FTY720 Abrogates Collagen-Induced Arthritis by Hindering Dendritic Cell Migration to Local Lymph Nodes
FTY720 Abrogates Collagen-Induced Arthritis by Hindering Dendritic Cell Migration to Local Lymph Nodes
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FTY720 通过阻碍树突状细胞迁移至局部淋巴结来消除胶原诱导的关节炎
DOI：
10.4049/jimmunol.1401842
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发表时间：
2015-11-01
影响因子：
4.4
通讯作者：
Sun, Erwei
中科院分区：
文献类型：
--
作者：
Han, Yanping;Li, Xing;Sun, Erwei
由于树突状细胞（DC）在类风湿性关节炎的发病机制中起关键作用，对其功能的调节可作为一种新的治疗方法。在本研究中，我们证明FTY720治疗通过调节DC功能显著抑制了DBA/1J小鼠胶原诱导性关节炎（CIA）的发病率和严重程度。在FTY720治疗的CIA小鼠中，观察到局部引流淋巴结（LNs）中DC数量减少。在体外，FTY720抑制脂多糖刺激的骨髓来源DC（BMDC）的迁移。DC上CCL19分泌减少以及CCR7下调可能解释了FTY720诱导DC迁移受损的机制。在DC诱导的小鼠关节炎模型中，FTY720治疗也抑制了关节炎的发病率和严重程度，这与注射的BMDC向引流LNs迁移减少相关。尽管在FTY720治疗的小鼠中观察到淋巴结DC上共刺激分子（CD40、CD80和CD86）以及I - A(q)表达水平较低，但体外分析显示FTY720对脂多糖刺激的BMDC成熟没有影响。此外，FTY720治疗的CIA小鼠的淋巴结细胞在胶原蛋白II和刀豆蛋白A刺激下促炎细胞因子的产生减少。此外，FTY720治疗后DC诱导关节炎小鼠引流淋巴结中Th1/Th2的比例降低。这一发现与FTY720抑制培养的BMDC中IL - 12p70产生的事实相符。综上所述，这些结果表明FTY720对DC迁移的抑制可能为治疗类风湿性关节炎等自身免疫性疾病提供一种新方法。
Because dendritic cells (DCs) play critical roles in the pathogenesis of rheumatoid arthritis, modulation of their functions could serve as a novel therapy. In this study, we demonstrated that FTY720 treatment significantly suppressed the incidence and severity of collagen-induced arthritis (CIA) in DBA/1J mice via the modulation of DC functions. In FTY720-treated CIA mice, a decrease in the number of DCs in local draining lymph nodes (LNs) was observed. In vitro, FTY720 inhibited the trafficking of LPS-stimulated bone marrow–derived DCs (BMDCs). Decreased secretion of CCL19 and downregulation of CCR7 on DCs may explain the mechanisms underlying the impairment of DC migration induced by FTY720. In a DC-induced mouse arthritis model, FTY720 treatment also suppressed the incidence and severity of arthritis, which was correlated with a decrease in the migration of injected BMDCs to draining LNs. Although lower levels of costimulatory molecules (CD40, CD80, and CD86) and I-Aq expressed on LN DCs were observed in FTY720-treated mice, in vitro analysis showed no effect of FTY720 on LPS-stimulated BMDC maturation. Furthermore, LN cells from FTY720-treated CIA mice displayed diminished production of proinflammatory cytokines in response to collagen II and Con A stimulation. In addition, the ratio of Th1/Th2 in the draining LNs of mice with DC-induced arthritis was decreased upon FTY720 treatment. This finding was consistent with the fact that FTY720 suppressed IL-12p70 production in cultured BMDCs. Taken together, these results indicate that inhibition of DC migration by FTY720 may provide a novel approach in treating autoimmune diseases such as rheumatoid arthritis.