JM, Fitzgerald KA (2012) TRIF licenses caspase-11-dependent NLRP3 inflammasome activation by gram-negative bacteria. Cell 150(3):606–619PubMedPubMedCentralGoogle Scholar
  122. 122.
    Aachoui Y, Leaf IA, Hagar JA, Fontana MF, Campos CG, Zak DE, Tan MH, Cotter PA, Vance RE, Aderem A, Miao EA (2013) Caspase-11 protects against bacteria that escape the vacuole. Science 339(6122):975–978PubMedPubMedCentralGoogle Scholar
  123. 123.
    Hagar JA, Powell DA, Aachoui Y, Ernst RK, Miao EA (2013) Cytoplasmic LPS activates caspase-11: implications in TLR4-independent endotoxic shock. Science 341(6151):1250–1253PubMedPubMedCentralGoogle Scholar
  124. 124.
    Kayagaki N, Wong MT, Stowe IB, Ramani SR, Gonzalez LC, Akashi-Takamura S, Miyake K, Zhang J, Lee WP, Muszynski A, Forsberg LS, Carlson RW, Dixit VM (2013) Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science 341(6151):1246–1249PubMedGoogle Scholar
  125. 125.
    Case CL, Kohler LJ, Lima JB, Strowig T, de Zoete MR, Flavell RA, Zamboni DS, Roy CR (2013) Caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila. Proc Natl Acad Sci U S A 110(5):1851–1856PubMedPubMedCentralGoogle Scholar
  126. 126.
    Broz P, Ruby T, Belhocine K, Bouley DM, Kayagaki N, Dixit VM, Monack DM (2012) Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1. Nature 490(7419):288–291PubMedPubMedCentralGoogle Scholar
  127. 127.
    Oberst A, Green DR (2011) It cuts both ways: reconciling the dual roles of caspase 8 in cell death and survival. Nat Rev Mol Cell Biol 12(11):757–763PubMedPubMedCentralGoogle Scholar
  128. 128.
    Maelfait J, Vercammen E, Janssens S, Schotte P, Haegman M, Magez S, Beyaert R (2008) Stimulation of Toll-like receptor 3 and 4 induces interleukin-1beta maturation by caspase-8. J Exp Med 205(9):1967–1973PubMedPubMedCentralGoogle Scholar
  129. 129.
    Kaiser WJ, Upton JW, Long AB, Livingston-Rosanoff D, Daley-Bauer LP, Hakem R, Caspary T, Mocarski ES (2011) RIP3 mediates the embryonic lethality of caspase-8-deficient mice. Nature 471(7338):368–372PubMedPubMedCentralGoogle Scholar
  130. 130.
    Dillon CP, Oberst A, Weinlich R, Janke LJ, Kang TB, Ben-Moshe T, Mak TW, Wallach D, Green DR (2012) Survival function of the FADD-CASPASE-8-cFLIP(L) complex. Cell Rep 1(5):401–407PubMedPubMedCentralGoogle Scholar
  131. 131.
    Oberst A, Dillon CP, Weinlich R, McCormick LL, Fitzgerald P, Pop C, Hakem R, Salvesen GS, Green DR (2011) Catalytic activity of the caspase-8-FLIP(L) complex inhibits RIPK3-dependent necrosis. Nature 471(7338):363–367PubMedPubMedCentralGoogle Scholar
  132. 132.
    Gurung P, Anand PK, Malireddi RK, Vande Walle L, Van Opdenbosch N, Dillon CP, Weinlich R, Green DR, Lamkanfi M, Kanneganti TD (2014) FADD and caspase-8 mediate priming and activation of the canonical and noncanonical Nlrp3 inflammasomes. J Immunol 192(4):1835–1846PubMedGoogle Scholar
  133. 133.
    Shenderov K, Riteau N, Yip R, Mayer-Barber KD, Oland S, Hieny S, Fitzgerald P, Oberst A, Dillon CP, Green DR, Cerundolo V, Sher A (2014) Cutting edge: endoplasmic reticulum stress licenses macrophages to produce mature IL-1beta in response to TLR4 stimulation through a caspase-8- and TRIF-dependent pathway. J Immunol 192(5):2029–2033PubMedGoogle Scholar
  134. 134.
    Kawasaki N, Asada R, Saito A, Kanemoto S, Imaizumi K (2012) Obesity-induced endoplasmic reticulum stress causes chronic inflammation in adipose tissue. Sci Rep 2:799PubMedPubMedCentralGoogle Scholar
  135. 135.
    Cnop M, Foufelle F, Velloso LA (2012) Endoplasmic reticulum stress, obesity and diabetes. Trends Mol Med 18(1):59–68PubMedGoogle Scholar
  136. 136.
    Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS (2004) Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306(5695):457–461PubMedGoogle Scholar
  137. 137.
    Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, Gorgun CZ, Hotamisligil GS (2006) Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science 313(5790):1137–1140PubMedGoogle Scholar
  138. 138.
    Bossaller L, Chiang PI, Schmidt-Lauber C, Ganesan S, Kaiser WJ, Rathinam VA, Mocarski ES, Subramanian D, Green DR, Silverman N, Fitzgerald KA, Marshak-Rothstein A, Latz E (2012) Cutting edge: FAS (CD95) mediates noncanonical IL-1beta and IL-18 maturation via caspase-8 in an RIP3-independent manner. J Immunol 189(12):5508–5512PubMedPubMedCentralGoogle Scholar
  139. 139.
    Gyrd-Hansen M, Meier P (2010) IAPs: from caspase inhibitors to modulators of NF-kappaB, inflammation and cancer. Nat Rev Cancer 10(8):561–574PubMedGoogle Scholar
  140. 140.
    Silke J, Meier P (2013) Inhibitor of apoptosis (IAP) proteins-modulators of cell death and inflammation. Cold Spring Harb Perspect Biol 5(2)Google Scholar
  141. 141.
    Vince JE, Wong WW, Gentle I, Lawlor KE, Allam R, O’Reilly L, Mason K, Gross O, Ma S, Guarda G, Anderton H, Castillo R, Hacker G, Silke J, Tschopp J (2012) Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity 36(2):215–227PubMedGoogle Scholar
  142. 142.
    Labbe K, McIntire CR, Doiron K, Leblanc PM, Saleh M (2011) Cellular inhibitors of apoptosis proteins cIAP1 and cIAP2 are required for efficient caspase-1 activation by the inflammasome. Immunity 35(6):897–907PubMedGoogle Scholar
  143. 143.
    Antonopoulos C, El Sanadi C, Kaiser WJ, Mocarski ES, Dubyak GR (2013) Proapoptotic chemotherapeutic drugs induce noncanonical processing and release of IL-1beta via caspase-8 in dendritic cells. J Immunol 191(9):4789–4803PubMedGoogle Scholar
  144. 144.
    Gringhuis SI, Kaptein TM, Wevers BA, Theelen B, van der Vlist M, Boekhout T, Geijtenbeek TB (2012) Dectin-1 is an extracellular pathogen sensor for the induction and processing of IL-1beta via a noncanonical caspase-8 inflammasome. Nat Immunol 13(3):246–254PubMedGoogle Scholar
  145. 145.
    Bellocchio S, Montagnoli C, Bozza S, Gaziano R, Rossi G, Mambula SS, Vecchi A, Mantovani A, Levitz SM, Romani L (2004) The contribution of the Toll-like/IL-1 receptor superfamily to innate and adaptive immunity to fungal pathogens in vivo. J Immunol 172(5):3059–3069PubMedGoogle Scholar
  146. 146.
    Vonk AG, Netea MG, van Krieken JH, Iwakura Y, van der Meer JW, Kullberg BJ (2006) Endogenous interleukin (IL)-1 alpha and IL-1 beta are crucial for host defense against disseminated candidiasis. J Infect Dis 193(10):1419–1426PubMedGoogle Scholar
  147. 147.
    Conti HR, Shen F, Nayyar N, Stocum E, Sun JN, Lindemann MJ, Ho AW, Hai JH, Yu JJ, Jung JW, Filler SG, Masso-Welch P, Edgerton M, Gaffen SL (2009) Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis. J Exp Med 206(2):299–311PubMedPubMedCentralGoogle Scholar
  148. 148.
    Hernandez-Santos N, Gaffen SL (2012) Th17 cells in immunity to Candida albicans. Cell Host Microbe 11(5):425–435PubMedPubMedCentralGoogle Scholar
  149. 149.
    Mencacci A, Bacci A, Cenci E, Montagnoli C, Fiorucci S, Casagrande A, Flavell RA, Bistoni F, Romani L (2000) Interleukin 18 restores defective Th1 immunity to Candida albicans in caspase 1-deficient mice. Infect Immun 68(9):5126–5131PubMedPubMedCentralGoogle Scholar
  150. 150.
    Fantuzzi G, Ku G, Harding MW, Livingston DJ, Sipe JD, Kuida K, Flavell RA, Dinarello CA (1997) Response to local inflammation of IL-1 beta-converting enzyme- deficient mice. J Immunol 158(4):1818–1824PubMedGoogle Scholar
  151. 151.
    Man SM, Tourlomousis P, Hopkins L, Monie TP, Fitzgerald KA, Bryant CE (2013) Salmonella infection induces recruitment of Caspase-8 to the inflammasome to modulate IL-1beta production. J Immunol 191(10):5239–5246PubMedGoogle Scholar
  152. 152.
    Kang TB, Yang SH, Toth B, Kovalenko A, Wallach D (2013) Caspase-8 blocks kinase RIPK3-mediated activation of the NLRP3 inflammasome. Immunity 38(1):27–40PubMedGoogle Scholar
  153. 153.
    Provoost S, Maes T, Pauwels NS, Vanden Berghe T, Vandenabeele P, Lambrecht BN, Joos GF, Tournoy KG (2011) NLRP3/caspase-1-independent IL-1beta production mediates diesel exhaust particle-induced pulmonary inflammation. J Immunol 187(6):3331–3337PubMedGoogle Scholar
  154. 154.
    Joosten LA, Netea MG, Fantuzzi G, Koenders MI, Helsen MM, Sparrer H, Pham CT, van der Meer JW, Dinarello CA, van den Berg WB (2009) Inflammatory arthritis in caspase 1 gene-deficient mice: contribution of proteinase 3 to caspase 1-independent production of bioactive interleukin-1beta. Arthritis Rheum 60(12):3651–3662PubMedPubMedCentralGoogle Scholar
  155. 155.
    Guma M, Ronacher L, Liu-Bryan R, Takai S, Karin M, Corr M (2009) Caspase 1-independent activation of interleukin-1beta in neutrophil-predominant inflammation. Arthritis Rheum 60(12):3642–3650PubMedPubMedCentralGoogle Scholar
  156. 156.
    Edye ME, Lopez-Castejon G, Allan SM, Brough D (2013) Acidosis drives damage-associated molecular pattern (DAMP)-induced interleukin-1 secretion via a caspase-1-independent pathway. J Biol Chem 288(42):30485–30494PubMedPubMedCentralGoogle Scholar
  157. 157.
    Mayer-Barber KD, Barber DL, Shenderov K, White SD, Wilson MS, Cheever A, Kugler D, Hieny S, Caspar P, Nunez G, Schlueter D, Flavell RA, Sutterwala FS, Sher A (2010) Caspase-1 independent IL-1beta production is critical for host resistance to mycobacterium tuberculosis and does not require TLR signaling in vivo. J Immunol 184(7):3326–3330PubMedPubMedCentralGoogle Scholar
  158. 158.
    Kono H, Orlowski GM, Patel Z, Rock KL (2012) The IL-1-dependent sterile inflammatory response has a substantial caspase-1-independent component that requires cathepsin C. J Immunol 189(7):3734–3740PubMedPubMedCentralGoogle Scholar
  159. 159.
    Schonbeck U, Mach F, Libby P (1998) Generation of biologically active IL-1 beta by matrix metalloproteinases: a novel caspase-1-independent pathway of IL-1 beta processing. J Immunol 161(7):3340–3346PubMedGoogle Scholar
  160. 160.
    Kawasaki Y, Xu ZZ, Wang X, Park JY, Zhuang ZY, Tan PH, Gao YJ, Roy K, Corfas G, Lo EH, Ji RR (2008) Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med 14(3):331–336PubMedPubMedCentralGoogle Scholar
  161. 161.
    McGuire MJ, Lipsky PE, Thiele DL (1993) Generation of active myeloid and lymphoid granule serine proteases requires processing by the granule thiol protease dipeptidyl peptidase I. J Biol Chem 268(4):2458–2467PubMedGoogle Scholar
  162. 162.
    Mizutani H, Schechter N, Lazarus G, Black RA, Kupper TS (1991) Rapid and specific conversion of precursor interleukin 1 beta (IL-1 beta) to an active IL-1 species by human mast cell chymase. J Exp Med 174(4):821–825PubMedGoogle Scholar
  163. 163.
    Pham CT, Ley TJ (1999) Dipeptidyl peptidase I is required for the processing and activation of granzymes A and B in vivo. Proc Natl Acad Sci U S A 96(15):8627–8632PubMedPubMedCentralGoogle Scholar
  164. 164.
    Netea MG, Simon A, van de Veerdonk F, Kullberg BJ, Van der Meer JW, Joosten LA (2010) IL-1beta processing in host defense: beyond the inflammasomes. PLoS Pathog 6(2):e1000661PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.Department of ImmunologySt. Jude Children’s Research HospitalMemphisUSA

Personalised recommendations