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

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 (S1P) (with mutated serines in the carboxyl terminus, leading to impaired receptor internalization) [S1P(S5A)] developed severe, T17-dominant experimental autoimmune encephalomyelitis. In this study, we demonstrate that S1P-mediated T17 polarization is not an intrinsic T cell effect, but dependent on sustained S1P signaling in myeloid cells. First, utilizing the S1P(S5A) mice in the EAE model, we observed that S1P 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 (CD45CD11bLy6C) monocytes contribute to T17 differentiation and neuroinflammation by regulating IL-6 expression. Finally, results from experiments utilizing myeloid cell-specific S1P overexpression (S1pr1:LysM) mice demonstrate that myeloid cell S1P directly contributes to severity of neuroinflammation. These findings reveal the critical contribution of myeloid-S1P signaling in CNS autoimmunity.