Molecular Neurobiology

, Volume 55, Issue 2, pp 1463–1476 | Cite as

RAGE-TLR Crosstalk Sustains Chronic Inflammation in Neurodegeneration

  • Kazimierz Gąsiorowski
  • Barbara Brokos
  • Valentina Echeverria
  • George E. Barreto
  • Jerzy LeszekEmail author


Chronic inflammatory reactions are consistenly present in neurodegeneration of Alzheimer type and are considered important factors that accelerate progression of the disease. Receptors of innate immunity participate in triggering and driving inflammatory reactions. For example, Toll-like receptors (TLRs) and receptor for advanced glycation end product (RAGE), major receptors of innate immunity, play a central role in perpetuation of inflammation. RAGE activation should be perceived as a primary mechanism which determines self-perpetuated chronic inflammation, and RAGE cooperation with TLRs amplifies inflammatory signaling. In this review, we highlight and discuss that RAGE-TLR crosstalk emerges as an important driving force of chronic inflammation in Alzheimer’s disease.


Chronic inflammation Rage TLR Self-perpetuated stimulation Neurodegeneration 


Compliance with Ethical Standards

Conflict of Interests

The authors declare that they have no conflict of interest.


  1. 1.
    Guillot-Sestier MV, Town T (2013) Innate immunity in Alzheimer’s disease: a complex affair. CNS Neurol Dis Drug Targets 12(5):593–607CrossRefGoogle Scholar
  2. 2.
    Heneka MT, Golenbock DT, Latz E (2015) Innate immunity in Alzheimer’s disease. Nat Immunol 16(3):229–236. doi: 10.1038/ni.3102 PubMedCrossRefGoogle Scholar
  3. 3.
    Leszek J, Barreto GE, Gasiorowski K, Koutsouraki E, Avila-Rodrigues M, Aliev G (2016) Inflammatory mechanisms and oxidative stress as key factors responsible for progression of neurodegeneration: role of brain innate immune system. CNS Neurol Dis Drug Targets 15(3):329–336CrossRefGoogle Scholar
  4. 4.
    Serpente M, Bonsi R, Scarpini E, Galimberti D (2014) Innate immune system and inflammation in Alzheimer’s disease: from pathogenesis to treatment. Neuroimmunomodulation 21(2–3):79–87. doi: 10.1159/000356529 PubMedCrossRefGoogle Scholar
  5. 5.
    Finch CE, Morgan TE (2007) Systemic inflammation, infection, ApoE alleles, and Alzheimer disease: a position paper. Curr Alzheimer Res 4(2):185–189PubMedCrossRefGoogle Scholar
  6. 6.
    Lehnardt S, Schott E, Trimbuch T, Laubisch D, Krueger C, Wulczyn G, Nitsch R, Weber JR (2008) A vicious cycle involving release of heat shock protein 60 from injured cells and activation of toll-like receptor 4 mediates neurodegeneration in the CNS. J Neurosci 28(10):2320–2331. doi: 10.1523/JNEUROSCI.4760-07.2008 PubMedCrossRefGoogle Scholar
  7. 7.
    Ohashi K, Burkart V, Flohe S, Kolb H (2000) Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol 164(2):558–561PubMedCrossRefGoogle Scholar
  8. 8.
    Olive C (2012) Pattern recognition receptors: sentinels in innate immunity and targets of new vaccine adjuvants. Expert Rev Vaccines 11(2):237–256. doi: 10.1586/erv.11.189 PubMedCrossRefGoogle Scholar
  9. 9.
    Schenten D, Medzhitov R (2011) The control of adaptive immune responses by the innate immune system. Adv Immunol 109:87–124. doi: 10.1016/B978-0-12-387664-5.00003-0 PubMedCrossRefGoogle Scholar
  10. 10.
    Qian C, Liu J, Cao X (2014) Innate signaling in the inflammatory immune disorders. Cytokine Growth Factor Rev 25(6):731–738. doi: 10.1016/j.cytogfr.2014.06.003 PubMedCrossRefGoogle Scholar
  11. 11.
    Fritz G (2011) RAGE: a single receptor fits multiple ligands. Trends Biochem Sci 36(12):625–632. doi: 10.1016/j.tibs.2011.08.008 PubMedCrossRefGoogle Scholar
  12. 12.
    Yu Y, Ye RD (2015) Microglial abeta receptors in Alzheimer’s disease. Cell Mol Neurobiol 35(1):71–83. doi: 10.1007/s10571-014-0101-6 PubMedCrossRefGoogle Scholar
  13. 13.
    Hajishengallis G, Lambris JD (2011) Microbial manipulation of receptor crosstalk in innate immunity. Nat Rev Immunol 11(3):187–200. doi: 10.1038/nri2918 PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Mercier BC, Ventre E, Fogeron ML, Debaud AL, Tomkowiak M, Marvel J, Bonnefoy N (2012) NOD1 cooperates with TLR2 to enhance T cell receptor-mediated activation in CD8 T cells. PLoS One 7(7):e42170. doi: 10.1371/journal.pone.0042170 PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Rojas A, Perez-Castro R, Gonzalez I, Delgado F, Romero J, Rojas I (2014) The emerging role of the receptor for advanced glycation end products on innate immunity. Int Rev Immunol 33(1):67–80. doi: 10.3109/08830185.2013.849702 PubMedCrossRefGoogle Scholar
  16. 16.
    Trinchieri G, Sher A (2007) Cooperation of toll-like receptor signals in innate immune defence. Nat Rev Immunol 7(3):179–190. doi: 10.1038/nri2038 PubMedCrossRefGoogle Scholar
  17. 17.
    Lehnardt S (2010) Innate immunity and neuroinflammation in the CNS: the role of microglia in toll-like receptor-mediated neuronal injury. Glia 58(3):253–263. doi: 10.1002/glia.20928 PubMedGoogle Scholar
  18. 18.
    Akira S (2003) Mammalian toll-like receptors. Curr Opin Immunol 15(1):5–11PubMedCrossRefGoogle Scholar
  19. 19.
    Arroyo DS, Soria JA, Gaviglio EA, Rodriguez-Galan MC, Iribarren P (2011) Toll-like receptors are key players in neurodegeneration. Int Immunopharmacol 11(10):1415–1421. doi: 10.1016/j.intimp.2011.05.006 PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Okun E, Griffioen KJ, Lathia JD, Tang SC, Mattson MP, Arumugam TV (2009) Toll-like receptors in neurodegeneration. Brain Res Rev 59(2):278–292. doi: 10.1016/j.brainresrev.2008.09.001 PubMedCrossRefGoogle Scholar
  21. 21.
    Cai Z, Shi Z, Sanchez A, Zhang T, Liu M, Yang J, Wang F, Zhang D (2009) Transcriptional regulation of Tlr11 gene expression in epithelial cells. J Biol Chem 284(48):33088–33096. doi: 10.1074/jbc.M109.050757 PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Bird L (2005) A new ligand for TLR11. Nat Rev Immunol 5(432). doi: 10.1038/nri1638
  23. 23.
    Kawai T, Akira S (2009) The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol 21(4):317–337. doi: 10.1093/intimm/dxp017 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Loo YM, Gale M Jr (2011) Immune signaling by RIG-I-like receptors. Immunity 34(5):680–692. doi: 10.1016/j.immuni.2011.05.003 PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Asea A (2008) Heat shock proteins and toll-like receptors. Handb Exp Pharmacol 183:111–127. doi: 10.1007/978-3-540-72167-3_6 CrossRefGoogle Scholar
  26. 26.
    Shimada M, Yanai Y, Okazaki T, Noma N, Kawashima I, Mori T, Richards JS (2008) Hyaluronan fragments generated by sperm-secreted hyaluronidase stimulate cytokine/chemokine production via the TLR2 and TLR4 pathway in cumulus cells of ovulated COCs, which may enhance fertilization. Development 135(11):2001–2011. doi: 10.1242/dev.020461 PubMedCrossRefGoogle Scholar
  27. 27.
    McGettrick AF, O’Neill LA (2004) The expanding family of MyD88-like adaptors in toll-like receptor signal transduction. Mol Immunol 41(6–7):577–582. doi: 10.1016/j.molimm.2004.04.006 PubMedCrossRefGoogle Scholar
  28. 28.
    O’Neill LA, Fitzgerald KA, Bowie AG (2003) The toll-IL-1 receptor adaptor family grows to five members. Trends Immunol 24(6):286–290PubMedCrossRefGoogle Scholar
  29. 29.
    Kawai T, Akira S (2007) TLR signaling. Semin Immunol 19(1):24–32. doi: 10.1016/j.smim.2006.12.004 PubMedCrossRefGoogle Scholar
  30. 30.
    Lee MS, Kim YJ (2007) Signaling pathways downstream of pattern-recognition receptors and their cross talk. Annu Rev Biochem 76:447–480. doi: 10.1146/annurev.biochem.76.060605.122847 PubMedCrossRefGoogle Scholar
  31. 31.
    Honda K, Taniguchi T (2006) IRFs: master regulators of signalling by toll-like receptors and cytosolic pattern-recognition receptors. Nat Rev Immunol 6(9):644–658. doi: 10.1038/nri1900 PubMedCrossRefGoogle Scholar
  32. 32.
    Ikushima H, Negishi H, Taniguchi T (2013) The IRF family transcription factors at the interface of innate and adaptive immune responses. Cold Spring Harb Symp Quant Biol 78:105–116. doi: 10.1101/sqb.2013.78.020321 PubMedCrossRefGoogle Scholar
  33. 33.
    Negishi H, Ohba Y, Yanai H, Takaoka A, Honma K, Yui K, Matsuyama T, Taniguchi T et al (2005) Negative regulation of toll-like-receptor signaling by IRF-4. Proc Natl Acad Sci U S A 102(44):15989–15994. doi: 10.1073/pnas.0508327102 PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Cooks T, Harris CC, Oren M (2014) Caught in the cross fire: p53 in inflammation. Carcinogenesis 35(8):1680–1690. doi: 10.1093/carcin/bgu134 PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Johnson RF, Perkins ND (2012) Nuclear factor-kappaB, p53, and mitochondria: regulation of cellular metabolism and the Warburg effect. Trends Biochem Sci 37(8):317–324. doi: 10.1016/j.tibs.2012.04.002 PubMedCrossRefGoogle Scholar
  36. 36.
    Perkins ND (2007) Integrating cell-signalling pathways with NF-kappaB and IKK function. Nat Rev Mol Cell Biol 8(1):49–62. doi: 10.1038/nrm2083 PubMedCrossRefGoogle Scholar
  37. 37.
    Schneider G, Henrich A, Greiner G, Wolf V, Lovas A, Wieczorek M, Wagner T, Reichardt S et al (2010) Cross talk between stimulated NF-kappaB and the tumor suppressor p53. Oncogene 29(19):2795–2806. doi: 10.1038/onc.2010.46 PubMedCrossRefGoogle Scholar
  38. 38.
    Schumm K, Rocha S, Caamano J, Perkins ND (2006) Regulation of p53 tumour suppressor target gene expression by the p52 NF-kappaB subunit. EMBO J 25(20):4820–4832. doi: 10.1038/sj.emboj.7601343 PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Schafer T, Scheuer C, Roemer K, Menger MD, Vollmar B (2003) Inhibition of p53 protects liver tissue against endotoxin-induced apoptotic and necrotic cell death. FASEB J 17(6):660–667. doi: 10.1096/fj.02-0774com PubMedCrossRefGoogle Scholar
  40. 40.
    Armstrong MB, Bian X, Liu Y, Subramanian C, Ratanaproeksa AB, Shao F, Yu VC, Kwok RP et al (2006) Signaling from p53 to NF-kappaB determines the chemotherapy responsiveness of neuroblastoma. Neoplasia 8(11):967–977. doi: 10.1593/neo.06574 PubMedCrossRefGoogle Scholar
  41. 41.
    Taura M, Eguma A, Suico MA, Shuto T, Koga T, Komatsu K, Komune T, Sato T et al (2008) p53 regulates toll-like receptor 3 expression and function in human epithelial cell lines. Mol Cell Biol 28(21):6557–6567. doi: 10.1128/MCB.01202-08 PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Yamamoto M, Sato S, Hemmi H, Uematsu S, Hoshino K, Kaisho T, Takeuchi O, Takeda K et al (2003) TRAM is specifically involved in the toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol 4(11):1144–1150. doi: 10.1038/ni986 PubMedCrossRefGoogle Scholar
  43. 43.
    Fitzgerald KA, McWhirter SM, Faia KL, Rowe DC, Latz E, Golenbock DT, Coyle AJ, Liao SM et al (2003) IKKepsilon and TBK1 are essential components of the IRF3 signaling pathway. Nat Immunol 4(5):491–496. doi: 10.1038/ni921 PubMedCrossRefGoogle Scholar
  44. 44.
    Sarkar SN, Peters KL, Elco CP, Sakamoto S, Pal S, Sen GC (2004) Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling. Nat Struct Mol Biol 11(11):1060–1067. doi: 10.1038/nsmb847 PubMedCrossRefGoogle Scholar
  45. 45.
    Trotta T, Porro C, Calvello R, Panaro MA (2014) Biological role of toll-like receptor-4 in the brain. J Neuroimmunol 268(1–2):1–12. doi: 10.1016/j.jneuroim.2014.01.014 PubMedCrossRefGoogle Scholar
  46. 46.
    Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M et al (2003) Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301(5633):640–643. doi: 10.1126/science.1087262 PubMedCrossRefGoogle Scholar
  47. 47.
    Covert MW, Leung TH, Gaston JE, Baltimore D (2005) Achieving stability of lipopolysaccharide-induced NF-kappaB activation. Science 309(5742):1854–1857. doi: 10.1126/science.1112304 PubMedCrossRefGoogle Scholar
  48. 48.
    Barton GM, Kagan JC (2009) A cell biological view of toll-like receptor function: regulation through compartmentalization. Nat Rev Immunol 9(8):535–542. doi: 10.1038/nri2587 PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Chaturvedi A, Pierce SK (2009) How location governs toll-like receptor signaling. Traffic 10(6):621–628. doi: 10.1111/j.1600-0854.2009.00899.x PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Nogawa S, Forster C, Zhang F, Nagayama M, Ross ME, Iadecola C (1998) Interaction between inducible nitric oxide synthase and cyclooxygenase-2 after cerebral ischemia. Proc Natl Acad Sci U S A 95(18):10966–10971PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Zhu Y, Zhu M, Lance P (2012) iNOS signaling interacts with COX-2 pathway in colonic fibroblasts. Exp Cell Res 318(16):2116–2127. doi: 10.1016/j.yexcr.2012.05.027 PubMedCrossRefGoogle Scholar
  52. 52.
    Clancy R, Varenika B, Huang W, Ballou L, Attur M, Amin AR, Abramson SB (2000) Nitric oxide synthase/COX cross-talk: nitric oxide activates COX-1 but inhibits COX-2-derived prostaglandin production. J Immunol 165(3):1582–1587PubMedCrossRefGoogle Scholar
  53. 53.
    Lucas K, Maes M (2013) Role of the toll like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Mol Neurobiol 48(1):190–204. doi: 10.1007/s12035-013-8425-7 PubMedCrossRefGoogle Scholar
  54. 54.
    Lafon M, Megret F, Lafage M, Prehaud C (2006) The innate immune facet of brain: human neurons express TLR-3 and sense viral dsRNA. J Mol Neurosci: MN 29(3):185–194. doi: 10.1385/JMN:29:3:185 PubMedCrossRefGoogle Scholar
  55. 55.
    Cameron JS, Alexopoulou L, Sloane JA, DiBernardo AB, Ma Y, Kosaras B, Flavell R, Strittmatter SM et al (2007) Toll-like receptor 3 is a potent negative regulator of axonal growth in mammals. J Neurosci 27(47):13033–13041. doi: 10.1523/JNEUROSCI.4290-06.2007 PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Farina C, Krumbholz M, Giese T, Hartmann G, Aloisi F, Meinl E (2005) Preferential expression and function of toll-like receptor 3 in human astrocytes. J Neuroimmunol 159(1–2):12–19. doi: 10.1016/j.jneuroim.2004.09.009 PubMedCrossRefGoogle Scholar
  57. 57.
    Ma Y, Haynes RL, Sidman RL, Vartanian T (2007) TLR8: an innate immune receptor in brain, neurons and axons. Cell Cycle 6(23):2859–2868. doi: 10.4161/cc.6.23.5018 PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Tang SC, Arumugam TV, Xu X, Cheng A, Mughal MR, Jo DG, Lathia JD, Siler DA et al (2007) Pivotal role for neuronal toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci U S A 104(34):13798–13803. doi: 10.1073/pnas.0702553104 PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    van Noort JM, Bsibsi M (2009) Toll-like receptors in the CNS: implications for neurodegeneration and repair. Prog Brain Res 175:139–148. doi: 10.1016/S0079-6123(09)17509-X PubMedCrossRefGoogle Scholar
  60. 60.
    Olson JK, Miller SD (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol 173(6):3916–3924PubMedCrossRefGoogle Scholar
  61. 61.
    Farina C, Aloisi F, Meinl E (2007) Astrocytes are active players in cerebral innate immunity. Trends Immunol 28(3):138–145. doi: 10.1016/ PubMedCrossRefGoogle Scholar
  62. 62.
    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):242–255. doi: 10.1002/glia.21094 PubMedCrossRefGoogle Scholar
  63. 63.
    Berchtold NC, Cribbs DH, Coleman PD, Rogers J, Head E, Kim R, Beach T, Miller C et al (2008) Gene expression changes in the course of normal brain aging are sexually dimorphic. Proc Natl Acad Sci U S A 105(40):15605–15610. doi: 10.1073/pnas.0806883105 PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Thomson CA, McColl A, Cavanagh J, Graham GJ (2014) Peripheral inflammation is associated with remote global gene expression changes in the brain. J Neuroinflammation 11:73. doi: 10.1186/1742-2094-11-73 PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Scholtzova H, Kascsak RJ, Bates KA, Boutajangout A, Kerr DJ, Meeker HC, Mehta PD, Spinner DS et al (2009) Induction of toll-like receptor 9 signaling as a method for ameliorating Alzheimer’s disease-related pathology. J Neurosci 29(6):1846–1854. doi: 10.1523/JNEUROSCI.5715-08.2009 PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Bierhaus A, Humpert PM, Morcos M, Wendt T, Chavakis T, Arnold B, Stern DM, Nawroth PP (2005) Understanding RAGE, the receptor for advanced glycation end products. J Mol Med 83(11):876–886. doi: 10.1007/s00109-005-0688-7 PubMedCrossRefGoogle Scholar
  67. 67.
    Zong H, Ward M, Stitt AW (2011) AGEs, RAGE, and diabetic retinopathy. Curr Diabetes Rep 11(4):244–252. doi: 10.1007/s11892-011-0198-7 CrossRefGoogle Scholar
  68. 68.
    Ding Q, Keller JN (2005) Evaluation of rage isoforms, ligands, and signaling in the brain. Biochim Biophys Acta 1746(1):18–27. doi: 10.1016/j.bbamcr.2005.08.006 PubMedCrossRefGoogle Scholar
  69. 69.
    Xie J, Reverdatto S, Frolov A, Hoffmann R, Burz DS, Shekhtman A (2008) Structural basis for pattern recognition by the receptor for advanced glycation end products (RAGE). J Biol Chem 283(40):27255–27269. doi: 10.1074/jbc.M801622200 PubMedCrossRefGoogle Scholar
  70. 70.
    Chuah YK, Basir R, Talib H, Tie TH, Nordin N (2013) Receptor for advanced glycation end products and its involvement in inflammatory diseases. Int J Inflamm 2013:403460. doi: 10.1155/2013/403460 CrossRefGoogle Scholar
  71. 71.
    Kierdorf K, Fritz G (2013) RAGE regulation and signaling in inflammation and beyond. J Leukoc Biol 94(1):55–68. doi: 10.1189/jlb.1012519 PubMedCrossRefGoogle Scholar
  72. 72.
    Manigrasso MB, Pan J, Rai V, Zhang J, Reverdatto S, Quadri N, DeVita RJ, Ramasamy R et al (2016) Small molecule inhibition of ligand-stimulated RAGE-DIAPH1 signal transduction. Sci Rep 6:22450. doi: 10.1038/srep22450 PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Rai V, Maldonado AY, Burz DS, Reverdatto S, Yan SF, Schmidt AM, Shekhtman A (2012) Signal transduction in receptor for advanced glycation end products (RAGE): solution structure of C-terminal rage (ctRAGE) and its binding to mDia1. J Biol Chem 287(7):5133–5144. doi: 10.1074/jbc.M111.277731 PubMedCrossRefGoogle Scholar
  74. 74.
    Xu Y, Toure F, Qu W, Lin L, Song F, Shen X, Rosario R, Garcia J et al (2010) Advanced glycation end product (AGE)-receptor for AGE (RAGE) signaling and up-regulation of Egr-1 in hypoxic macrophages. J Biol Chem 285(30):23233–23240. doi: 10.1074/jbc.M110.117457 PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Yan SF, Ramasamy R, Schmidt AM (2010) Soluble RAGE: therapy and biomarker in unraveling the RAGE axis in chronic disease and aging. Biochem Pharmacol 79(10):1379–1386. doi: 10.1016/j.bcp.2010.01.013 PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Hudson BI, Kalea AZ, Del Mar AM, Harja E, Boulanger E, D’Agati V, Schmidt AM (2008) Interaction of the RAGE cytoplasmic domain with diaphanous-1 is required for ligand-stimulated cellular migration through activation of Rac1 and Cdc42. J Biol Chem 283(49):34457–34468. doi: 10.1074/jbc.M801465200 PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Fages C, Nolo R, Huttunen HJ, Eskelinen E, Rauvala H (2000) Regulation of cell migration by amphoterin. J Cell Sci 113(Pt 4):611–620PubMedGoogle Scholar
  78. 78.
    Lander HM, Tauras JM, Ogiste JS, Hori O, Moss RA, Schmidt AM (1997) Activation of the receptor for advanced glycation end products triggers a p21(ras)-dependent mitogen-activated protein kinase pathway regulated by oxidant stress. J Biol Chem 272(28):17810–17814PubMedCrossRefGoogle Scholar
  79. 79.
    Leclerc E, Fritz G, Weibel M, Heizmann CW, Galichet A (2007) S100B and S100A6 differentially modulate cell survival by interacting with distinct RAGE (receptor for advanced glycation end products) immunoglobulin domains. J Biol Chem 282(43):31317–31331. doi: 10.1074/jbc.M703951200 PubMedCrossRefGoogle Scholar
  80. 80.
    Taguchi A, Blood DC, del Toro G, Canet A, Lee DC, Qu W, Tanji N, Lu Y et al (2000) Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 405(6784):354–360. doi: 10.1038/35012626 PubMedCrossRefGoogle Scholar
  81. 81.
    Yeh CH, Sturgis L, Haidacher J, Zhang XN, Sherwood SJ, Bjercke RJ, Juhasz O, Crow MT et al (2001) Requirement for p38 and p44/p42 mitogen-activated protein kinases in RAGE-mediated nuclear factor-kappaB transcriptional activation and cytokine secretion. Diabetes 50(6):1495–1504PubMedCrossRefGoogle Scholar
  82. 82.
    Park SW, Kim JH, Park SM, Moon M, Lee KH, Park KH, Park WJ, Kim JH (2015) RAGE mediated intracellular Abeta uptake contributes to the breakdown of tight junction in retinal pigment epithelium. Oncotarget 6(34):35263–35273. doi: 10.18632/oncotarget.5894 PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G et al (2009) RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci U S A 106(47):20021–20026. doi: 10.1073/pnas.0905686106 PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Huttunen HJ, Fages C, Rauvala H (1999) Receptor for advanced glycation end products (RAGE)-mediated neurite outgrowth and activation of NF-kappaB require the cytoplasmic domain of the receptor but different downstream signaling pathways. J Biol Chem 274(28):19919–19924PubMedCrossRefGoogle Scholar
  85. 85.
    Bianchi R, Kastrisianaki E, Giambanco I, Donato R (2011) S100B protein stimulates microglia migration via RAGE-dependent up-regulation of chemokine expression and release. J Biol Chem 286(9):7214–7226. doi: 10.1074/jbc.M110.169342 PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Lin L, Park S, Lakatta EG (2009) RAGE signaling in inflammation and arterial aging. Front Biosci 14:1403–1413CrossRefGoogle Scholar
  87. 87.
    Riehl A, Nemeth J, Angel P, Hess J (2009) The receptor RAGE: bridging inflammation and cancer. Cell Commun Signal CCS 7:12. doi: 10.1186/1478-811X-7-12 PubMedCrossRefGoogle Scholar
  88. 88.
    Sims GP, Rowe DC, Rietdijk ST, Herbst R, Coyle AJ (2010) HMGB1 and RAGE in inflammation and cancer. Annu Rev Immunol 28:367–388. doi: 10.1146/annurev.immunol.021908.132603 PubMedCrossRefGoogle Scholar
  89. 89.
    Piras S, Furfaro AL, Domenicotti C, Traverso N, Marinari UM, Pronzato MA, Nitti M (2016) RAGE expression and ROS generation in neurons: differentiation versus damage. Oxidative Med Cell Longev 2016:9348651. doi: 10.1155/2016/9348651 CrossRefGoogle Scholar
  90. 90.
    Sorci G, Riuzzi F, Giambanco I, Donato R (2013) RAGE in tissue homeostasis, repair and regeneration. Biochim Biophys Acta 1833(1):101–109. doi: 10.1016/j.bbamcr.2012.10.021 PubMedCrossRefGoogle Scholar
  91. 91.
    Lue LF, Walker DG, Brachova L, Beach TG, Rogers J, Schmidt AM, Stern DM, Yan SD (2001) Involvement of microglial receptor for advanced glycation endproducts (RAGE) in Alzheimer’s disease: identification of a cellular activation mechanism. Exp Neurol 171(1):29–45. doi: 10.1006/exnr.2001.7732 PubMedCrossRefGoogle Scholar
  92. 92.
    Miller MC, Tavares R, Johanson CE, Hovanesian V, Donahue JE, Gonzalez L, Silverberg GD, Stopa EG (2008) Hippocampal RAGE immunoreactivity in early and advanced Alzheimer’s disease. Brain Res 1230:273–280. doi: 10.1016/j.brainres.2008.06.124 PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Sasaki N, Toki S, Chowei H, Saito T, Nakano N, Hayashi Y, Takeuchi M, Makita Z (2001) Immunohistochemical distribution of the receptor for advanced glycation end products in neurons and astrocytes in Alzheimer’s disease. Brain Res 888(2):256–262PubMedCrossRefGoogle Scholar
  94. 94.
    Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, Nagashima M, Lundh ER et al (1995) The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem 270(43):25752–25761PubMedCrossRefGoogle Scholar
  95. 95.
    Rong LL, Yan SF, Wendt T, Hans D, Pachydaki S, Bucciarelli LG, Adebayo A, Qu W et al (2004) RAGE modulates peripheral nerve regeneration via recruitment of both inflammatory and axonal outgrowth pathways. FASEB J 18(15):1818–1825. doi: 10.1096/fj.04-1900com PubMedCrossRefGoogle Scholar
  96. 96.
    Srikanth V, Maczurek A, Phan T, Steele M, Westcott B, Juskiw D, Munch G (2011) Advanced glycation endproducts and their receptor RAGE in Alzheimer’s disease. Neurobiol Aging 32(5):763–777. doi: 10.1016/j.neurobiolaging.2009.04.016 PubMedCrossRefGoogle Scholar
  97. 97.
    Takeuchi M, Yamagishi S (2008) Possible involvement of advanced glycation end-products (AGEs) in the pathogenesis of Alzheimer’s disease. Curr Pharm Des 14(10):973–978PubMedCrossRefGoogle Scholar
  98. 98.
    Vistoli G, De Maddis D, Cipak A, Zarkovic N, Carini M, Aldini G (2013) Advanced glycoxidation and lipoxidation end products (AGEs and ALEs): an overview of their mechanisms of formation. Free Radic Res 47(Suppl 1):3–27. doi: 10.3109/10715762.2013.815348 PubMedCrossRefGoogle Scholar
  99. 99.
    Choi BR, Cho WH, Kim J, Lee HJ, Chung C, Jeon WK, Han JS (2014) Increased expression of the receptor for advanced glycation end products in neurons and astrocytes in a triple transgenic mouse model of Alzheimer’s disease. Exp Mol Med 46:e75. doi: 10.1038/emm.2013.147 PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Donahue JE, Flaherty SL, Johanson CE, Duncan JA 3rd, Silverberg GD, Miller MC, Tavares R, Yang W et al (2006) RAGE, LRP-1, and amyloid-beta protein in Alzheimer’s disease. Acta Neuropathol 112(4):405–415. doi: 10.1007/s00401-006-0115-3 PubMedCrossRefGoogle Scholar
  101. 101.
    Girones X, Guimera A, Cruz-Sanchez CZ, Ortega A, Sasaki N, Makita Z, Lafuente JV, Kalaria R et al (2004) N epsilon-carboxymethyllysine in brain aging, diabetes mellitus, and Alzheimer’s disease. Free Radic Biol Med 36(10):1241–1247. doi: 10.1016/j.freeradbiomed.2004.02.006 PubMedCrossRefGoogle Scholar
  102. 102.
    Vazzana N, Santilli F, Cuccurullo C, Davi G (2009) Soluble forms of RAGE in internal medicine. Intern Emerg Med 4(5):389–401. doi: 10.1007/s11739-009-0300-1 PubMedCrossRefGoogle Scholar
  103. 103.
    Qin J, Goswami R, Dawson S, Dawson G (2008) Expression of the receptor for advanced glycation end products in oligodendrocytes in response to oxidative stress. J Neurosci Res 86(11):2414–2422. doi: 10.1002/jnr.21692 PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Emanuele E, D’Angelo A, Tomaino C, Binetti G, Ghidoni R, Politi P, Bernardi L, Maletta R et al (2005) Circulating levels of soluble receptor for advanced glycation end products in Alzheimer disease and vascular dementia. Arch Neurol 62(11):1734–1736. doi: 10.1001/archneur.62.11.1734 PubMedCrossRefGoogle Scholar
  105. 105.
    Chen X, Walker DG, Schmidt AM, Arancio O, Lue LF, Yan SD (2007) RAGE: a potential target for abeta-mediated cellular perturbation in Alzheimer’s disease. Curr Mol Med 7(8):735–742PubMedCrossRefGoogle Scholar
  106. 106.
    Schmidt AM, Sahagan B, Nelson RB, Selmer J, Rothlein R, Bell JM (2009) The role of RAGE in amyloid-beta peptide-mediated pathology in Alzheimer’s disease. Curr Opin Investig Drugs 10(7):672–680PubMedGoogle Scholar
  107. 107.
    Yan SS, Chen D, Yan S, Guo L, Du H, Chen JX (2012) RAGE is a key cellular target for Abeta-induced perturbation in Alzheimer’s disease. Front Biosci (Schol Ed) 4:240–250CrossRefGoogle Scholar
  108. 108.
    Li XH, Lv BL, Xie JZ, Liu J, Zhou XW, Wang JZ (2012) AGEs induce Alzheimer-like tau pathology and memory deficit via RAGE-mediated GSK-3 activation. Neurobiol Aging 33(7):1400–1410. doi: 10.1016/j.neurobiolaging.2011.02.003 PubMedCrossRefGoogle Scholar
  109. 109.
    Xie J, Mendez JD, Mendez-Valenzuela V, Aguilar-Hernandez MM (2013) Cellular signalling of the receptor for advanced glycation end products (RAGE). Cell Signal 25(11):2185–2197. doi: 10.1016/j.cellsig.2013.06.013 PubMedCrossRefGoogle Scholar
  110. 110.
    Cai Z, Liu N, Wang C, Qin B, Zhou Y, Xiao M, Chang L, Yan LJ et al (2016) Role of RAGE in Alzheimer’s disease. Cell Mol Neurobiol 36(4):483–495. doi: 10.1007/s10571-015-0233-3 PubMedCrossRefGoogle Scholar
  111. 111.
    Villarreal A, Seoane R, Gonzalez Torres A, Rosciszewski G, Angelo MF, Rossi A, Barker PA, Ramos AJ (2014) S100B protein activates a RAGE-dependent autocrine loop in astrocytes: implications for its role in the propagation of reactive gliosis. J Neurochem 131(2):190–205. doi: 10.1111/jnc.12790 PubMedCrossRefGoogle Scholar
  112. 112.
    Guglielmotto M, Aragno M, Tamagno E, Vercellinatto I, Visentin S, Medana C, Catalano MG, Smith MA et al (2012) AGEs/RAGE complex upregulates BACE1 via NF-kappaB pathway activation. Neurobiol Aging 33(1):196 e113–196 e127. doi: 10.1016/j.neurobiolaging.2010.05.026 CrossRefGoogle Scholar
  113. 113.
    Sakaguchi M, Murata H, Yamamoto K, Ono T, Sakaguchi Y, Motoyama A, Hibino T, Kataoka K et al (2011) TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding. PLoS One 6(8):e23132. doi: 10.1371/journal.pone.0023132 PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Ishihara K, Tsutsumi K, Kawane S, Nakajima M, Kasaoka T (2003) The receptor for advanced glycation end-products (RAGE) directly binds to ERK by a D-domain-like docking site. FEBS Lett 550(1–3):107–113PubMedCrossRefGoogle Scholar
  115. 115.
    Ibrahim ZA, Armour CL, Phipps S, Sukkar MB (2013) RAGE and TLRs: relatives, friends or neighbours? Mol Immunol 56(4):739–744. doi: 10.1016/j.molimm.2013.07.008 PubMedCrossRefGoogle Scholar
  116. 116.
    van Beijnum JR, Buurman WA, Griffioen AW (2008) Convergence and amplification of toll-like receptor (TLR) and receptor for advanced glycation end products (RAGE) signaling pathways via high mobility group B1 (HMGB1). Angiogenesis 11(1):91–99. doi: 10.1007/s10456-008-9093-5 PubMedCrossRefGoogle Scholar
  117. 117.
    Yamamoto Y, Yamamoto H (2013) RAGE-mediated inflammation, type 2 diabetes, and diabetic vascular complication. Front Endocrinol 4:105. doi: 10.3389/fendo.2013.00105 CrossRefGoogle Scholar
  118. 118.
    Kubo-Murai M, Hazeki K, Sukenobu N, Yoshikawa K, Nigorikawa K, Inoue K, Yamamoto T, Matsumoto M et al (2007) Protein kinase Cdelta binds TIRAP/Mal to participate in TLR signaling. Mol Immunol 44(9):2257–2264. doi: 10.1016/j.molimm.2006.11.005 PubMedCrossRefGoogle Scholar
  119. 119.
    Loegering DJ, Lennartz MR (2011) Protein kinase C and toll-like receptor signaling. Enzyme Res 2011:537821. doi: 10.4061/2011/537821 PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Shen Y, Kawamura I, Nomura T, Tsuchiya K, Hara H, Dewamitta SR, Sakai S, Qu H et al (2010) Toll-like receptor 2- and MyD88-dependent phosphatidylinositol 3-kinase and Rac1 activation facilitates the phagocytosis of Listeria monocytogenes by murine macrophages. Infect Immun 78(6):2857–2867. doi: 10.1128/IAI.01138-09 PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    Fan H, Sun B, Gu Q, Lafond-Walker A, Cao S, Becker LC (2002) Oxygen radicals trigger activation of NF-kappaB and AP-1 and upregulation of ICAM-1 in reperfused canine heart. Am J Phys Heart Circ Phys 282(5):H1778–H1786. doi: 10.1152/ajpheart.00796.2000 Google Scholar
  122. 122.
    Karin M, Takahashi T, Kapahi P, Delhase M, Chen Y, Makris C, Rothwarf D, Baud V et al (2001) Oxidative stress and gene expression: the AP-1 and NF-kappaB connections. Bio Factors 15(2–4):87–89Google Scholar
  123. 123.
    Shihab PK, Al-Roub A, Al-Ghanim M, Al-Mass A, Behbehani K, Ahmad R (2015) TLR2 and AP-1/NF-kappaB are involved in the regulation of MMP-9 elicited by heat killed Listeria monocytogenes in human monocytic THP-1 cells. J Inflamm 12:32. doi: 10.1186/s12950-015-0077-0 CrossRefGoogle Scholar
  124. 124.
    West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, Walsh MC, Choi Y et al (2011) TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 472(7344):476–480. doi: 10.1038/nature09973 PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Dekker LV, Leitges M, Altschuler G, Mistry N, McDermott A, Roes J, Segal AW (2000) Protein kinase C-beta contributes to NADPH oxidase activation in neutrophils. Biochem J 347(Pt 1):285–289PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Kazimierz Gąsiorowski
    • 1
  • Barbara Brokos
    • 1
  • Valentina Echeverria
    • 2
  • George E. Barreto
    • 3
    • 4
  • Jerzy Leszek
    • 5
    Email author
  1. 1.Department of Basic Medical SciencesWrocław Medical UniversityWrocławPoland
  2. 2.Facultad de Ciencias de la SaludUniversidad San SebastiánConcepciónChile
  3. 3.Departamento de Nutrición y Bioquímica, Facultad de CienciasPontificia Universidad JaverianaBogotá D.C.Colombia
  4. 4.Instituto de Ciencias Biomédicas, Universidad Autónoma de ChileSantiagoChile
  5. 5.Clinic of PsychiatryWrocław Medical UniversityWrocławPoland

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