Deficiency of the G protein Gαq ameliorates experimental autoimmune encephalomyelitis with impaired DC-derived IL-6 production and Th17 differentiation
Deficiency of the G protein Gαq ameliorates experimental autoimmune encephalomyelitis with impaired DC-derived IL-6 production and Th17 differentiation
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G 蛋白 Galphaq 的缺乏可改善实验性自身免疫性脑脊髓炎，并导致 DC 衍生的 IL-6 产生和 Th17 分化受损
DOI：
10.1038/cmi.2016.65
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发表时间：
2017-06-01
影响因子：
24.1
通讯作者：
Du, Changsheng
中科院分区：
文献类型：
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作者：
Lai, Weiming;Cai, Yingying;Du, Changsheng
据报道，许多G蛋白偶联受体（GPCR）参与多发性硬化（MS）的发病机制，并且在所有鉴定的GPCR中，大约40%依赖于G α q/11 G蛋白家族来刺激肌醇脂质信号传导。然而，G α亚基在MS发病机制中的功能仍不清楚。在这项研究中，我们试图确定Gaq在实验性自身免疫性脑脊髓炎（EAE）发病机制中的作用，EAE是一种众所周知的MS小鼠模型。我们发现，与野生型小鼠相比，G α q敲除小鼠表现出不太严重的EAE症状，临床评分较低，白细胞浸润减少，脱髓鞘不太广泛。此外，在Gaq敲除EAE小鼠中观察到显著较低百分比的Th 17细胞，其是MS发病机制中的关键参与者之一。体外研究表明，CD 4（+）T细胞中Gaq的缺乏直接损害Th 17分化。此外，Gaq的缺乏显著损害DC来源的IL-6产生，从而抑制Th 17分化和参与DC产生的IL-6减少的G α q-PLC β-PKC和Gaq-MAPK信号通路。总之，我们的数据强调了G α q在调节Th 17分化和MS发病机制中的关键作用。
Many G protein-coupled receptors (GPCRs) are reported to be involved in the pathogenesis of multiple sclerosis (MS), and similar to 40% of all identified GPCRs rely on the G alpha q/11 G protein family to stimulate inositol lipid signaling. However, the function of G alpha subunits in MS pathogenesis is still unknown. In this study, we attempted to determine the role of Gaq in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a well-known mouse model of MS. We discovered that compared with wild-type mice, G alpha q-knockout mice exhibited less severe EAE symptoms, with lower clinical scores, reduced leukocyte infiltration and less extensive demyelination. Moreover, a significantly lower percentage of Th17 cells, one of the key players in MS pathogenesis, was observed in Gaq-knockout EAE mice. Studies in vitro demonstrated that deficiency of Gaq in CD4(+) T cells directly impaired Th17 differentiation. In addition, deficiency of Gaq significantly impaired DC-derived IL-6 production, thus inhibiting Th17 differentiation and the G alpha q-PLC beta-PKC and Gaq-MAPKs signaling pathways involved in the reduced IL-6 production by DCs. In summary, our data highlighted the critical role of G alpha q in regulating Th17 differentiation and MS pathogenesis.