The critical role of sphingosine-1-phosphate (S1P) signaling in lymphocyte trafficking is well recognized, however, the contribution of myeloid cell-S1P signaling in neuroimmunity is less well understood. We previously reported that C57BL/6J mice harboring phosphorylation defective S1P receptor 1 (S1P1) (with mutated serines in the carboxyl terminus, leading to impaired receptor internalization) [S1P1(S5A)] developed severe, TH17-dominant experimental autoimmune encephalomyelitis. In this study, we demonstrate that S1P1-mediated TH17 polarization is not an intrinsic T cell effect, but dependent on sustained S1P1 signaling in myeloid cells. First, utilizing the S1P1(S5A) mice in the EAE model, we observed that S1P1 activated and enhanced antigen presentation function in myeloid cells. Second, sequential phosphorylation of STAT3 occurred in dendritic cells, monocytes, and macrophages/microglia during neuroinflammation. Third, we show that pro-inflammatory (CD45hiCD11b+Ly6Chi) monocytes contribute to TH17 differentiation and neuroinflammation by regulating IL-6 expression. Finally, results from experiments utilizing myeloid cell-specific S1P1 overexpression (S1pr1f/stop/f:LysMCre) mice demonstrate that myeloid cell S1P1 directly contributes to severity of neuroinflammation. These findings reveal the critical contribution of myeloid-S1P1 signaling in CNS autoimmunity.

中文翻译：

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髓鞘鞘氨醇-1-磷酸受体1对于中枢神经系统自身免疫和神经炎症很重要。

鞘氨醇-1-磷酸（S1P）信号传导在淋巴细胞运输中的关键作用是众所周知的，但是，对髓样细胞-S1P信号传导在神经免疫中的作用了解得很少。我们先前曾报道，携带磷酸化缺陷的S1P受体1（S1P1）（羧基末端的丝氨酸突变，导致受体内化受损）的C57BL / 6J小鼠[S1P1（S5A）]发展为以TH17为主的严重实验性自身免疫性脑脊髓炎。在这项研究中，我们证明S1P1介导的TH17极化不是固有的T细胞效应，而是依赖于髓样细胞中持续的S1P1信号传导。首先，利用EAE模型中的S1P1（S5A）小鼠，我们观察到S1P1在髓样细胞中激活和增强了抗原呈递功能。第二，STAT3的顺序磷酸化发生在神经炎症过程中的树突状细胞，单核细胞和巨噬细胞/小胶质细胞中。第三，我们显示促炎性（CD45hiCD11b + Ly6Chi）单核细胞通过调节IL-6表达来促进TH17分化和神经炎症。最后，利用髓样细胞特异性S1P1过表达（S1pr1f / stop / f：LysMCre）小鼠的实验结果表明，髓样细胞S1P1直接导致神经炎症的严重程度。这些发现揭示了髓样-S1P1信号在中枢神经系统自身免疫中的关键作用。利用髓样细胞特异性S1P1过表达（S1pr1f / stop / f：LysMCre）小鼠进行实验的结果表明，髓样细胞S1P1直接导致神经炎症的严重程度。这些发现揭示了髓样-S1P1信号在中枢神经系统自身免疫中的关键作用。利用髓样细胞特异性S1P1过表达（S1pr1f / stop / f：LysMCre）小鼠进行实验的结果表明，髓样细胞S1P1直接导致神经炎症的严重程度。这些发现揭示了髓样-S1P1信号在中枢神经系统自身免疫中的关键作用。