Skip to main content
SpringerLink
Log in

Receptor for Advanced Glycation End Products (RAGE) in Type 1 Diabetes Pathogenesis

  • Pathogenesis of Type 1 Diabetes (A Pugliese, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

The receptor for advanced glycation end products (RAGE) is a novel protein increasingly studied in the pathogenesis of type 1 diabetes (T1D). RAGE is expressed by several immune cell types, including T cells, antigen-presenting cells, endothelial cells, and the endocrine cells of the pancreatic islets. RAGE binds various ligands including advanced glycation end products (AGEs), high-mobility group box protein 1 (HMGB1), S100 proteins, β-amyloid, β-sheet fibrils, and lipopolysaccharide. AGEs are a particularly interesting ligand because their exogenous introduction into the body can be accelerated by the consumption of AGE-rich processed foods. This review will detail RAGE isoforms and its ligands and discuss how RAGE binding on the aforementioned cells could be linked to T1D pathogenesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Vissing H, Aagaard L, Tommerup N, Boel E. Localization of the human gene for advanced glycosylation end product-specific receptor (AGER) to chromosome 6p21.3. Genomics. 1994;24:606–8.

    Article  CAS  PubMed  Google Scholar 

  2. Forbes JM, Soderlund J, Yap FY, Knip M, Andrikopoulos S, Ilonen J, et al. Receptor for advanced glycation end-products (RAGE) provides a link between genetic susceptibility and environmental factors in type 1 diabetes. Diabetologia. 2011;54:1032–42.

    Article  CAS  PubMed  Google Scholar 

  3. Fritz G. RAGE: a single receptor fits multiple ligands. Trends Biochem Sci. 2011;36:625–32.

    Article  CAS  PubMed  Google Scholar 

  4. Xue J, Rai V, Singer D, Chabierski S, Xie J, Reverdatto S, et al. Advanced glycation end product recognition by the receptor for AGEs. Structure. 2011;19:722–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, et al. 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. 1995;270:25752–61.

    Article  CAS  PubMed  Google Scholar 

  6. Yamamoto Y, Harashima A, Saito H, Tsuneyama K, Munesue S, Motoyoshi S, et al. Septic shock is associated with receptor for advanced glycation end products ligation of LPS. J Immunol. 2011;186:3248–57.

    Article  CAS  PubMed  Google Scholar 

  7. L. Wang, T. Chen, J. Wu, and Q. Huang. Lipopolysaccharide-induced inflammation is associated with receptor for advanced glycation end products in human endothelial cells (1096.5). FASEB J. 28. 2014.

  8. Hofmann MA, Drury S, Fu C, Qu W, Taguchi A, Lu Y, et al. RAGE mediates a novel proinflammatory axis: a central cell surface receptor for S100/calgranulin polypeptides. Cell. 1999;97:889–901.

    Article  CAS  PubMed  Google Scholar 

  9. Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, et al. RAGE and amyloid-beta peptide neurotoxicity in Alzheimer’s disease. Nature. 1996;382:685–91.

    Article  CAS  PubMed  Google Scholar 

  10. Wilton R, Yousef MA, Saxena P, Szpunar M, Stevens FJ. Expression and purification of recombinant human receptor for advanced glycation endproducts in Escherichia coli. Protein Expr Purif. 2006;47:25–35.

    Article  CAS  PubMed  Google Scholar 

  11. Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014;383:69–82.

    Article  PubMed  Google Scholar 

  12. International Diabetes Federation. IDF diabetes atlas. 7th ed. Brussels: International Diabetes Federation; 2015.

    Google Scholar 

  13. Todd JA, Bell JI, McDevitt HO. HLA-DQ beta gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature. 1987;329:599–604.

    Article  CAS  PubMed  Google Scholar 

  14. Lucassen AM, Julier C, Beressi JP, Boitard C, Froguel P, Lathrop M, et al. Susceptibility to insulin dependent diabetes mellitus maps to a 4.1 kb segment of DNA spanning the insulin gene and associated VNTR. Nat Genet. 1993;4:305–10.

    Article  CAS  PubMed  Google Scholar 

  15. Polychronakos C, Li Q. Understanding type 1 diabetes through genetics: advances and prospects. Nat Rev Genet. 2011;12:781–92.

    Article  CAS  PubMed  Google Scholar 

  16. Bakay M, Pandey R, Hakonarson H. Genes involved in type 1 diabetes: an update. Genes (Basel). 2013;4:499–521.

    Google Scholar 

  17. Tishkoff SA, Verrelli BC. Patterns of human genetic diversity: implications for human evolutionary history and disease. Annu Rev Genomics Hum Genet. 2003;4:293–340.

    Article  CAS  PubMed  Google Scholar 

  18. Eisenbarth GS. Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med. 1986;314:1360–8.

    Article  CAS  PubMed  Google Scholar 

  19. Virk J, Li J, Vestergaard M, Obel C, Lu M, Olsen J. Early life disease programming during the preconception and prenatal period: making the link between stressful life events and type-1 diabetes. PLoS One. 2010;5, e11523.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Podar T, Solntsev A, Karvonen M, Padaiga Z, Brigis G, Urbonaite B, et al. Increasing incidence of childhood-onset type I diabetes in 3 Baltic countries and Finland 1983-1998. Diabetologia. 2001;44 Suppl 3:B17–20.

    Article  PubMed  Google Scholar 

  21. W.-P. You and M. Henneberg, Type 1 diabetes prevalence increasing globally and regionally: the role of natural selection and life expectancy at birth. BMJ Open Diabetes Research & Care. 4. 2016.

  22. Oikarinen S, Martiskainen M, Tauriainen S, Huhtala H, Ilonen J, Veijola R, et al. Enterovirus RNA in blood is linked to the development of type 1 diabetes. Diabetes. 2011;60:276–9.

    Article  CAS  PubMed  Google Scholar 

  23. Lonnrot M, Korpela K, Knip M, Ilonen J, Simell O, Korhonen S, et al. Enterovirus infection as a risk factor for beta-cell autoimmunity in a prospectively observed birth cohort: the Finnish Diabetes Prediction and Prevention Study. Diabetes. 2000;49:1314–8.

    Article  CAS  PubMed  Google Scholar 

  24. Chehadeh W, Kerr-Conte J, Pattou F, Alm G, Lefebvre J, Wattre P, et al. Persistent infection of human pancreatic islets by coxsackievirus B is associated with alpha interferon synthesis in beta cells. J Virol. 2000;74:10153–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Horwitz MS, Bradley LM, Harbertson J, Krahl T, Lee J, Sarvetnick N. Diabetes induced by Coxsackie virus: initiation by bystander damage and not molecular mimicry. Nat Med. 1998;4:781–5.

    Article  CAS  PubMed  Google Scholar 

  26. Akerblom HK, Virtanen SM, Ilonen J, Savilahti E, Vaarala O, Reunanen A, et al. Dietary manipulation of beta cell autoimmunity in infants at increased risk of type 1 diabetes: a pilot study. Diabetologia. 2005;48:829–37.

    Article  CAS  PubMed  Google Scholar 

  27. Knip M, Akerblom HK, Becker D, Dosch HM, Dupre J, Fraser W, et al. Hydrolyzed infant formula and early beta-cell autoimmunity: a randomized clinical trial. JAMA. 2014;311:2279–87.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Dong JY, Zhang WG, Chen JJ, Zhang ZL, Han SF, Qin LQ. Vitamin D intake and risk of type 1 diabetes: a meta-analysis of observational studies. Nutrients. 2013;5:3551–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Martin T, Campbell RK. Vitamin D and diabetes. Diabetes Spectrum. 2011;24:113–8.

    Article  Google Scholar 

  30. Norris JM, Yin X, Lamb MM, Barriga K, Seifert J, Hoffman M, et al. Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes. JAMA. 2007;298:1420–8.

    Article  CAS  PubMed  Google Scholar 

  31. Hindmarsh PC, Matthews DR, Di Silvio L, Kurtz AB, Brook CG. Relation between height velocity and fasting insulin concentrations. Arch Dis Child. 1988;63:665–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hypponen E, Kenward MG, Virtanen SM, Piitulainen A, Virta-Autio P, Tuomilehto J, et al. Infant feeding, early weight gain, and risk of type 1 diabetes. Childhood Diabetes in Finland (DiMe) Study Group. Diabetes Care. 1999;22:1961–5.

    Article  CAS  PubMed  Google Scholar 

  33. Murri M, Leiva I, Gomez-Zumaquero JM, Tinahones FJ, Cardona F, Soriguer F, et al. Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. BMC Med. 2013;11:46.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Brown CT, Davis-Richardson AG, Giongo A, Gano KA, Crabb DB, Mukherjee N, et al. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS One. 2011;6, e25792.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Akirav EM, Preston-Hurlburt P, Garyu J, Henegariu O, Clynes R, Schmidt AM, et al. RAGE expression in human T cells: a link between environmental factors and adaptive immune responses. PLoS One. 2012;7, e34698.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Han XQ, Gong ZJ, Xu SQ, Li X, Wang LK, Wu SM, et al. Advanced glycation end products promote differentiation of CD4(+) T helper cells toward pro-inflammatory response. J Huazhong Univ Sci Technol Med Sci. 2014;34:10–7.

    Article  CAS  PubMed  Google Scholar 

  37. Wild CA, Bergmann C, Fritz G, Schuler P, Hoffmann TK, Lotfi R, et al. HMGB1 conveys immunosuppressive characteristics on regulatory and conventional T cells. Int Immunol. 2012;24:485–94.

    Article  CAS  PubMed  Google Scholar 

  38. Moser B, Janik S, Schiefer AI, Mullauer L, Bekos C, Scharrer A, et al. Expression of RAGE and HMGB1 in thymic epithelial tumors, thymic hyperplasia and regular thymic morphology. PLoS One. 2014;9, e94118.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Pellat-Deceunynck C, Mellerin MP, Labarriere N, Jego G, Moreau-Aubry A, Harousseau JL, et al. The cancer germ-line genes MAGE-1, MAGE-3 and PRAME are commonly expressed by human myeloma cells. Eur J Immunol. 2000;30:803–9.

    Article  CAS  PubMed  Google Scholar 

  40. Hama S, Takeichi O, Saito I, Ito K. Involvement of inducible nitric oxide synthase and receptor for advanced glycation end products in periapical granulomas. J Endod. 2007;33:137–41.

    Article  PubMed  Google Scholar 

  41. Miura J, Uchigata Y, Yamamoto Y, Takeuchi M, Sakurai S, Watanabe T, et al. AGE down-regulation of monocyte RAGE expression and its association with diabetic complications in type 1 diabetes. J Diabetes Complicat. 2004;18:53–9.

    Article  PubMed  Google Scholar 

  42. Z. Li, M. J. Scott, E. K. Fan, Y. Li, J. Liu, G. Xiao, et al.. Tissue damage negatively regulates LPS-induced macrophage necroptosis. Cell Death Differ. 2016.

  43. Dumitriu IE, Baruah P, Valentinis B, Voll RE, Herrmann M, Nawroth PP, et al. Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products. J Immunol. 2005;174:7506–15.

    Article  CAS  PubMed  Google Scholar 

  44. Buttari B, Profumo E, Facchiano F, Ozturk EI, Segoni L, Saso L, et al. Resveratrol prevents dendritic cell maturation in response to advanced glycation end products. Oxid Med Cell Longev. 2013;2013:574029.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Dumitriu IE, Baruah P, Bianchi ME, Manfredi AA, Rovere-Querini P. Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells. Eur J Immunol. 2005;35:2184–90.

    Article  CAS  PubMed  Google Scholar 

  46. Parodi M, Pedrazzi M, Cantoni C, Averna M, Patrone M, Cavaletto M, et al. Natural killer (NK)/melanoma cell interaction induces NK-mediated release of chemotactic High Mobility Group Box-1 (HMGB1) capable of amplifying NK cell recruitment. Oncoimmunology. 2015;4, e1052353.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Moser B, Desai DD, Downie MP, Chen Y, Yan SF, Herold K, et al. Receptor for advanced glycation end products expression on T cells contributes to antigen-specific cellular expansion in vivo. J Immunol. 2007;179:8051–8.

    Article  CAS  PubMed  Google Scholar 

  48. Loser K, Vogl T, Voskort M, Lueken A, Kupas V, Nacken W, et al. The Toll-like receptor 4 ligands Mrp8 and Mrp14 are crucial in the development of autoreactive CD8+ T cells. Nat Med. 2010;16:713–7.

    Article  CAS  PubMed  Google Scholar 

  49. Chen Y, Akirav EM, Chen W, Henegariu O, Moser B, Desai D, et al. RAGE ligation affects T cell activation and controls T cell differentiation. J Immunol. 2008;181:4272–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Matsuoka N, Itoh T, Watarai H, Sekine-Kondo E, Nagata N, Okamoto K, et al. High-mobility group box 1 is involved in the initial events of early loss of transplanted islets in mice. J Clin Invest. 2010;120:735–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Koyama M, Cheong M, Markey KA, Gartlan KH, Kuns RD, Locke KR, et al. Donor colonic CD103+ dendritic cells determine the severity of acute graft-versus-host disease. J Exp Med. 2015;212:1303–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Narumi K, Miyakawa R, Ueda R, Hashimoto H, Yamamoto Y, Yoshida T, et al. Proinflammatory proteins S100A8/S100A9 activate NK cells via interaction with RAGE. J Immunol. 2015;194:5539–48.

    Article  CAS  PubMed  Google Scholar 

  53. Xu Y, Zhan Y, Lew AM, Naik SH, Kershaw MH. Differential development of murine dendritic cells by GM-CSF versus Flt3 ligand has implications for inflammation and trafficking. J Immunol. 2007;179:7577–84.

    Article  CAS  PubMed  Google Scholar 

  54. Yonekura H, Yamamoto Y, Sakurai S, Petrova RG, Abedin MJ, Li H, et al. Novel splice variants of the receptor for advanced glycation end-products expressed in human vascular endothelial cells and pericytes, and their putative roles in diabetes-induced vascular injury. Biochem J. 2003;370:1097–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Basta G, Lazzerini G, Massaro M, Simoncini T, Tanganelli P, Fu C, et al. Advanced glycation end products activate endothelium through signal-transduction receptor RAGE: a mechanism for amplification of inflammatory responses. Circulation. 2002;105:816–22.

    Article  CAS  PubMed  Google Scholar 

  56. Guzman-Ruiz R, Ortega F, Rodriguez A, Vazquez-Martinez R, Diaz-Ruiz A, Garcia-Navarro S, et al. Alarmin high-mobility group B1 (HMGB1) is regulated in human adipocytes in insulin resistance and influences insulin secretion in beta-cells. Int J Obes (Lond). 2014;38:1545–54.

    Article  CAS  Google Scholar 

  57. Han D, Yamamoto Y, Munesue S, Motoyoshi S, Saito H, Win MT, et al. Induction of receptor for advanced glycation end products by insufficient leptin action triggers pancreatic beta-cell failure in type 2 diabetes. Genes Cells. 2013;18:302–14.

    Article  CAS  PubMed  Google Scholar 

  58. Zhu Y, Shu T, Lin Y, Wang H, Yang J, Shi Y, et al. Inhibition of the receptor for advanced glycation endproducts (RAGE) protects pancreatic beta-cells. Biochem Biophys Res Commun. 2011;404:159–65.

    Article  CAS  PubMed  Google Scholar 

  59. Kaji Y, Usui T, Ishida S, Yamashiro K, Moore TC, Moore J, et al. Inhibition of diabetic leukostasis and blood-retinal barrier breakdown with a soluble form of a receptor for advanced glycation end products. Invest Ophthalmol Vis Sci. 2007;48:858–65.

    Article  PubMed  Google Scholar 

  60. Sun L, Sun C, Liang Z, Li H, Chen L, Luo H, et al. FSP1(+) fibroblast subpopulation is essential for the maintenance and regeneration of medullary thymic epithelial cells. Sci Rep. 2015;5:14871.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Buckman LB, Anderson-Baucum EK, Hasty AH, Ellacott K. Regulation of S100B in white adipose tissue by obesity in mice. Adipocyte. 2014;3:215–20.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Lander HM, Tauras JM, Ogiste JS, Hori O, Moss RA, Schmidt AM. 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. 1997;272:17810–4.

    Article  CAS  PubMed  Google Scholar 

  63. Li J, Schmidt AM. Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products. J Biol Chem. 1997;272:16498–506.

    Article  CAS  PubMed  Google Scholar 

  64. Yan SD, Schmidt AM, Anderson GM, Zhang J, Brett J, Zou YS, et al. Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins. J Biol Chem. 1994;269:9889–97.

    CAS  PubMed  Google Scholar 

  65. Harja E, Bu DX, Hudson BI, Chang JS, Shen X, Hallam K, et al. Vascular and inflammatory stresses mediate atherosclerosis via RAGE and its ligands in apoE−/− mice. J Clin Invest. 2008;118:183–94.

    Article  CAS  PubMed  Google Scholar 

  66. Guh JY, Huang JS, Chen HC, Hung WC, Lai YH, Chuang LY. Advanced glycation end product-induced proliferation in NRK-49F cells is dependent on the JAK2/STAT5 pathway and cyclin D1. Am J Kidney Dis. 2001;38:1096–104.

    Article  CAS  PubMed  Google Scholar 

  67. Hudson BI, Carter AM, Harja E, Kalea AZ, Arriero M, Yang H, et al. Identification, classification, and expression of RAGE gene splice variants. FASEB J. 2008;22:1572–80.

    Article  CAS  PubMed  Google Scholar 

  68. Kalea AZ, Reiniger N, Yang H, Arriero M, Schmidt AM, Hudson BI. Alternative splicing of the murine receptor for advanced glycation end-products (RAGE) gene. FASEB J. 2009;23:1766–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Cheng A, Dong Y, Zhu F, Liu Y, Hou FF, Nie J. AGE-LDL activates Toll like receptor 4 pathway and promotes inflammatory cytokines production in renal tubular epithelial cells. Int J Biol Sci. 2013;9:94–107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Araki N, Higashi T, Mori T, Shibayama R, Kawabe Y, Kodama T, et al. Macrophage scavenger receptor mediates the endocytic uptake and degradation of advanced glycation end products of the Maillard reaction. Eur J Biochem. 1995;230:408–15.

    Article  CAS  PubMed  Google Scholar 

  71. Ohgami N, Nagai R, Ikemoto M, Arai H, Kuniyasu A, Horiuchi S, et al. Cd36, a member of the class b scavenger receptor family, as a receptor for advanced glycation end products. J Biol Chem. 2001;276:3195–202.

    Article  CAS  PubMed  Google Scholar 

  72. Pullerits R, Brisslert M, Jonsson IM, Tarkowski A. Soluble receptor for advanced glycation end products triggers a proinflammatory cytokine cascade via beta2 integrin Mac-1. Arthritis Rheum. 2006;54:3898–907.

    Article  CAS  PubMed  Google Scholar 

  73. Salonen KM, Ryhanen SJ, Forbes JM, Harkonen T, Ilonen J, Laine AP, et al. Circulating concentrations of soluble receptor for AGE are associated with age and AGER gene polymorphisms in children with newly diagnosed type 1 diabetes. Diabetes Care. 2014;37:1975–81. This was the first study to demonstrate that a RAGE isoform associated with progression towards overt type 1 diabetes.

    Article  CAS  PubMed  Google Scholar 

  74. Salonen KM, Ryhanen SJ, Forbes JM, Borg DJ, Harkonen T, Ilonen J, et al. Decrease in circulating concentrations of soluble receptors for advanced glycation end products at the time of seroconversion to autoantibody positivity in children with prediabetes. Diabetes Care. 2015;38:665–70.

    CAS  PubMed  Google Scholar 

  75. Koschinsky T, He CJ, Mitsuhashi T, Bucala R, Liu C, Buenting C, et al. Orally absorbed reactive glycation products (glycotoxins): an environmental risk factor in diabetic nephropathy. Proc Natl Acad Sci U S A. 1997;94:6474–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Singh R, Barden A, Mori T, Beilin L. Advanced glycation end-products: a review. Diabetologia. 2001;44:129–46.

    Article  CAS  PubMed  Google Scholar 

  77. Poulsen MW, Hedegaard RV, Andersen JM, de Courten B, Bügel S, Nielsen J, et al. Advanced glycation endproducts in food and their effects on health. Food Chem Toxicol. 2013;60:10–37.

    Article  CAS  PubMed  Google Scholar 

  78. Beyan H, Riese H, Hawa MI, Beretta G, Davidson HW, Hutton JC, et al. Glycotoxin and autoantibodies are additive environmentally determined predictors of type 1 diabetes: a twin and population study. Diabetes. 2012;61:1192–8. This was the first study to demonstrate that RAGE ligands, AGEs, acted as independent predictors for type 1 diabetes progression in ICA+ children.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Barat P, Cammas B, Lacoste A, Harambat J, Vautier V, Nacka F, et al. Advanced glycation end products in children with type 1 diabetes: family matters? Diabetes Care. 2012;35:e1.

    Article  PubMed  Google Scholar 

  80. Mericq V, Piccardo C, Cai W, Chen X, Zhu L, Striker GE, et al. Maternally transmitted and food-derived glycotoxins: a factor preconditioning the young to diabetes? Diabetes Care. 2010;33:2232–7.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Coughlan MT, Yap FY, Tong DC, Andrikopoulos S, Gasser A, Thallas-Bonke V, et al. Advanced glycation end products are direct modulators of beta-cell function. Diabetes. 2011;60:2523–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Peppa M, He C, Hattori M, McEvoy R, Zheng F, Vlassara H. Fetal or neonatal low-glycotoxin environment prevents autoimmune diabetes in NOD mice. Diabetes. 2003;52:1441–8.

    Article  CAS  PubMed  Google Scholar 

  83. Leslie RD, Beyan H, Sawtell P, Boehm BO, Spector TD, Snieder H. Level of an advanced glycated end product is genetically determined: a study of normal twins. Diabetes. 2003;52:2441–4.

    Article  CAS  PubMed  Google Scholar 

  84. Jaisson S, Gillery P. Evaluation of nonenzymatic posttranslational modification-derived products as biomarkers of molecular aging of proteins. Clin Chem. 2010;56:1401–12.

    Article  PubMed  Google Scholar 

  85. Doyle HA, Mamula MJ. Post-translational protein modifications in antigen recognition and autoimmunity. Trends Immunol. 2001;22:443–9.

    Article  CAS  PubMed  Google Scholar 

  86. Delong T, Wiles TA, Baker RL, Bradley B, Barbour G, Reisdorph R, et al. Pathogenic CD4 T cells in type 1 diabetes recognize epitopes formed by peptide fusion. Science. 2016;351:711–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. van Lummel M, Duinkerken G, van Veelen PA, de Ru A, Cordfunke R, Zaldumbide A, et al. Posttranslational modification of HLA-DQ binding islet autoantigens in type 1 diabetes. Diabetes. 2014;63:237–47.

    Article  PubMed  CAS  Google Scholar 

  88. McLaughlin RJ, Spindler MP, van Lummel M, Roep BO. Where, how, and when: positioning posttranslational modification within type 1 diabetes pathogenesis. Curr Diabetes Rep. 2016;16:1–9.

    Article  CAS  Google Scholar 

  89. Abdel-Wahab YH, O’Harte FP, Boyd AC, Barnett CR, Flatt PR. Glycation of insulin results in reduced biological activity in mice. Acta Diabetol. 1997;34:265–70.

    Article  CAS  PubMed  Google Scholar 

  90. Abdel-Wahab YH, O’Harte FP, Ratcliff H, McClenaghan NH, Barnett CR, Flatt PR. Glycation of insulin in the islets of Langerhans of normal and diabetic animals. Diabetes. 1996;45:1489–96.

    Article  CAS  PubMed  Google Scholar 

  91. Hunter SJ, Boyd AC, O’Harte FP, McKillop AM, Wiggam MI, Mooney MH, et al. Demonstration of glycated insulin in human diabetic plasma and decreased biological activity assessed by euglycemic-hyperinsulinemic clamp technique in humans. Diabetes. 2003;52:492–8.

    Article  CAS  PubMed  Google Scholar 

  92. Oliveira LM, Lages A, Gomes RA, Neves H, Familia C, Coelho AV, et al. Insulin glycation by methylglyoxal results in native-like aggregation and inhibition of fibril formation. BMC Biochem. 2011;12:41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Vay D, Vidali M, Allochis G, Cusaro C, Rolla R, Mottaran E, et al. Antibodies against advanced glycation end product Nepsilon-(carboxymethyl)lysine in healthy controls and diabetic patients. Diabetologia. 2000;43:1385–8.

    Article  CAS  PubMed  Google Scholar 

  94. Turk Z, Ljubic S, Turk N, Benko B. Detection of autoantibodies against advanced glycation endproducts and AGE-immune complexes in serum of patients with diabetes mellitus. Clin Chim Acta. 2001;303:105–15.

    Article  CAS  PubMed  Google Scholar 

  95. Ahmad S, Moinuddin, Shahab U, Habib S, Salman Khan M, Alam K, et al. Glycoxidative damage to human DNA: neo-antigenic epitopes on DNA molecule could be a possible reason for autoimmune response in type 1 diabetes. Glycobiology. 2014;24:281–91.

    Article  CAS  PubMed  Google Scholar 

  96. Mir AR, Moinuddin. Glycoxidation of histone proteins in autoimmune disorders. Clin Chim Acta. 2015;450:25–30.

    Article  CAS  PubMed  Google Scholar 

  97. Chikazawa M, Otaki N, Shibata T, Miyashita H, Kawai Y, Maruyama S, et al. Multispecificity of immunoglobulin M antibodies raised against advanced glycation end products: involvement of electronegative potential of antigens. J Biol Chem. 2013;288:13204–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Ligier S, Fortin PR, Newkirk MM. A new antibody in rheumatoid arthritis targeting glycated IgG: IgM anti-IgG-AGE. Rheumatology. 1998;37:1307–14.

    Article  CAS  Google Scholar 

  99. Goodwin GH, Sanders C, Johns EW. A new group of chromatin-associated proteins with a high content of acidic and basic amino acids. Eur J Biochem. 1973;38:14–9.

    Article  CAS  PubMed  Google Scholar 

  100. Penfold SA, Coughlan MT, Patel SK, Srivastava PM, Sourris KC, Steer D, et al. Circulating high-molecular-weight RAGE ligands activate pathways implicated in the development of diabetic nephropathy. Kidney Int. 2010;78:287–95.

    Article  CAS  PubMed  Google Scholar 

  101. Tian J, Avalos AM, Mao SY, Chen B, Senthil K, Wu H, et al. Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 2007;8:487–96.

    Article  CAS  PubMed  Google Scholar 

  102. Yang X, Wang H, Zhang M, Liu J, Lv B, Chen F. HMGB1: a novel protein that induced platelets active and aggregation via Toll-like receptor-4, NF-kappaB and cGMP dependent mechanisms. Diagn Pathol. 2015;10:134.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A, et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 2003;22:5551–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Degryse B, Bonaldi T, Scaffidi P, Muller S, Resnati M, Sanvito F, et al. The high mobility group (HMG) boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells. J Cell Biol. 2001;152:1197–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Urbonaviciute V, Furnrohr BG, Meister S, Munoz L, Heyder P, De Marchis F, et al. Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J Exp Med. 2008;205:3007–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Han J, Zhong J, Wei W, Wang Y, Huang Y, Yang P, et al. Extracellular high-mobility group box 1 acts as an innate immune mediator to enhance autoimmune progression and diabetes onset in NOD mice. Diabetes. 2008;57:2118–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Donato R, Cannon BR, Sorci G, Riuzzi F, Hsu K, Weber DJ, et al. Functions of S100 proteins. Curr Mol Med. 2013;13:24–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Schafer BW, Fritschy JM, Murmann P, Troxler H, Durussel I, Heizmann CW, et al. Brain S100A5 is a novel calcium-, zinc-, and copper ion-binding protein of the EF-hand superfamily. J Biol Chem. 2000;275:30623–30.

    Article  CAS  PubMed  Google Scholar 

  109. Leukert N, Vogl T, Strupat K, Reichelt R, Sorg C, Roth J. Calcium-dependent tetramer formation of S100A8 and S100A9 is essential for biological activity. J Mol Biol. 2006;359:961–72.

    Article  CAS  PubMed  Google Scholar 

  110. Ostendorp T, Leclerc E, Galichet A, Koch M, Demling N, Weigle B, et al. Structural and functional insights into RAGE activation by multimeric S100B. EMBO J. 2007;26:3868–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. K. M. Wartchow, A. C. Tramontina, D. F. de Souza, R. Biasibetti, L. D. Bobermin, and C. A. Goncalves. Insulin stimulates S100B secretion and these proteins antagonistically modulate brain glucose metabolism. Neurochem Res. 2016.

  112. Rammes A, Roth J, Goebeler M, Klempt M, Hartmann M, Sorg C. Myeloid-related protein (MRP) 8 and MRP14, calcium-binding proteins of the S100 family, are secreted by activated monocytes via a novel, tubulin-dependent pathway. J Biol Chem. 1997;272:9496–502.

    Article  CAS  PubMed  Google Scholar 

  113. Tardif MR, Chapeton-Montes JA, Posvandzic A, Page N, Gilbert C, Tessier PA. Secretion of S100A8, S100A9, and S100A12 by neutrophils involves reactive oxygen species and potassium efflux. J Immunol Res. 2015;2015:296149.

    Article  PubMed  PubMed Central  Google Scholar 

  114. Passey RJ, Williams E, Lichanska AM, Wells C, Hu S, Geczy CL, et al. A null mutation in the inflammation-associated S100 protein S100A8 causes early resorption of the mouse embryo. J Immunol. 1999;163:2209–16.

    CAS  PubMed  Google Scholar 

  115. Hobbs JA, May R, Tanousis K, McNeill E, Mathies M, Gebhardt C, et al. Myeloid cell function in MRP-14 (S100A9) null mice. Mol Cell Biol. 2003;23:2564–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Bouma G, Coppens JM, Lam-Tse WK, Luini W, Sintnicolaas K, Levering WH, et al. An increased MRP8/14 expression and adhesion, but a decreased migration towards proinflammatory chemokines of type 1 diabetes monocytes. Clin Exp Immunol. 2005;141:509–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Bouma G, Lam-Tse WK, Wierenga-Wolf AF, Drexhage HA, Versnel MA. Increased serum levels of MRP-8/14 in type 1 diabetes induce an increased expression of CD11b and an enhanced adhesion of circulating monocytes to fibronectin. Diabetes. 2004;53:1979–86.

    Article  CAS  PubMed  Google Scholar 

  118. Ikemoto M, Matsumoto S, Egawa H, Okitsu T, Iwanaga Y, Umemoto S, et al. A case with transient increases in serum S100A8/A9 levels implying acute inflammatory responses after pancreatic islet transplantation. Ann Clin Biochem. 2007;44:570–2.

    Article  CAS  PubMed  Google Scholar 

  119. Xiong Z, O’Hanlon D, Becker LE, Roder J, MacDonald JF, Marks A. Enhanced calcium transients in glial cells in neonatal cerebellar cultures derived from S100B null mice. Exp Cell Res. 2000;257:281–9.

    Article  CAS  PubMed  Google Scholar 

  120. Winer S, Tsui H, Lau A, Song A, Li X, Cheung RK, et al. Autoimmune islet destruction in spontaneous type 1 diabetes is not beta-cell exclusive. Nat Med. 2003;9:198–205.

    Article  CAS  PubMed  Google Scholar 

  121. Gomez-Tourino I, Simon-Vazquez R, Alonso-Lorenzo J, Arif S, Calvino-Sampedro C, Gonzalez-Fernandez A, et al. Characterization of the autoimmune response against the nerve tissue S100beta in patients with type 1 diabetes. Clin Exp Immunol. 2015;180:207–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lotosh NG, Savel’eva EK, Selishcheva AA, Savel’ev SV. Autoantibodies to neuron-specific proteins S100, GFAP, MBP and NGF in the serum of rats with streptozotocin-induced diabetes. Bull Exp Biol Med. 2013;155:48–51.

    Article  CAS  PubMed  Google Scholar 

  123. Serre L, Fazilleau N, Guerder S. Central tolerance spares the private high-avidity CD4(+) T-cell repertoire specific for an islet antigen in NOD mice. Eur J Immunol. 2015;45:1946–56.

    Article  CAS  PubMed  Google Scholar 

  124. Jin X, Yao T, Zhou Z, Zhu J, Zhang S, Hu W, et al. Advanced glycation end products enhance macrophages polarization into M1 phenotype through activating RAGE/NF-kappaB pathway. Biomed Res Int. 2015;2015:732450.

    PubMed  PubMed Central  Google Scholar 

  125. Yan SF, Ramasamy R, Schmidt AM. Mechanisms of disease: advanced glycation end-products and their receptor in inflammation and diabetes complications. Nat Rev Endocrinol. 2008;4:285–93.

    CAS  Google Scholar 

  126. Qin Q, Niu J, Wang Z, Xu W, Qiao Z, Gu Y. Heparanase induced by advanced glycation end products (AGEs) promotes macrophage migration involving RAGE and PI3K/AKT pathway. Cardiovasc Diabetol. 2013;12:37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Friggeri A, Banerjee S, Biswas S, de Freitas A, Liu G, Bierhaus A, et al. Participation of the receptor for advanced glycation end products in efferocytosis. J Immunol. 2011;186:6191–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Hamilton JA. Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol. 2008;8:533–44.

    Article  CAS  PubMed  Google Scholar 

  129. Yui S, Sasaki T, Araki N, Horiuchi S, Yamazaki M. Induction of macrophage growth by advanced glycation end products of the Maillard reaction. J Immunol. 1994;152:1943–9.

    CAS  PubMed  Google Scholar 

  130. Tesch G, Sourris KC, Summers SA, McCarthy D, Ward MS, Borg DJ, et al. Deletion of bone-marrow-derived receptor for AGEs (RAGE) improves renal function in an experimental mouse model of diabetes. Diabetologia. 2014;57:1977–85.

    Article  CAS  PubMed  Google Scholar 

  131. Rojas A, Delgado-Lopez F, Perez-Castro R, Gonzalez I, Romero J, Rojas I, et al. HMGB1 enhances the protumoral activities of M2 macrophages by a RAGE-dependent mechanism. Tumour Biol. 2016;37:3321–9.

    Article  CAS  PubMed  Google Scholar 

  132. Kang R, Chen R, Xie M, Cao L, Lotze MT, Tang D, et al. The receptor for advanced glycation end products activates the AIM2 inflammasome in acute pancreatitis. J Immunol. 2016;196:4331–7.

    Article  CAS  PubMed  Google Scholar 

  133. Fernandes-Alnemri T, Yu J-W, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009;458:509–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Lehuen A, Diana J, Zaccone P, Cooke A. Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol. 2010;10:501–13.

    Article  CAS  PubMed  Google Scholar 

  135. Flodström-Tullberg M, Yadav D, Hägerkvist R, Tsai D, Secrest P, Stotland A, et al. Target cell expression of suppressor of cytokine signaling-1 prevents diabetes in the NOD mouse. Diabetes. 2003;52:2696–700.

    Article  PubMed  Google Scholar 

  136. Chong MMW, Chen Y, Darwiche R, Dudek NL, Irawaty W, Santamaria P, et al. Suppressor of cytokine signaling-1 overexpression protects pancreatic β cells from CD8+ T cell-mediated autoimmune destruction. J Immunol. 2004;172:5714–21.

    Article  CAS  PubMed  Google Scholar 

  137. Rodacki M, Svoren B, Butty V, Besse W, Laffel L, Benoist C, et al. Altered natural killer cells in type 1 diabetic patients. Diabetes. 2007;56:177–85.

    Article  CAS  PubMed  Google Scholar 

  138. Brauner H, Elemans M, Lemos S, Broberger C, Holmberg D, Flodstrom-Tullberg M, et al. Distinct phenotype and function of NK cells in the pancreas of nonobese diabetic mice. J Immunol. 2010;184:2272–80.

    Article  CAS  PubMed  Google Scholar 

  139. DeMarco RA, Fink MP, Lotze MT. Monocytes promote natural killer cell interferon gamma production in response to the endogenous danger signal HMGB1. Mol Immunol. 2005;42:433–44.

    Article  CAS  PubMed  Google Scholar 

  140. Sinha P, Okoro C, Foell D, Freeze HH, Ostrand-Rosenberg S, Srikrishna G. Proinflammatory S100 proteins regulate the accumulation of myeloid-derived suppressor cells. J Immunol. 2008;181:4666–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Ichikawa M, Williams R, Wang L, Vogl T, Srikrishna G. S100A8/A9 activate key genes and pathways in colon tumor progression. Mol Cancer Res. 2011;9:133–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Cheng P, Corzo CA, Luetteke N, Yu B, Nagaraj S, Bui MM, et al. Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein. J Exp Med. 2008;205:2235–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Sade-Feldman M, Kanterman J, Ish-Shalom E, Elnekave M, Horwitz E, Baniyash M. Tumor necrosis factor-alpha blocks differentiation and enhances suppressive activity of immature myeloid cells during chronic inflammation. Immunity. 2013;38:541–54.

    Article  CAS  PubMed  Google Scholar 

  144. Sunahori K, Yamamura M, Yamana J, Takasugi K, Kawashima M, Yamamoto H, et al. The S100A8/A9 heterodimer amplifies proinflammatory cytokine production by macrophages via activation of nuclear factor kappa B and p38 mitogen-activated protein kinase in rheumatoid arthritis. Arthritis Res Ther. 2006;8:R69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  145. Schelbergen RF, Blom AB, de Munter W, Vogl T, Roth J, van den Berg WB, et al. Alarmins s100a8 and s100a9 stimulate production of pro-inflammatory cytokines in M2 macrophages without changing their M2 membrane phenotype. Ann Rheum Dis. 2012;71:A76.

    Article  Google Scholar 

  146. Matteucci E, Ghimenti M, Di Beo S, Giampietro O. Altered proportions of naïve, central memory and terminally differentiated central memory subsets among CD4+ and CD8+ T cells expressing CD26 in patients with type 1 diabetes. J Clin Immunol. 2011;31:977–84.

    Article  CAS  PubMed  Google Scholar 

  147. M. L. Bian, O. Haigh, D. Munster, M. Harris, A. Cotterill, J. J. Miles, et al.. Reactivated CD4+ Tm cells of T1D patients and siblings display an exaggerated effector phenotype with heightened sensitivity to activation-induced cell death. Diabetes. 2014.

  148. Nagareddy PR, Murphy AJ, Stirzaker RA, Hu Y, Yu S, Miller RG, et al. Hyperglycemia promotes myelopoiesis and impairs the resolution of atherosclerosis. Cell Metab. 2013;17:695–708. This study showed that the S100A8/A9 levels correlate with leukocyte counts in individuals with type 1 diabetes, and the interaction of S100A8/A9 and RAGE promote myelopoiesis in hyperglycaemic environments.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Nagareddy PR, Kraakman M, Masters SL, Stirzaker RA, Gorman DJ, Grant RW, et al. Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity. Cell Metab. 2014;19:821–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Reis C, Sousa E. Dendritic cells in a mature age. Nat Rev Immunol. 2006;6:476–83.

    Article  CAS  Google Scholar 

  151. Heilmann M, Wellner A, Gadermaier G, Ilchmann A, Briza P, Krause M, et al. Ovalbumin modified with pyrraline, a Maillard reaction product, shows enhanced T-cell immunogenicity. J Biol Chem. 2014;289:7919–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Ilchmann A, Burgdorf S, Scheurer S, Waibler Z, Nagai R, Wellner A, et al. Glycation of a food allergen by the Maillard reaction enhances its T-cell immunogenicity: role of macrophage scavenger receptor class A type I and II. J Allergy Clin Immunol. 2010;125:175-83. e1–11.

    Article  CAS  Google Scholar 

  153. Hilmenyuk T, Bellinghausen I, Heydenreich B, Ilchmann A, Toda M, Grabbe S, et al. Effects of glycation of the model food allergen ovalbumin on antigen uptake and presentation by human dendritic cells. Immunology. 2010;129:437–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Kumar RK, Herbert C, Foster PS. The “classical” ovalbumin challenge model of asthma in mice. Curr Drug Targets. 2008;9:485–94.

    Article  CAS  PubMed  Google Scholar 

  155. Buttari B, Profumo E, Capozzi A, Facchiano F, Saso L, Sorice M, et al. Advanced glycation end products of human beta(2) glycoprotein I modulate the maturation and function of DCs. Blood. 2011;117:6152–61.

    Article  CAS  PubMed  Google Scholar 

  156. Price CL, Sharp PS, North ME, Rainbow SJ, Knight SC. Advanced glycation end products modulate the maturation and function of peripheral blood dendritic cells. Diabetes. 2004;53:1452–8.

    Article  CAS  PubMed  Google Scholar 

  157. Schmidt A, Oberle N, Krammer PH. Molecular mechanisms of Treg-mediated T cell suppression. Front Immunol. 2012;3:51.

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Pejnovic NN, Pantic JM, Jovanovic IP, Radosavljevic GD, Milovanovic MZ, Nikolic IG, et al. Galectin-3 deficiency accelerates high-fat diet-induced obesity and amplifies inflammation in adipose tissue and pancreatic islets. Diabetes. 2013;62:1932–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Su Z, Sun C, Zhou C, Liu Y, Zhu H, Sandoghchian S, et al. HMGB1 blockade attenuates experimental autoimmune myocarditis and suppresses Th17-cell expansion. Eur J Immunol. 2011;41:3586–95.

    Article  CAS  PubMed  Google Scholar 

  160. Tang Q, Li J, Zhu H, Li P, Zou Z, Xiao Y. Hmgb1-IL-23-IL-17-IL-6-Stat3 axis promotes tumor growth in murine models of melanoma. Mediat Inflamm. 2013;2013:713859.

    Google Scholar 

  161. Zhang LT, Yao YM, Yao FH, Huang LF, Dong N, Yu Y, et al. Association between high-mobility group box-1 protein release and immune function of dendritic cells in thermal injury. J Interferon Cytokine Res. 2010;30:487–95.

    Article  CAS  PubMed  Google Scholar 

  162. Kim TS, Gorski SA, Hahn S, Murphy KM, Braciale TJ. Distinct dendritic cell subsets dictate the fate decision between effector and memory CD8(+) T cell differentiation by a CD24-dependent mechanism. Immunity. 2014;40:400–13. This study showed that CD8+ T cell activation could be regulated via CD24 through HMGB1 engagement of T cell RAGE.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Manfredi AA, Capobianco A, Esposito A, De Cobelli F, Canu T, Monno A, et al. Maturing dendritic cells depend on RAGE for in vivo homing to lymph nodes. J Immunol. 2008;180:2270–5.

    Article  CAS  PubMed  Google Scholar 

  164. Huber JP, Ramos HJ, Gill MA, Farrar JD. Cutting edge: type I IFN reverses human Th2 commitment and stability by suppressing GATA3. J Immunol. 2010;185:813–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Duan L, Wang CY, Chen J, Gong Q, Zhu P, Zheng F, et al. High-mobility group box 1 promotes early acute allograft rejection by enhancing IL-6-dependent Th17 alloreactive response. Lab Invest. 2011;91:43–53.

    Article  CAS  PubMed  Google Scholar 

  166. Zhang Y, Yao YM, Huang LF, Dong N, Yu Y, Sheng ZY. The potential effect and mechanism of high-mobility group box 1 protein on regulatory T cell-mediated immunosuppression. J Interferon Cytokine Res. 2011;31:249–57.

    Article  CAS  PubMed  Google Scholar 

  167. Mu L, Zhang Y, Sun B, Wang J, Xie X, Li N, et al. Activation of the receptor for advanced glycation end products (RAGE) exacerbates experimental autoimmune myasthenia gravis symptoms. Clin Immunol. 2011;141:36–48.

    Article  CAS  PubMed  Google Scholar 

  168. Kim TS, Kang YJ, Kim JY, Lee S, Lee WJ, Sohn Y, et al. Up-regulated S100 calcium binding protein A8 in Plasmodium-infected patients correlates with CD4(+)CD25(+)Foxp3 regulatory T cell generation. Malar J. 2015;14:385.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  169. Savinov AY, Rozanov DV, Strongin AY. Specific inhibition of autoimmune T cell transmigration contributes to beta cell functionality and insulin synthesis in non-obese diabetic (NOD) mice. J Biol Chem. 2007;282:32106–11.

    Article  CAS  PubMed  Google Scholar 

  170. Lozanoska-Ochser B, Peakman M. Level of major histocompatibility complex class I expression on endothelium in non-obese diabetic mice influences CD8 T cell adhesion and migration. Clin Exp Immunol. 2009;157:119–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Matsui T, Oda E, Higashimoto Y, Yamagishi S. Glyceraldehyde-derived pyridinium (GLAP) evokes oxidative stress and inflammatory and thrombogenic reactions in endothelial cells via the interaction with RAGE. Cardiovasc Diabetol. 2015;14:1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Sun W, Jiao Y, Cui B, Gao X, Xia Y, Zhao Y. Immune complexes activate human endothelium involving the cell-signaling HMGB1-RAGE axis in the pathogenesis of lupus vasculitis. Lab Investig; J Tech Methods Pathol. 2013;93:626–38.

    Article  CAS  Google Scholar 

  173. Fiuza C, Bustin M, Talwar S, Tropea M, Gerstenberger E, Shelhamer JH, et al. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood. 2003;101:2652–60.

    Article  CAS  PubMed  Google Scholar 

  174. Ehlermann P, Eggers K, Bierhaus A, Most P, Weichenhan D, Greten J, et al. Increased proinflammatory endothelial response to S100A8/A9 after preactivation through advanced glycation end products. Cardiovasc Diabetol. 2006;5:6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Chavakis T, Bierhaus A, Al-Fakhri N, Schneider D, Witte S, Linn T, et al. The pattern recognition receptor (RAGE) is a counterreceptor for leukocyte integrins: a novel pathway for inflammatory cell recruitment. J Exp Med. 2003;198:1507–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Frommhold D, Kamphues A, Hepper I, Pruenster M, Lukic IK, Socher I, et al. RAGE and ICAM-1 cooperate in mediating leukocyte recruitment during acute inflammation in vivo. Blood. 2010;116:841–9.

    Article  CAS  PubMed  Google Scholar 

  177. Kirstein M, Brett J, Radoff S, Ogawa S, Stern D, Vlassara H. Advanced protein glycosylation induces transendothelial human monocyte chemotaxis and secretion of platelet-derived growth factor: role in vascular disease of diabetes and aging. Proc Natl Acad Sci U S A. 1990;87:9010–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Lee BW, Chae HY, Kwon SJ, Park SY, Ihm J, Ihm SH. RAGE ligands induce apoptotic cell death of pancreatic beta-cells via oxidative stress. Int J Mol Med. 2010;26:813–8.

    CAS  PubMed  Google Scholar 

  179. Li M, Song L, Gao X, Chang W, Qin X. Toll-like receptor 4 on islet [beta] cells senses expression changes in high-mobility group box 1 and contributes to the initiation of type 1 diabetes. Exp Mol Med. 2012;44:260–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Luciano Viviani G, Puddu A, Sacchi G, Garuti A, Storace D, Durante A, et al. Glycated fetal calf serum affects the viability of an insulin-secreting cell line in vitro. Metabolism. 2008;57:163–9.

    Article  PubMed  CAS  Google Scholar 

  181. Shu T, Zhu Y, Wang H, Lin Y, Ma Z, Han X. AGEs decrease insulin synthesis in pancreatic beta-cell by repressing Pdx-1 protein expression at the post-translational level. PLoS ONE. 2011;6, e18782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Zhao Z, Zhao C, Zhang XH, Zheng F, Cai W, Vlassara H, et al. Advanced glycation end products inhibit glucose-stimulated insulin secretion through nitric oxide-dependent inhibition of cytochrome C oxidase and adenosine triphosphate synthesis. Endocrinology. 2009;150:2569–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

JMF is supported by a fellowship from the National Health and Medical Research Council of Australia; DJB is supported by a Diabetes Australia Research Grant (Y16G); SSL is supported by an Australian Postgraduate Award (The University of Queensland) and Frank Clair Scholarship (Mater Research); and the authors acknowledge the ongoing support of the Mater Foundation. We apologize to those groups who made important contributions that could not be considered here due to space limitations.

Author information

Author notes

    Authors and Affiliations

    1. Glycation and Diabetes, Mater Research Institute, Translational Research Institute, The University of Queensland, 37 Kent St, Woolloongabba, Brisbane, Queensland, Australia

      Sherman S. Leung, Josephine M. Forbes & Danielle J. Borg

    2. School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia

      Sherman S. Leung

    3. Mater Clinical School, School of Medicine, The University of Queensland, Brisbane, Queensland, Australia

      Josephine M. Forbes

    Authors
    1. Sherman S. Leung
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Josephine M. Forbes
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Danielle J. Borg
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Josephine M. Forbes.

    Ethics declarations

    Conflict of Interest

    Sherman S. Leung, Josephine M. Forbes, and Danielle J. Borg declare that they have no conflict of interest.

    Human and Animal Rights and Informed Consent

    This article does not contain any unpublished studies with human or animal subjects performed by any of the authors.

    Additional information

    This article is part of the Topical Collection on Pathogenesis of Type 1 Diabetes

    Josephine M. Forbes and Danielle J. Borg contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Leung, S.S., Forbes, J.M. & Borg, D.J. Receptor for Advanced Glycation End Products (RAGE) in Type 1 Diabetes Pathogenesis. Curr Diab Rep 16, 100 (2016). https://doi.org/10.1007/s11892-016-0782-y

    Download citation

    • Published:

    • DOI: https://doi.org/10.1007/s11892-016-0782-y

    Keywords

    Search

    Navigation