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Myeloid sphingosine-1-phosphate receptor 1 is important for CNS autoimmunity and neuroinflammation

Tsai, HC;Nguyen, K;Hashemi, E;Engleman, E;Hla, T;Han, MH;

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. Copyright 2019. Published by Elsevier Ltd.