TLR9依赖的p38MAPK信号通路对鼠原发性舍格伦综合征的影响

doi:10.3969/j.issn.1005-4979.2016.04.005

《口腔颌面外科杂志》 ›› 2016, Vol. 26 ›› Issue (4): 256-263. doi: 10.3969/j.issn.1005-4979.2016.04.005

TLR9依赖的p38MAPK信号通路对鼠原发性舍格伦综合征的影响

曹宁宁，郑凌艳，俞创奇，石欢，高绮曼，陈婵

上海交通大学医学院附属第九人民医院·口腔医学院口腔外科，上海市口腔医学重点实验室，上海 200011

收稿日期:2016-03-01 修回日期:2016-06-01 出版日期:2016-08-28 发布日期:2016-09-24
通讯作者: 郑凌艳，副主任医师. E-mail: zhenglingyan73@163.com E-mail:zhenglingyan73@163.com
作者简介:曹宁宁（1991—），男，山东济宁人，硕士研究生. E-mail: caoningning0529@163.com
基金资助:
国家自然科学基金资助项目(81100766)；上海市重点学科建设项目（S30206）

Inhibition of TLR9-dependent p38MAPK Signaling Pathway Attenuates the Pathogenesis of primary Sjogren's Syndrome in Mouse

CAO Ning-ning, ZHENG Ling-yan, YU Chuang-qi, SHI Huan, GAO Qi-man, CHEN Chan

Department of Oral Surgery, the Ninth People's Hospital, College of Stomatology, School of Medicine, Shanghai Jiaotong University, Shanghai Key Laboratory of Stomatology, Shanghai 200011, China

Received:2016-03-01 Revised:2016-06-01 Online:2016-08-28 Published:2016-09-24

摘要/Abstract

摘要： 目的：在动物模型NOD（非肥胖型糖尿病）鼠中，观察研究Toll样受体9 （Toll Like Receptor 9, TLR9）依赖的p38MAPK信号通路在原发性舍格伦综合征发病机制中的作用。方法：实验选取5周龄的雌性NOD小鼠，分别给予3种抑制剂：ODN2088、VX-792、羟氯喹。利用流式细胞学技术检测小鼠外周血淋巴细胞的情况。利用免疫组化检测小鼠下颌下腺TLR9及p-p38 MAPK的表达情况。利用酶联免疫吸附测定（enzyme-linked immunosorbent assay，ELISA）检测小鼠外周血中血浆抗体的表达。利用Tunel方法检测小鼠下颌下腺腺上皮细胞的凋亡。同时，观察小鼠刺激性唾液流率的改变以及下颌下腺病理学改变。结果：只有ODN2088组的NOD小鼠的唾液流率显著增加。在所有被给予羟氯喹的NOD鼠和未接受治疗的NOD鼠中，下颌下腺均有淋巴细胞浸润灶的出现。但在ODN2088组中，只有1只NOD小鼠出现下颌下腺的淋巴细胞浸润灶。在VX-702组中，所有NOD小鼠均未发现淋巴细胞浸润灶。所有实验组的外周血淋巴细胞的数目显著减少。ODN2088组NOD小鼠的抗SSA/Ro抗体和抗SSB/La抗体的浓度是所有实验组中最低的。结论：TLR9依赖的p38MAPK信号通路的抑制，能一定程度上减轻原发性舍格伦综合征动物模型NOD鼠的临床表现。

关键词: 原发性舍格伦综合征, , , 非肥胖型糖尿病鼠（NOD鼠）, , , Toll样受体（TLR9）, , , p38 MAPK, , , 流式细胞术, , , 抑制剂

Abstract: Objective: To observe whether the inhibition of TLR9-dependent p38 MAPK pathway are associated with attenuation of symptoms and signs in the pathogenesis of primary Sjogren's syndrome(pSS). Methods: NOD/Ltj mice were selected as a model of pSS and Balb/c mice were used as control group. NOD/Ltj mice were treated by 3 inhibitors: ODN2088, VX-702, and hydroxychloroquine respectively. The changes of stimulated salivary flow rate was measured and the histopathology of submandibular gland was evaluated by HE stain. Peripheral blood mononuclear cells (PBMCs) derived from NOD and Balb/c mice were analysis by flow cytometry. The plasma derived from peripheral blood of NOD and Balb/c mice was analyzed by ELISA. Tunel method to detect epithelial cell apoptosis was performed on submandibular gland sections in NOD mice and Balb/c mice. Results: Compared with NOD/Ltj mice, only the salivary secretion of NOD/Ltj mice given ODN2088 was significantly increased. Periductal inflammatory cell foci were observed in the submandibularglands in the whole NOD mice given hydroxychloroquine, 1/5 of the NOD mice given ODN2088 and all of the NOD mice without any treatment. There were no lymphocytes foci in the NOD mice received VX-702. The number of lymphocytes was extremely low in NOD mice given VX-702, the NOD mice given ODN2088 and NOD mice given hydroxychloroquine. Titers of anti-SSA/Ro and anti-SSB/La in plasma of NOD mice given ODN2088 were the lowest among all groups. Conclusion: Inhibition of TLR9-dependent p38MAPK signaling pathway could alleviate the clinical symptoms of pSS to a certain extent. In addition, The activation of TLR9-dependent p38MAPK signaling pathway palys an important role in the pathogenesis of pSS in NOD/Ltj mice.

Key words: primary Sjogren's syndrome, NOD, TLR9, p38 MAPK, flow cytometry, inhibitor

中图分类号:

R781.77

曹宁宁，郑凌艳，俞创奇，石欢，高绮曼，陈婵. TLR9依赖的p38MAPK信号通路对鼠原发性舍格伦综合征的影响[J]. 《口腔颌面外科杂志》, 2016, 26(4): 256-263.

CAO Ning-ning, ZHENG Ling-yan, YU Chuang-qi, SHI Huan, GAO Qi-man, CHEN Chan. Inhibition of TLR9-dependent p38MAPK Signaling Pathway Attenuates the Pathogenesis of primary Sjogren's Syndrome in Mouse[J]. 《Journal of Oral and Maxillofacial Surgery》, 2016, 26(4): 256-263.

https://journal06.magtech.org.cn/Jweb_joms/CN/Y2016/V26/I4/256

参考文献

[1] Feltsan T, Stanko P, Mracna J. Sjogren′s syndrome in present[J]. Bratisl Lek Listy, 2012, 113(8):514-516.

[2] Bayetto K, Logan RM. Sjogren's syndrome: a review of aetiology, pathogenesis, diagnosis and management[J]. Aust Dent J, 2010, 55(Suppl 1 ):39-47.

[3] Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for Sjogren's syndrome: a revised version of the European criteria proposed by the American-European consensus group[J]. Ann Rheum Dis, 2002, 61(6):554-558.

[4] Bournia VK, Vlachoyiannopoulos PG.Subgroups of Sjogren syndrome patients according to serological profiles[J]. J Autoimmun, 2012, 39（1-2）:15-26.

[5] Nikolov NP，Illei GG. Pathogenesis of Sjogren's syndrome[J]. Curr Opin Rheumatol, 2009, 21(5):465-470.

[6] Voulgarelis M, Tzioufas AG. Pathogenetic mechanisms in the initiation and perpetuation of Sjogren's syndrome[J].Nat Rev Rheumatol, 2010, 6(9):529-537.

[7] Spachidou MP, Bourazopoulou E, Maratheftis CI, et al.. Expression of functional Toll-like receptors by salivary gland epithelial cells: increased mRNA expression in cellsderived from patients with primary Sjogren's syndrome[J]. Clin Exp Immunol, 2007, 147(3):497-503.

[8] Means TK, Latz E, Hayashi F, et al. Human lupus autoantibody-DNA complexes activate DCs through cooperation of CD32 and TLR9[J]. J Clin Invest, 2005, 115(2): 407-417.

[9] Guerrier T, Le Pottier L, Devauchelle V, et al. Role of Toll-like receptors in primary Sjogren's syndrome with a special emphasis on B-cell maturation within exocrine tissues[J]. J Autoimmun, 2012, 39(1-2):69-76.

[10] Rifkin IR, Leadbetter EA, Busconi L, et al. Toll-like receptors, endogenous ligands, and systemic autoimmune disease[J]. Immunol Rev, 2005, 204:27-42.

[11] Mavragani CP, Crow MK. Activation of the type I interferon pathway in primary Sjogren's syndrome[J]. J Autoimmun, 2010, 35(3):225-231.

[12] Gupta GK, Agrawal DK. CpG oligodeoxynucleotides as TLR9 agonists: therapeutic application in allergy and asthma[J]. BioDrugs, 2010, 24(4):225-235.

[13] Damjanov N, Kauffman RS, Spencer-Green GT. Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies[J]. Arthritis Rheum, 2009, 60(5):1232-1241.

[14] Dominguez C，Powers DA，Tamayo. N.p38 MAP kinase inhibitors: many are made, but few are chosen[J]. Curr Opin Drug Discov Devel，2005, 8(4):421-430.

[15] Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA[J]. Nature, 2000, 408(6813):740-745.

[16] Ho PP, Fontoura P, Ruiz PJ, et al. An immunomodulatoryGpG oligonucleotide for the treatment of autoimmunity via the innate and adaptive immunesystems[J]. J Immunol, 2003, 171(9):4920-4926.

[17] Krieg AM. CpG motifs in bacterial DNA and their immune effects[J]. Annu Rev Immunol, 2002, 20:709-760.

[18] Dong L, Ito S, Ishii KJ, et al. Suppressive oligodeoxynucleotides delay the onset of glomerulonephritis and prolong survival in lupus-prone NZB x NZW mice[J]. Arthritis Rheum, 2005, 52(2):651-658.

[19] Zwerina J, Hayer S, Redlich K, et al. Activation of p38 MAPK is a key step in tumor necrosis factor-mediated inflammatory bone destruction[J]. Arthritis Rheum, 2006, 54(2):463-472.

[20] Damjanov N, Kauffman RS, Spencer-Green GT:.Efficacy, pharmacodynamics, and safety of VX-702, a novel p38 MAPK inhibitor, in rheumatoid arthritis: results of two randomized, double-blind, placebo-controlled clinical studies[J]. Arthritis Rheum, 2009, 60(5):1232-1241.

[21] Zheng L, Zhang Z, Yu C, et al.Expression of Toll-like receptors 7, 8, and 9 in primary Sjogren's syndrome[J]. Oral Surg Oral Med Oral PatholOoral Radiol Endod, 2010, 109(6):844-850.

[22] Zheng L, Zhang Z, Yu C, et al. Association between IFN-alpha and primary Sjogren's syndrome[J]. Oral Surg Oral Med Oral Pathol Oral RadiolEndod，2009, 107(1):e12-e18.

[23] Willeke P, Schotte H, Schluter B, et al. Interleukin 1beta and tumour necrosis factor alpha secreting cells are increased in the peripheral blood of patients with primary Sjogren's syndrome[J]. Ann Rheum Dis, 2003, 62(4):359-362.

[24] Shi H, Yu CQ, Xie LS, et al. Activation of TLR9-dependent p38MAPK pathway in the pathogenesis of primary Sjogren's syndrome in NOD/Ltj mouse[J]. J Oral Pathol Med, 2014, 43(10):785-791.

[25] Greenspan JS, Daniels TE, Talal N, et al. The histopathology of Sjogren's syndrome in labial salivary gland biopsies[J]. Oral Surg Oral Med Oral Pathol, 1974, 37(2):217-229.

[26] Ping L，Ogawa N，Zhang Y，et al. p38 mitogen-activated protein kinase and nuclear factor-kB facilitate CD40-mediated salivary epithelial cell death[J]. J Rheumatol, 2012, 39(6):1256-1264.

[27] Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity[J]. Cell, 2006, 124（4）:783-801.

[28] Honda K, Yanai H, Takaoka A, et al. Regulation of the type IIFN induction: a current view[J]. Int Immunol, 2005, 17（11）:1367-1378.

[29] Ning S, Pagano JS, Barber GN. IRF7: activation, regulation, modification and function[J]. Genes Immun, 2011, 12(6):399-414.

[30] Sweeney SE. Targeting interferon regulatory factors to inhibit activation of the type I IFN response:implications for treatment of autoimmune disorders[J]. Cell Immunol, 2011, 271(2):342-349.

[31] Chen HC, Zhan X, Tran KK, et al. Selectively targeting the toll-like receptor 9 (TLR9)--IRF 7 signaling pathway by polymer blendparticles[J]. Biomaterials, 2013, 34(27):6464-6472.

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TLR9依赖的p38MAPK信号通路对鼠原发性舍格伦综合征的影响

Inhibition of TLR9-dependent p38MAPK Signaling Pathway Attenuates the Pathogenesis of primary Sjogren's Syndrome in Mouse

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