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Activation of TLR 9‐dependent p38 MAPK pathway in the pathogenesis of primary S jögren's syndrome in NOD / L tj mouse
Author(s) -
Shi Huan,
Yu ChuangQi,
Xie LiSong,
Wang ZhiJun,
Zhang Ping,
Zheng LingYan
Publication year - 2014
Publication title -
journal of oral pathology and medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.887
H-Index - 83
eISSN - 1600-0714
pISSN - 0904-2512
DOI - 10.1111/jop.12209
Subject(s) - nod , pathogenesis , peripheral blood mononuclear cell , medicine , receptor , mapk/erk pathway , endocrinology , immunology , pathology , chemistry , signal transduction , diabetes mellitus , biochemistry , in vitro
Objective The objective of this study was to investigate the potential role of T oll‐like receptor 9‐dependent p38 MAPK signaling pathway in the pathogenesis of primary S jögren's syndrome (p SS ) in NOD / L tj mouse, aiming to identify an ideal target therapy model for human p SS . Methods NOD / L tj mice were chosen as a model of p SS . The T oll‐like receptor 9 and p‐p38 MAPK double‐positive peripheral blood mononuclear cells ( PBMC s) of 4‐, 5‐, 8‐, 10‐, and 15‐week‐old NOD / L tj mouse were analyzed by flow cytometry. The expressions of T oll‐like receptor 9 and p‐p38 MAPK in the submandibular gland ( SMG ) were also examined by immunohistochemistry. The change of stimulated salivary flow rate was dynamically measured, and the histopathology of SMG was evaluated by hematoxylin and eosin stain. Results The stimulated salivary flow rate in NOD / L tj was reduced to 50–60% of the flow rate of control mice since the fifth week onwards. The T oll‐like receptor 9 and p‐p38 MAPK double‐positive PBMC s in both groups increased gradually from 5 weeks, peaked at 8 weeks and then gradually decreased at 10 weeks, yet the percentage of T oll‐like receptor 9 and p‐p38 MAPK double‐positive PBMC s in 5‐, 8‐, and 10‐week‐old NOD / L tj mouse was significantly increased compared with those in control subjects. After the 10th week onwards, there were no significant differences in the T oll‐like receptor 9 and p‐p38 MAPK double‐positive PBMC s between NOD / L tj mice and controls. Immunohistochemical staining showed that T oll‐like receptor 9 was positive in the acinar epithelium cells and infiltrating lymphocytes in NOD / L tj mice. p‐p38 MAPK was detected in infiltrating lymphocytes and few ductal or acinar epithelium cells adjacent to infiltrating lymphocytes in NOD / L tj mice. Conclusions From the fifth week till the tenth week, T oll‐like receptor 9 and p‐p38 MAPK double‐positive PBMC s were significantly increased in NOD / L tj mice, accompanied with reduced stimulated salivary flow rate and T oll‐like receptor 9 or p‐p38 MAPK positive infiltrating lymphocytes observed in the SMG of NOD / L tj mouse. Our results indicated that activation of T oll‐like receptor 9‐depended p38 MAPK signal pathway in PBMC s was an early event in p SS which made NOD / L tj as an ideal therapy model to test the treatment effects of p38 MAPK or T oll‐like receptor 9 inhibitors on p SS .