Paroxetine alleviates T lymphocyte activation and infiltration to joints of collagen-induced arthritis.
Paroxetine alleviates T lymphocyte activation and infiltration to joints of collagen-induced arthritis.
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DOI：
10.1038/srep45364
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发表时间：
2017-03-28
影响因子：
4.6
通讯作者：
Wei W
中科院分区：
文献类型：
--
作者：
Wang Q;Wang L;Wu L;Zhang M;Hu S;Wang R;Han Y;Wu Y;Zhang L;Wang X;Sun W;Wei W
T细胞浸润滑膜组织是类风湿性关节炎（RA）的早期致病机制。在目前的工作中，我们发现 G 蛋白偶联受体激酶 2 (GRK2) 在胶原诱导性关节炎 (CIA) 的 T 细胞中大量表达。帕罗西汀是一种 GRK2 抑制剂，主要通过抑制 CD4+ 辅助 T (Th) 细胞和 CD8+ 细胞毒性 T (Tc) 细胞向滑膜组织的迁移来保护关节免受炎症和破坏。同时，帕罗西汀通过提高Thnaive、Tcnaive和调节性Th细胞的频率，使Th/Tc、效应器Th（Theff）/幼稚Th（Thnaive）和效应器Tc（Tceff）/幼稚Tc（Tcnaive）的平衡恢复平衡；减少增加的Theff，激活Th和Tceff，具有与甲氨蝶呤（MTX）相似的作用。此外，治疗大鼠的血清和滑膜IL-1β、TNF-α和CX3CL1表达均得到有效抑制。体外实验证实帕罗西汀通过阻断 GRK2 活性来抑制 CX3CL1 诱导的 T 细胞迁移。在三个 MAPK 家族中，帕罗西汀被发现能够降低 ERK 的磷酸化。这项研究阐明，帕罗西汀通过抑制 ERK 通路对 T 细胞活化和滑膜组织浸润产生抑制作用，从而减轻 CIA 大鼠的症状。
T cell infiltration to synovial tissue is an early pathogenic mechanism of rheumatoid arthritis (RA). In the present work, we reveal that G protein coupled receptor kinase 2 (GRK2) is abundantly expressed in T cells of collagen-induced arthritis (CIA). A GRK2 inhibitor, paroxetine protects the joints from inflammation and destruction, primarily through inhibition of both CD4+ helper T (Th) cell and CD8+ cytotoxic T (Tc) cell migration to synovial tissue. Meanwhile, paroxetine restores the balance of Th/Tc, effector Th (Theff)/ naïve Th (Thnaive) and effector Tc (Tceff)/ naïve Tc (Tcnaive) to equilibrium by elevating the frequency of Thnaive, Tcnaive and regulatory Th cells; reducing the increased Theff, activated Th and Tceff, having a similar effect as methotrexate (MTX). In addition, both serum and synovial IL-1β, TNF-α and CX3CL1 expression was effectively inhibited in treated rats. In vitro assay confirmed that paroxetine inhibits CX3CL1-induced T cell migration through blocking the activity of GRK2. Among three MAPK families, paroxetine was found to be able to decrease the phosphorylation of ERK. This study elucidates that paroxetine attenuates the symptoms of CIA rats due to its inhibitory effect on T cell activation and infiltration to synovial tissue via suppression of ERK pathway.