RKIP mediates autoimmune inflammation by positively regulating IL-17R signaling
RKIP mediates autoimmune inflammation by positively regulating IL-17R signaling
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RKIP 通过正向调节 IL-17R 信号传导介导自身免疫炎症
DOI：
10.15252/embr.201744951
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发表时间：
2018-06-01
期刊：
影响因子：
7.7
通讯作者：
Wang, Xiaojian
中科院分区：
文献类型：
--
作者：
Lin, Wenlong;Wang, Ning;Wang, Xiaojian
Th17 细胞通过分泌白细胞介素 17 (IL-17) 来促进自身免疫性疾病的发展，白细胞介素 17 会激活上皮细胞、巨噬细胞、小胶质细胞和常驻神经外胚层细胞上表达的受体 (IL-17R)。然而，IL-17R 介导的信号传导导致自身免疫性疾病发生的机制尚未完全阐明。在这里，我们证明小鼠 Raf-1 激酶抑制剂蛋白 (RKIP) 缺陷可改善实验性自身免疫性脑脊髓炎 (EAE) 的症状。过继性 T 细胞转移实验表明 RKIP 在 Th17 介导的免疫反应中起主要作用，但在 Th1 介导的免疫反应中不起主导作用。 RKIP 缺陷对离体 Th17 细胞分化没有影响，也不影响 EAE 小鼠中 Th17 细胞分化。然而，RKIP 显着促进 IL-17R 诱导的促炎细胞因子和趋化因子的产生。从机制上讲，RKIP 直接与 IL-17RA 和 Act1 相互作用，促进 IL-17R-Act1 复合物的形成，从而增强 MAPK 和 P65 介导的 NF-B 激活和下游细胞因子的产生。总之，这些发现表明 RKIP 在 IL-17R 信号传导中充当 IL-17R-Act1 轴的重要调节剂，促进 IL-17 诱导的炎症和自身免疫性神经炎症。
Th17 cells contribute to the development of autoimmune diseases by secreting interleukin-17 (IL-17), which activates its receptor (IL-17R) that is expressed on epithelial cells, macrophages, microglia, and resident neuroectodermal cells. However, the mechanisms through which IL-17R-mediated signaling contributes to the development of autoimmune disease have not been completely elucidated. Here, we demonstrate that Raf-1 kinase inhibitor protein (RKIP) deficiency in mice ameliorates the symptoms of experimental autoimmune encephalomyelitis (EAE). Adoptive T-cell-transfer experiments demonstrate that RKIP plays a predominant role in Th17-mediated, but not in Th1-mediated immune responses. RKIP deficiency has no effect on Th17-cell differentiation ex vivo, nor does it affect Th17-cell differentiation in EAE mice. However, RKIP significantly promotes IL-17R-induced proinflammatory cytokine and chemokine production. Mechanistically, RKIP directly interacts with IL-17RA and Act1 to promote the formation of an IL-17R-Act1 complex, resulting in enhanced MAPK- and P65-mediated NF-B activation and downstream cytokine production. Together, these findings indicate that RKIP functions as an essential modulator of the IL-17R-Act1 axis in IL-17R signaling, which promotes IL-17-induced inflammation and autoimmune neuroinflammation.