Toll like Receptor 9 (TLR9) and its Role in Development of Autoimmune Diseases

doi:10.3969/j.issn.1005-4979.2019.05.011

Abstract

Abstract: Toll-like receptor 9 (TLR9) is a pattern recognition receptor that activates signaling pathway by identifying the unmethylated Cytosine - phosphate - cytosine (CpG DNA) motifs of viruses and bacteria, triggering both innate and adaptive immune responses. More studies have shown that activation of TLR9 plays an important role in the occurrence and development of autoimmune diseases. This review summarizes the research progress of TLR9 pathway in various autoimmune diseases in recent years, providing evidence for searching the new targets for the treatment of autoimmune diseases.

Key words: TLR9, autoimmune disease, SLE, MS, psoriasis, Sjgren's syndrome

摘要： Toll样受体9（TLR9)是一种模式识别受体，通过识别病毒和细菌上未甲基化的胞嘧啶-磷酸-鸟嘧啶（CpG DNA）基序，激活信号通路，引发固有免疫应答和适应性免疫应答。越来越多的研究表明TLR9的激活在自身免疫性疾病的发生发展中发挥重要作用。本文总结了近年来TLR9通路在各种自身免疫性疾病中的研究进展，为寻找治疗自身免疫性疾病的新靶点提供依据。

关键词: Toll样受体9（TLR9）, 自身免疫性疾病, 系统性红斑狼疮, 多发性硬化, 银屑病, 舍格伦综合症

CLC Number:

R782

YE Lei1,2, SHI Huan1,2, ZHENG Ling-yan1,2, YU Chuang-qi1,2. Toll like Receptor 9 (TLR9) and its Role in Development of Autoimmune Diseases[J]. 《Journal of Oral and Maxillofacial Surgery》, doi: 10.3969/j.issn.1005-4979.2019.05.011.

叶蕾1,2，石欢1,2，郑凌艳1,2，俞创奇1,2. Toll样受体9（TLR9）及其在自身免疫性疾病发生发展中的作用[J]. 《口腔颌面外科杂志》, doi: 10.3969/j.issn.1005-4979.2019.05.011.

/ / Recommend / Download Citations

URL: https://journal06.magtech.org.cn/Jweb_joms/EN/10.3969/j.issn.1005-4979.2019.05.011

https://journal06.magtech.org.cn/Jweb_joms/EN/Y2019/V29/I5/290

References

[1] Lee YH, Bae SC, Kim JH, et al. Toll-like receptor polymorphisms and rheumatoid arthritis: a systematic review [J]. Rheumatol Int, 2014, 34[1]:111-116. [2] Chen JQ, Szodoray P, Zeher M. Toll-like receptor Pathways in Autoimmune Diseases [J]. Clin Rev Allergy Immunol, 2016, 50[1]:1-17. [3] Celhar T, Magalh?es R, Fairhurst AM. TLR7 and TLR9 in SLE: when sensing self goes wrong[J]. Immunol Res, 2012, 53[1-3]:58-77. [4] Muto M, Manfroi B, Suzuki H, et al. Toll-like receptor 9 stimulation induces aberrant expression of a proliferation-inducing ligand by tonsillar germinal center B cells in IgA nephropathy[J]. J Am Soc Nephrol, 2017, 28[4]:1227-1238. [5] Mortezagholi S, Babaloo Z, Rahimzadeh P, et al. Evaluation of TLR9 expression on PBMCs and CpG ODN-TLR9 ligation on IFN-alpha production in SLE patients [J]. Immunopharmacol Immunotoxicol, 2017, 39[1]:11-18. [6] Tsao JT, Hsieh SC, Chiang BL, et al. Altered IL-10 and TNF-alpha production in peripheral blood mononuclear cells of systemic lupus erythematosus patients after Toll-like receptor 2,4, or 9activation [J]. Clin Exp Med, 2012, 12[3]:153-158. [7] Gies V, Schickel JN, Jung S, et al. Impaired TLR9 responses in B cells from patients with systemic lupus erythematosus [J]. JCI Insight, 2018, 3[5]: e96795. [8] Desnues B, Macedo AB, Roussel-Queval A, et al. TLR8 on dendritic cells and TLR9 on B cells restrain TLR7-mediated spontaneous autoimmunity in C57BL/6 mice[J]. Proc Natl Acad Sci U S A, 2014,111[4]:1497–1502. [9] Mills RE, Lam VC, Tan A, et al. Unbiased modifier screen reveals that signal strength determines the regulatory role murine TLR9 plays in autoantibody production [J]. J Immunol, 2015, 194[8]:3675-3686. [10] Celhar T, Yasuga H, Lee HY, et al. Toll-like receptor 9 deficiency breaks tolerance to RNA-associated antigens and up-regulates Toll-like receptor 7 protein in SLE1 mice[J]. Arthritis Rheumatol, 2018, 70[10]:1597-1609. [11] Liu Y, Seto NL, Carmona-Rivera C, et al. Accelerated model of lupus autoimmunity and vasculopathy driven by Toll-like receptor 7/9 imbalance[J]. Lupus Sci Med, 2018,5[1]: e000259. [12] Jackson SW, Scharping NE, Kolhatkar NS, et al. Opposing impact of B cell-intrinsic TLR7 and TLR9 signals on autoantibody repertoire and systemic inflammation[J]. J Immunol, 2014, 192[10]:4525-4532. [13] Murayama G, Furusawa N, Chiba A, et al. Enhanced IFN-alpha production is associated with increased TLR7 retention in the lysosomes of palasmacytoid dendritic cells in systemic lupus erythematosus[J]. Arthritis Res Ther, 2017, 19[1]:234. [14] Yuan Y, Yang M, Wang K, et al. Excessive activation of the TLR9/TGF-β1/PDGF-B pathway in the peripheral blood of patients with systemic lupus erythematosus [J]. Arthritis Res Ther, 2017, 19[1]:70. [15] Miranda-Hernandez S, Baxter AG. Role of Toll-like receptors in multiple sclerosis[J]. Am J Clin Exp Immunol, 2013, 2[1]: 75-93. [16] Crooks J, Gargaro M, Vacca C, et al. CpG Type A Induction of an Early Protective Environment in Experimental Multiple Sclerosis[J]. Mediators Inflamm, 2017, 1-12. [17] Zhou Y, Fang L, Peng L, et al. TLR9 and its signaling pathway in multiple sclerosis[J]. J Neurol Sci, 2017, 373:95-99. [18] White M, Webster G, O'Sullivan D, et al. Targeting innate receptors with MIS416 reshapes Th responses and suppresses CNS disease in a mouse model of multiple sclerosis [J]. PLoS One, 2014, 9[1]:e87712. [19] Eriksen AB, Berge T, Gustavsen MW, et al. Retinoic acid enhances the levels of IL-10 in TLR-stimulated B cells from patients with relapsing-remitting multiple sclerosis [J]. J Neuroimmunol, 2015, 278:11-18. [20] Tripathi D, Venkatasubramanian S, Cheekatla SS, et al. A TLR9 agonist promotes IL-22-dependent pancreatic islet allograft survival in type 1 diabetic mice[J]. Nat Commun, 2016, 7:13896. [21] Tai N, Wong FS, Wen L. The role of the innate immune system in destruction of pancreatic beta cells in NOD mice and humans with type I diabetes[J]. J Autoimmun, 2016, 71:26-34. [22] Wong FS, Hu C, Zhang L, et al. The role of Toll-like receptors 3 and 9 in the development of autoimmune diabetes in NOD mice[J]. Ann N Y Acad Sci, 2008, 1150:146-148. [23] Zhang Y, Lee AS, Shameli A, et al. TLR9 blockade inhibits activation of diabetogenic CD8+ T cells and delays autoimmune diabetes[J]. J Immunol, 2010, 184[10]:5645-5653. [24] Kayserova J, Vcelakova J, Stechova K, et al. Decreased dendritic cell numbers but increased TLR9-mediated interferon-alpha production in first degree relatives of type 1 diabetes patients [J]. Clin Immunol, 2014, 153(1):49-55. [25] Tai N, Wong FS, Wen L. TLR9 deficiency promotes CD73 expression in T cells and diabetes protection in nonobese diabetic mice [J]. J Immunol, 2013, 191(6):2926-2937. [26] Balak DM, van Doorn MB, Arbeit RD, et al. IMO-8400, a Toll-like receptor 7, 8, and 9 antagonist, demonstrates clinical activity in a phase 2a, randomized, placebo-controlled trial in patients with moderate-to-severe plaque psoriasis [J]. Clin Immunol, 2017, 174:63-72. [27] Li ZJ, Choi DK, Sohn KC, et al. Induction of Interleukin-22 (IL-22) production in CD4(+) T Cells by IL-17A secreted from CpG-stimulated keratinocytes[J]. Ann Dermatol, 2016, 28(5):579-585. [28] Rahmani F, Rezaei N. Therapeutic targeting of Toll-like receptors: a review of Toll-like receptors and their signaling pathways in psoriasis [J]. Expert Rev Clin Immunol, 2016, 12(12):1289-1298. [29] Kim SY, Hur MS, Choi BG, et al. A preliminary study of new single polymorphisms in the T helper type 17 pathway for psoriasis in the Korean population [J]. Clin Exp Immunol, 2017, 187(2):251-258. [30] Donetti E, Cornaghi L, Arnaboldi F, et al. Epidermal barrier reaction to an in vitro psoriatic microenvironment [J]. Exp Cell Res, 2017, 360(2):180-188. [31] Liu W, Yang X, Wang N, et al. Multiple immunosuppressive effects of CpG-c41 on intracellular TLR-Mediated inflammation [J]. Mediators Inflamm, 2017, 2017:1-10. [32] Lai CY, Yeh DW, Lu CH, et al. Identification of Thiostrepton as a novel inhibitor for Psoriasis-like inflammation induced by TLR7-9 [J]. J Immunol, 2015, 195(8):3912-3921. [33] Mavragani CP, Moutsopoulos HM. Sj?觟gren's syndrom [J]. Annu Rev Pathol, 2014, 9(3):273-285. [34] Zheng L, Zhang Z, Yu C, et al. Expression of Toll-like receptors 7,8, and 9 in primary Sj?觟gren's syndrome [J]. Oral Surg Oral Med Oral Pathol Oral Radiol Endod, 2010, 109(6):844-850. [35] Guerrier T, Le Pottier L, Youinou P, et al. Importance of Toll-like receptors for B lymphocyte survival in primary Sj?觟gren's syndrome [J]. Bull Group Int Rech Sci Stomatol Odontol, 2013, 52(1):e1-6. [36] Guerrier T, Le Pottier L, Devauchelle V, et al. Role of Toll-like receptors in primary Sj?觟gren's syndrome with a special emphasis on B-cell maturation within exocrine tissues [J]. J Autoimmun, 2012, 39(1-2):69-76. [37] Karlsen M, Jonsson R, Brun JG, et al. TLR-7 and -9 stimulation of peripheral blood B cells indicate altered TLR signalling in primary Sj?觟gren's Syndrome patients by increased secretion of cytokines [J]. Scand J Immunol, 2015, 82(6):523-531. [38] Shi H, Yu CQ, Xie LS, et al. Activation of TLR9-dependent p38MAPK pathway in the pathogenesis of primary Sj?觟gren's syndrome in NOD/Ltj mouse [J]. J Oral Pathol Med, 2014, 43(10):785-791. [39] Adi G G , Yochai W , Geula H , et al. Activation of the alternative NFkappaB pathway improves disease symptoms in a model of Sj?觟gren's syndrome [J]. PLoS One, 2011, 6(12):e28727. [40] Katherine M , Joanne S , Sheila B , et al. Immune tolerance to apoptotic self is mediated primarily by regulatory B1a cells [J]. Front Immunol. 2017, 8:1952.

Please choose a citation manager

Content to export