Role of Sphingosine 1-Phosphate (S1P) Receptor 1 in Experimental Autoimmune Encephalomyelitis —I

Abstract

Infiltration of myelin-specific helper T (Th) cells into the central\rnervous system (CNS) plays a key role in pathogenesis of experimental\rautoimmune encephalomyelitis (EAE). In this study, we investigated the\rinvolvement of sphingosine 1-phosphate (S1P)-S1P receptor 1 (S1P1) axis in\rlymphocytes for EAE development when C57BL/6 mice were immunized with myelin\roliogodendrocyte glycoprotein (MOG). The expression of S1P1 mRNA and S1P\rresponsiveness of lymphocytes in draining lymph nodes (DLN) were down-regulated\rmarkedly after MOG immunization until onset of EAE. Accompanying with\rreacquisition of down-regulated S1P1 transcript and S1P responsiveness in DLN\rlymphocytes, MOG-immunized mice developed EAE symptoms with significant\rinfiltration of Th1 and Th17 cells into the CNS and a marked elevation of IFN-γ,\rT-bet, IL-17, and RORγt mRNA expressions. Prophylactic administration of\ran S1P1 functional antagonist, fingolimod hydrochloride (FTY720, 0.3 mg/kg,\rorally) significantly inhibited EAE development and almost completely prevented\rinfiltration of Th1 and Th17 cells into the CNS with a marked reduction of IFN-γ,\rT-bet, IL-17, and RORγt mRNA expressions. Similar results were obtained\rby treatment with an S1P1-selective agonist, SEW2871 or an S1P lyase inhibitor,\r2-acetyl-4-tetrahydroxybutylimidazole. Moreover, FTY720-phosphate and SEW2871\rinhibited in vitro migration of Th1 and Th17 cells toward S1P but did\rnot affect cytokine production or generation of Th1 or Th17 cells. These\rresults suggest that reacquisition of S1P1 expression in DLN lymphocytes plays\ra major role in trafficking of myelin antigen-specific Th1/Th17 cells from DLN\rto the CNS in EAE and that prophylactic effect of FTY720 on EAE is\rpredominantly caused by functional antagonism via lymphocytic S1P1.