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 (S1P₁) (with mutated serines in the carboxyl terminus, leading to impaired receptor internalization) [S1P₁(S5A)] developed severe, T_H17-dominant experimental autoimmune encephalomyelitis. In this study, we demonstrate that S1P₁-mediated T_H17 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 occurred in dendritic cells, monocytes, and macrophages/microglia during neuroinflammation. Third, we show that pro-inflammatory (CD45^hiCD11b⁺Ly6C^hi) monocytes contribute to T_H17 differentiation and neuroinflammation by regulating IL-6 expression. Finally, results from experiments utilizing myeloid cell-specific S1P₁ overexpression (S1pr1^f/stop/f:LysM^Cre) 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.

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