Journal of Molecular Medicine

, Volume 96, Issue 8, pp 741–751 | Cite as

Epigenetic regulation of Toll-like receptors and its roles in type 1 diabetes

  • Zhiguo Xie
  • Gan Huang
  • Zhen Wang
  • Shuoming Luo
  • Peilin Zheng
  • Zhiguang ZhouEmail author


The immune system can be divided into adaptive immunity and innate immunity. Adaptive immunity has been confirmed to be involved in the pathogenesis of autoimmune diseases, including type 1 diabetes (T1D). However, the role of innate immunity in T1D has only been studied recently. T1D is caused by selective autoimmune destruction of pancreatic islet β cells. A series of studies have suggested that TLRs play a critical role in the pathogenesis of T1D. Aberrant TLR signaling will change immune homeostasis and result in immunopathological conditions such as endotoxin shock and autoimmune responses. Thus, TLR signaling pathways are supposed to be strictly and finely regulated. Epigenetics has recently been proven to be a new regulator of TLR expression. DNA methylation, histone modification, and microRNAs are the three main epigenetic modifications. This review will mainly focus on these epigenetic mechanisms of regulation of TLRs and the role of TLRs in the pathogenesis of T1D.


Toll-like receptor Type 1 diabetes Epigenetics DNA methylation MicroRNA 


Funding information

This work was supported by grants from the National Key Research and Development Program of China (2016YFC1305000), the National Natural Science Foundation of China (No. 81400783), the National Key Technology R&D program (2015BAI12B13), and the strategic forerunner project of Central South University (ZLXD2016003).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Medzhitov R (2007) Recognition of microorganisms and activation of the immune response. Nature 449:819–826CrossRefPubMedGoogle Scholar
  2. 2.
    Barton GM, Medzhitov R (2003) Toll-like receptor signaling pathways. Science 300:1524–1525CrossRefPubMedGoogle Scholar
  3. 3.
    Cook DN, Pisetsky DS, Schwartz DA (2004) Toll-like receptors in the pathogenesis of human disease. Nat Immunol 5:975–979CrossRefPubMedGoogle Scholar
  4. 4.
    Qian C, Cao X (2013) Regulation of Toll-like receptor signaling pathways in innate immune responses. Ann N Y Acad Sci 1283:67–74CrossRefPubMedGoogle Scholar
  5. 5.
    Haehnel V, Schwarzfischer L, Fenton MJ, Rehli M (2002) Transcriptional regulation of the human toll-like receptor 2 gene in monocytes and macrophages. J Immunol 168:5629–5637CrossRefPubMedGoogle Scholar
  6. 6.
    Morse ZJ, Horwitz MS (2017) Innate viral receptor signaling determines type 1 diabetes onset. Front Endocrinol (Lausanne) 8:249. CrossRefGoogle Scholar
  7. 7.
    Atkinson MA, Eisenbarth GS, Michels AW (2014) Type 1 diabetes. Lancet 383:69–82CrossRefPubMedGoogle Scholar
  8. 8.
    Xie Z, Chang C, Zhou Z (2014) Molecular mechanisms in autoimmune type 1 diabetes: a critical review. Clin Rev Allergy Immunol 47:174–192CrossRefPubMedGoogle Scholar
  9. 9.
    Liu Y, Yin H, Zhao M, Lu Q (2014) TLR2 and TLR4 in autoimmune diseases: a comprehensive review. Clin Rev Allergy Immunol 47:136–147CrossRefPubMedGoogle Scholar
  10. 10.
    Lemaitre B, Nicolas E, Michaut L, Reichhart JM, Hoffmann JA (1996) The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973–983CrossRefPubMedGoogle Scholar
  11. 11.
    Roach JC, Glusman G, Rowen L, Kaur A, Purcell MK, Smith KD, Hood LE, Aderem A (2005) The evolution of vertebrate Toll-like receptors. Proc Natl Acad Sci U S A 102:9577–9582CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–650CrossRefPubMedGoogle Scholar
  13. 13.
    Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T, Endres S, Hartmann G (2002) Quantitative expression of toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 168:4531–4537CrossRefPubMedGoogle Scholar
  14. 14.
    Muzio M, Bosisio D, Polentarutti N, D'Amico G, Stoppacciaro A, Mancinelli R, van't Veer C, Penton-Rol G, Ruco LP, Allavena P, Mantovani A (2000) Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol 164:5998–6004CrossRefPubMedGoogle Scholar
  15. 15.
    Caramalho I, Lopes-Carvalho T, Ostler D, Zelenay S, Haury M, Demengeot J (2003) Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide. J Exp Med 197:403–411CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Wen L, Peng J, Li Z, Wong FS (2004) The effect of innate immunity on autoimmune diabetes and the expression of Toll-like receptors on pancreatic islets. J Immunol 172:3173–3180CrossRefPubMedGoogle Scholar
  17. 17.
    Zarember KA, Godowski PJ (2002) Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 168:554–561CrossRefPubMedGoogle Scholar
  18. 18.
    Meylan E, Tschopp J, Karin M (2006) Intracellular pattern recognition receptors in the host response. Nature 442:39–44CrossRefPubMedGoogle Scholar
  19. 19.
    Alisi A, Carsetti R, Nobili V (2011) Pathogen- or damage-associated molecular patterns during nonalcoholic fatty liver disease development. Hepatology 54:1500–1502CrossRefPubMedGoogle Scholar
  20. 20.
    Carty M, Goodbody R, Schroder M, Stack J, Moynagh PN, Bowie AG (2006) The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nat Immunol 7:1074–1081CrossRefPubMedGoogle Scholar
  21. 21.
    O'Neill LA, Bowie AG (2007) The family of five: TIR-domain-containing adaptors in Toll-like receptor signalling. Nat Rev Immunol 7:353–364CrossRefPubMedGoogle Scholar
  22. 22.
    Brodsky I, Medzhitov R (2007) Two modes of ligand recognition by TLRs. Cell 130:979–981CrossRefPubMedGoogle Scholar
  23. 23.
    Kawai T, Akira S (2007) Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med 13:460–469CrossRefPubMedGoogle Scholar
  24. 24.
    Akira S, Takeda K (2004) Toll-like receptor signalling. Nat Rev Immunol 4:499–511CrossRefPubMedGoogle Scholar
  25. 25.
    Zipris D (2008) Innate immunity and its role in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes 15:326–331CrossRefPubMedGoogle Scholar
  26. 26.
    Yamamoto M, Sato S, Hemmi H, Hoshino K, Kaisho T, Sanjo H, Takeuchi O, Sugiyama M, Okabe M, Takeda K, Akira S (2003) Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science 301:640–643CrossRefPubMedGoogle Scholar
  27. 27.
    Montero Vega MT, de Andres Martin A (2009) The significance of toll-like receptors in human diseases. Allergol Immunopathol (Madr) 37:252–263CrossRefGoogle Scholar
  28. 28.
    Liew FY, Xu D, Brint EK, O'Neill LA (2005) Negative regulation of toll-like receptor-mediated immune responses. Nat Rev Immunol 5:446–458CrossRefPubMedGoogle Scholar
  29. 29.
    Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403:41–45CrossRefPubMedGoogle Scholar
  30. 30.
    Borgel J, Guibert S, Li Y, Chiba H, Schubeler D, Sasaki H, Forne T, Weber M (2010) Targets and dynamics of promoter DNA methylation during early mouse development. Nat Genet 42:1093–1100CrossRefPubMedGoogle Scholar
  31. 31.
    Magalhaes M, Rivals I, Claustres M, Varilh J, Thomasset M, Bergougnoux A, Mely L, Leroy S, Corvol H, Guillot L, Murris M, Beyne E, Caimmi D, Vachier I, Chiron R, De Sario A (2017) DNA methylation at modifier genes of lung disease severity is altered in cystic fibrosis. Clin Epigenetics 9:19. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Smith AK, Conneely KN, Kilaru V, Mercer KB, Weiss TE, Bradley B, Tang Y, Gillespie CF, Cubells JF, Ressler KJ (2011) Differential immune system DNA methylation and cytokine regulation in post-traumatic stress disorder. Am J Med Genet B Neuropsychiatr Genet 156B:700–708CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Johnson CM, Tapping RI (2007) Microbial products stimulate human Toll-like receptor 2 expression through histone modification surrounding a proximal NF-kappaB-binding site. J Biol Chem 282:31197–31205CrossRefPubMedGoogle Scholar
  34. 34.
    Thakur BK, Dasgupta N, Ta A, Das S (2016) Physiological TLR5 expression in the intestine is regulated by differential DNA binding of Sp1/Sp3 through simultaneous Sp1 dephosphorylation and Sp3 phosphorylation by two different PKC isoforms. Nucleic Acids Res 44:5658–5672CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Zampetaki A, Xiao Q, Zeng L, Hu Y, Xu Q (2006) TLR4 expression in mouse embryonic stem cells and in stem cell-derived vascular cells is regulated by epigenetic modifications. Biochem Biophys Res Commun 347:89–99CrossRefPubMedGoogle Scholar
  36. 36.
    Takahashi K, Sugi Y, Hosono A, Kaminogawa S (2009) Epigenetic regulation of TLR4 gene expression in intestinal epithelial cells for the maintenance of intestinal homeostasis. J Immunol 183:6522–6529CrossRefPubMedGoogle Scholar
  37. 37.
    Kim TW, Lee SJ, Oh BM, Lee H, Uhm TG, Min JK, Park YJ, Yoon SR, Kim BY, Kim JW, Choe YK, Lee HG (2016) Epigenetic modification of TLR4 promotes activation of NF-kappaB by regulating methyl-CpG-binding domain protein 2 and Sp1 in gastric cancer. Oncotarget 7:4195–4209PubMedGoogle Scholar
  38. 38.
    McKernan DP, Hennessy C (2017) Epigenetic modifications influence TLR3 expression and activity. FASEB J 31:1060.1065–1060.1065Google Scholar
  39. 39.
    Djebali S, Davis CA, Merkel A, Dobin A, Lassmann T, Mortazavi A, Tanzer A, Lagarde J, Lin W, Schlesinger F, Xue C, Marinov GK, Khatun J, Williams BA, Zaleski C, Rozowsky J, Roder M, Kokocinski F, Abdelhamid RF, Alioto T, Antoshechkin I, Baer MT, Bar NS, Batut P, Bell K, Bell I, Chakrabortty S, Chen X, Chrast J, Curado J, Derrien T, Drenkow J, Dumais E, Dumais J, Duttagupta R, Falconnet E, Fastuca M, Fejes-Toth K, Ferreira P, Foissac S, Fullwood MJ, Gao H, Gonzalez D, Gordon A, Gunawardena H, Howald C, Jha S, Johnson R, Kapranov P, King B, Kingswood C, Luo OJ, Park E, Persaud K, Preall JB, Ribeca P, Risk B, Robyr D, Sammeth M, Schaffer L, See LH, Shahab A, Skancke J, Suzuki AM, Takahashi H, Tilgner H, Trout D, Walters N, Wang H, Wrobel J, Yu Y, Ruan X, Hayashizaki Y, Harrow J, Gerstein M, Hubbard T, Reymond A, Antonarakis SE, Hannon G, Giddings MC, Ruan Y, Wold B, Carninci P, Guigo R, Gingeras TR (2012) Landscape of transcription in human cells. Nature 489:101–108CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    O'Connell RM, Rao DS, Chaudhuri AA, Baltimore D (2010) Physiological and pathological roles for microRNAs in the immune system. Nat Rev Immunol 10:111–122CrossRefPubMedGoogle Scholar
  41. 41.
    O'Neill LA, Sheedy FJ, McCoy CE (2011) MicroRNAs: the fine-tuners of Toll-like receptor signalling. Nat Rev Immunol 11:163–175CrossRefPubMedGoogle Scholar
  42. 42.
    Fabbri M, Paone A, Calore F, Galli R, Croce CM (2013) A new role for microRNAs, as ligands of Toll-like receptors. RNA Biol 10:169–174CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Olivieri F, Rippo MR, Prattichizzo F, Babini L, Graciotti L, Recchioni R, Procopio AD (2013) Toll like receptor signaling in “inflammaging”: microRNA as new players. Immun Ageing 10:11CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    He S, Chu J, Wu LC, Mao H, Peng Y, Alvarez-Breckenridge CA, Hughes T, Wei M, Zhang J, Yuan S, Sandhu S, Vasu S, Benson DM Jr, Hofmeister CC, He X, Ghoshal K, Devine SM, Caligiuri MA, Yu J (2013) MicroRNAs activate natural killer cells through Toll-like receptor signaling. Blood 121:4663–4671CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Fabbri M, Paone A, Calore F, Galli R, Gaudio E, Santhanam R, Lovat F, Fadda P, Mao C, Nuovo GJ, Zanesi N, Crawford M, Ozer GH, Wernicke D, Alder H, Caligiuri MA, Nana-Sinkam P, Perrotti D, Croce CM (2012) MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A 109:E2110–E2116CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    He WA, Calore F, Londhe P, Canella A, Guttridge DC, Croce CM (2014) Microvesicles containing miRNAs promote muscle cell death in cancer cachexia via TLR7. Proc Natl Acad Sci U S A 111:4525–4529CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Lehmann SM, Kruger C, Park B, Derkow K, Rosenberger K, Baumgart J, Trimbuch T, Eom G, Hinz M, Kaul D, Habbel P, Kalin R, Franzoni E, Rybak A, Nguyen D, Veh R, Ninnemann O, Peters O, Nitsch R, Heppner FL, Golenbock D, Schott E, Ploegh HL, Wulczyn FG, Lehnardt S (2012) An unconventional role for miRNA: let-7 activates Toll-like receptor 7 and causes neurodegeneration. Nat Neurosci 15:827–835CrossRefPubMedGoogle Scholar
  48. 48.
    Park CK, Xu ZZ, Berta T, Han Q, Chen G, Liu XJ, Ji RR (2014) Extracellular microRNAs activate nociceptor neurons to elicit pain via TLR7 and TRPA1. Neuron 82:47–54CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Philippe L, Alsaleh G, Suffert G, Meyer A, Georgel P, Sibilia J, Wachsmann D, Pfeffer S (2012) TLR2 expression is regulated by microRNA miR-19 in rheumatoid fibroblast-like synoviocytes. J Immunol 188:454–461CrossRefPubMedGoogle Scholar
  50. 50.
    Benakanakere MR, Li Q, Eskan MA, Singh AV, Zhao J, Galicia JC, Stathopoulou P, Knudsen TB, Kinane DF (2009) Modulation of TLR2 protein expression by miR-105 in human oral keratinocytes. J Biol Chem 284:23107–23115CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Guo H, Chen Y, Hu X, Qian G, Ge S, Zhang J (2013) The regulation of Toll-like receptor 2 by miR-143 suppresses the invasion and migration of a subset of human colorectal carcinoma cells. Mol Cancer 12:77CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Jiang C, Zhu W, Xu J, Wang B, Hou W, Zhang R, Zhong N, Ning Q, Han Y, Yu H, Sun J, Meng L, Lu S (2014) MicroRNA-26a negatively regulates toll-like receptor 3 expression of rat macrophages and ameliorates pristane induced arthritis in rats. Arthritis Res Ther 16:R9CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Androulidaki A, Iliopoulos D, Arranz A, Doxaki C, Schworer S, Zacharioudaki V, Margioris AN, Tsichlis PN, Tsatsanis C (2009) The kinase Akt1 controls macrophage response to lipopolysaccharide by regulating microRNAs. Immunity 31:220–231CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Agudo J, Ruzo A, Tung N, Salmon H, Leboeuf M, Hashimoto D, Becker C, Garrett-Sinha LA, Baccarini A, Merad M, Brown BD (2014) The miR-126-VEGFR2 axis controls the innate response to pathogen-associated nucleic acids. Nat Immunol 15:54–62CrossRefPubMedGoogle Scholar
  55. 55.
    Huang G, Xiang Y, Pan L, Li X, Luo S, Zhou Z (2013) Zinc transporter 8 autoantibody (ZnT8A) could help differentiate latent autoimmune diabetes in adults (LADA) from phenotypic type 2 diabetes mellitus. Diabetes Metab Res Rev 29:363–368CrossRefPubMedGoogle Scholar
  56. 56.
    Zhou Z, Xiang Y, Ji L, Jia W, Ning G, Huang G, Yang L, Lin J, Liu Z, Hagopian WA, Leslie RD, Group LCS (2013) Frequency, immunogenetics, and clinical characteristics of latent autoimmune diabetes in China (LADA China study): a nationwide, multicenter, clinic-based cross-sectional study. Diabetes 62:543–550CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Liu L, Li X, Xiang Y, Huang G, Lin J, Yang L, Zhao Y, Yang Z, Hou C, Li Y, Liu J, Zhu D, Leslie RD, Wang X, Zhou Z, Group LCS (2015) Latent autoimmune diabetes in adults with low-titer GAD antibodies: similar disease progression with type 2 diabetes: a nationwide, multicenter prospective study (LADA China study 3). Diabetes Care 38:16–21CrossRefPubMedGoogle Scholar
  58. 58.
    Lehuen A, Diana J, Zaccone P, Cooke A (2010) Immune cell crosstalk in type 1 diabetes. Nat Rev Immunol 10:501–513CrossRefPubMedGoogle Scholar
  59. 59.
    Devaraj S, Dasu MR, Park SH, Jialal I (2009) Increased levels of ligands of Toll-like receptors 2 and 4 in type 1 diabetes. Diabetologia 52:1665–1668CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Devaraj S, Dasu MR, Rockwood J, Winter W, Griffen SC, Jialal I (2008) Increased toll-like receptor (TLR) 2 and TLR4 expression in monocytes from patients with type 1 diabetes: further evidence of a proinflammatory state. J Clin Endocrinol Metab 93:578–583CrossRefPubMedGoogle Scholar
  61. 61.
    Du T, Zhou ZG, You S, Lin J, Yang L, Zhou WD, Huang G, Chao C (2009) Regulation by 1, 25-dihydroxy-vitamin D3 on altered TLRs expression and response to ligands of monocyte from autoimmune diabetes. Clin Chim Acta 402:133–138CrossRefPubMedGoogle Scholar
  62. 62.
    Zheng C, Zhou Z, Yang L, Lin J, Huang G, Li X, Zhou W, Wang X, Liu Z (2011) Fulminant type 1 diabetes mellitus exhibits distinct clinical and autoimmunity features from classical type 1 diabetes mellitus in Chinese. Diabetes Metab Res Rev 27:70–78CrossRefPubMedGoogle Scholar
  63. 63.
    Shibasaki S, Imagawa A, Tauriainen S, Iino M, Oikarinen M, Abiru H, Tamaki K, Seino H, Nishi K, Takase I, Okada Y, Uno S, Murase-Mishiba Y, Terasaki J, Makino H, Shimomura I, Hyoty H, Hanafusa T (2010) Expression of toll-like receptors in the pancreas of recent-onset fulminant type 1 diabetes. Endocr J 57:211–219CrossRefPubMedGoogle Scholar
  64. 64.
    Wang Z, Zheng Y, Hou C, Yang L, Li X, Lin J, Huang G, Lu Q, Wang CY, Zhou Z (2013) DNA methylation impairs TLR9 induced Foxp3 expression by attenuating IRF-7 binding activity in fulminant type 1 diabetes. J Autoimmun 41:50–59CrossRefPubMedGoogle Scholar
  65. 65.
    Vallois D, Grimm CH, Avner P, Boitard C, Rogner UC (2007) The type 1 diabetes locus Idd6 controls TLR1 expression. J Immunol 179:3896–3903CrossRefPubMedGoogle Scholar
  66. 66.
    Alyanakian MA, Grela F, Aumeunier A, Chiavaroli C, Gouarin C, Bardel E, Normier G, Chatenoud L, Thieblemont N, Bach JF (2006) Transforming growth factor-beta and natural killer T-cells are involved in the protective effect of a bacterial extract on type 1 diabetes. Diabetes 55:179–185CrossRefPubMedGoogle Scholar
  67. 67.
    Wen L, Ley RE, Volchkov PY, Stranges PB, Avanesyan L, Stonebraker AC, Hu C, Wong FS, Szot GL, Bluestone JA, Gordon JI, Chervonsky AV (2008) Innate immunity and intestinal microbiota in the development of type 1 diabetes. Nature 455:1109–1113CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Paun A, Yau C, Danska JS (2017) The influence of the microbiome on type 1 diabetes. J Immunol 198:590–595CrossRefPubMedGoogle Scholar
  69. 69.
    Yiu JH, Dorweiler B, Woo CW (2017) Interaction between gut microbiota and toll-like receptor: from immunity to metabolism. J Mol Med (Berl) 95:13–20CrossRefGoogle Scholar
  70. 70.
    Amiset L, Fend L, Gatard-Scheikl T, Rittner K, Duong V, Rooke R, Muller S, Bonnefoy JY, Preville X, Haegel H (2012) TLR2 ligation protects effector T cells from regulatory T-cell mediated suppression and repolarizes T helper responses following MVA-based cancer immunotherapy. Oncoimmunology 1:1271–1280CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Wong FS, Wen L (2008) Toll-like receptors and diabetes. Ann N Y Acad Sci 1150:123–132CrossRefPubMedGoogle Scholar
  72. 72.
    Crellin NK, Garcia RV, Hadisfar O, Allan SE, Steiner TS, Levings MK (2005) Human CD4+ T cells express TLR5 and its ligand flagellin enhances the suppressive capacity and expression of FOXP3 in CD4+CD25+ T regulatory cells. J Immunol 175:8051–8059CrossRefPubMedGoogle Scholar
  73. 73.
    Filippi CM, Ehrhardt K, Estes EA, Larsson P, Oldham JE, von Herrath MG (2011) TLR2 signaling improves immunoregulation to prevent type 1 diabetes. Eur J Immunol 41:1399–1409CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Karumuthil-Melethil S, Perez N, Li R, Vasu C (2008) Induction of innate immune response through TLR2 and dectin 1 prevents type 1 diabetes. J Immunol 181:8323–8334CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Chen Q, Davidson TS, Huter EN, Shevach EM (2009) Engagement of TLR2 does not reverse the suppressor function of mouse regulatory T cells, but promotes their survival. J Immunol 183:4458–4466CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Al Shamsi M, Shahin A, Iwakura Y, Lukic ML, Mensah-Brown EP (2013) Pam3CSK(4) enhanced beta cell loss and diabetogenesis: the roles of IFN-gamma and IL-17. Clin Immunol 149:86–96CrossRefPubMedGoogle Scholar
  77. 77.
    Ewel CH, Sobel DO, Zeligs BJ, Bellanti JA (1992) Poly I:C accelerates development of diabetes mellitus in diabetes-prone BB rat. Diabetes 41:1016–1021CrossRefPubMedGoogle Scholar
  78. 78.
    Sobel DO, Goyal D, Ahvazi B, Yoon JW, Chung YH, Bagg A, Harlan DM (1998) Low dose poly I:C prevents diabetes in the diabetes prone BB rat. J Autoimmun 11:343–352CrossRefPubMedGoogle Scholar
  79. 79.
    Sobel DO, Newsome J, Ewel CH, Bellanti JA, Abbassi V, Creswell K, Blair O (1992) Poly I:C induces development of diabetes mellitus in BB rat. Diabetes 41:515–520CrossRefPubMedGoogle Scholar
  80. 80.
    Guberski DL, Thomas VA, Shek WR, Like AA, Handler ES, Rossini AA, Wallace JE, Welsh RM (1991) Induction of type I diabetes by Kilham’s rat virus in diabetes-resistant BB/Wor rats. Science 254:1010–1013CrossRefPubMedGoogle Scholar
  81. 81.
    Zipris D, Lien E, Nair A, Xie JX, Greiner DL, Mordes JP, Rossini AA (2007) TLR9-signaling pathways are involved in Kilham rat virus-induced autoimmune diabetes in the biobreeding diabetes-resistant rat. J Immunol 178:693–701CrossRefPubMedGoogle Scholar
  82. 82.
    Zipris D, Lien E, Xie JX, Greiner DL, Mordes JP, Rossini AA (2005) TLR activation synergizes with Kilham rat virus infection to induce diabetes in BBDR rats. J Immunol 174:131–142CrossRefPubMedGoogle Scholar
  83. 83.
    Tirabassi RS, Guberski DL, Blankenhorn EP, Leif JH, Woda BA, Liu Z, Winans D, Greiner DL, Mordes JP (2010) Infection with viruses from several families triggers autoimmune diabetes in LEW*1WR1 rats: prevention of diabetes by maternal immunization. Diabetes 59:110–118CrossRefPubMedGoogle Scholar
  84. 84.
    Pirie FJ, Pegoraro R, Motala AA, Rauff S, Rom L, Govender T, Esterhuizen TM (2005) Toll-like receptor 3 gene polymorphisms in South African Blacks with type 1 diabetes. Tissue Antigens 66:125–130CrossRefPubMedGoogle Scholar
  85. 85.
    Assmann TS, Brondani Lde A, Bauer AC, Canani LH, Crispim D (2014) Polymorphisms in the TLR3 gene are associated with risk for type 1 diabetes mellitus. Eur J Endocrinol 170:519–527CrossRefPubMedGoogle Scholar
  86. 86.
    Park Y, Park S, Yoo E, Kim D, Shin H (2004) Association of the polymorphism for Toll-like receptor 2 with type 1 diabetes susceptibility. Ann N Y Acad Sci 1037:170–174CrossRefPubMedGoogle Scholar
  87. 87.
    Bjørnvold M, Munthe-Kaas MC, Egeland T, Joner G, Dahl-Jorgensen K, Njolstad PR, Akselsen HE, Gervin K, Carlsen KC, Carlsen KH, Undlien DE (2009) A TLR2 polymorphism is associated with type 1 diabetes and allergic asthma. Genes Immun 10:181–187CrossRefPubMedGoogle Scholar
  88. 88.
    Santin I, Bilbao JR, de Nanclares GP, Calvo B, Castano L (2006) No association of TLR2 and TLR4 polymorphisms with type I diabetes mellitus in the Basque population. Ann N Y Acad Sci 1079:268–272CrossRefPubMedGoogle Scholar
  89. 89.
    Dezsofi A, Szebeni B, Hermann CS, Kapitany A, Veres G, Sipka S, Korner A, Madacsy L, Korponay-Szabo I, Rajczy K, Arato A (2008) Frequencies of genetic polymorphisms of TLR4 and CD14 and of HLA-DQ genotypes in children with celiac disease, type 1 diabetes mellitus, or both. J Pediatr Gastroenterol Nutr 47:283–287CrossRefPubMedGoogle Scholar
  90. 90.
    Sun C, Zhi D, Shen S, Luo F, Sanjeevi CB (2014) SNPs in the exons of Toll-like receptors are associated with susceptibility to type 1 diabetes in Chinese population. Hum Immunol 75:1084–1088CrossRefPubMedGoogle Scholar
  91. 91.
    Uciechowski P, Imhoff H, Lange C, Meyer CG, Browne EN, Kirsten DK, Schroder AK, Schaaf B, Al-Lahham A, Reinert RR, Reiling N, Haase H, Hatzmann A, Fleischer D, Heussen N, Kleines M, Rink L (2011) Susceptibility to tuberculosis is associated with TLR1 polymorphisms resulting in a lack of TLR1 cell surface expression. J Leukoc Biol 90:377–388CrossRefPubMedGoogle Scholar
  92. 92.
    Johnson CM, Lyle EA, Omueti KO, Stepensky VA, Yegin O, Alpsoy E, Hamann L, Schumann RR, Tapping RI (2007) Cutting edge: a common polymorphism impairs cell surface trafficking and functional responses of TLR1 but protects against leprosy. J Immunol 178:7520–7524CrossRefPubMedGoogle Scholar
  93. 93.
    Eisenbarth GS (1986) Type I diabetes mellitus. A chronic autoimmune disease. N Engl J Med 314:1360–1368CrossRefPubMedGoogle Scholar
  94. 94.
    Bednar KJ, Ridgway WM (2014) Targeting innate immunity for treatment of type 1 diabetes. Immunotherapy 6:1239–1242CrossRefPubMedGoogle Scholar
  95. 95.
    Needell JC, Zipris D (2017) Targeting innate immunity for type 1 diabetes prevention. Curr Diab Rep 17:113. CrossRefPubMedGoogle Scholar
  96. 96.
    Bednar KJ, Tsukamoto H, Kachapati K, Ohta S, Wu Y, Katz JD, Ascherman DP, Ridgway WM (2015) Reversal of new-onset type 1 diabetes with an agonistic TLR4/MD-2 monoclonal antibody. Diabetes 64:3614–3626CrossRefPubMedGoogle Scholar
  97. 97.
    Hara N, Alkanani AK, Dinarello CA, Zipris D (2014) Histone deacetylase inhibitor suppresses virus-induced proinflammatory responses and type 1 diabetes. J Mol Med (Berl) 92:93–102CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Zhiguo Xie
    • 1
    • 2
  • Gan Huang
    • 1
    • 2
  • Zhen Wang
    • 1
    • 2
  • Shuoming Luo
    • 1
    • 2
  • Peilin Zheng
    • 1
    • 2
  • Zhiguang Zhou
    • 1
    • 2
    Email author
  1. 1.Department of Metabolism & Endocrinology, The Second Xiangya HospitalCentral South UniversityChangshaChina
  2. 2.Key Laboratory of Diabetes Immunology (Central South University), Ministry of EducationNational Clinical Research Center for Metabolic DiseasesChangshaChina

Personalised recommendations