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Role of sphingosine 1-phosphate (S1P) receptor 1 in experimental autoimmune encephalomyelitisI

Seki, N;Maeda, Y;Kataoka, H;Sugahara, K;Chi, K;

Infiltration of myelin-specific helper T (Th) cells into the central nervous system (CNS) plays a key role in pathogenesis of experimental autoimmune encephalomyelitis (EAE). In this study, we investigated the involvement of sphingosine 1-phosphate (S1P)-S1P receptor 1 (S1P1) axis in lymphocytes for EAE development when C57BL/6 mice were immu- nized with myelin oliogodendrocyte glycoprotein (MOG). The expression of S1P1 mRNA and S1P responsiveness of lymphocytes in draining lymph nodes (DLN) were down-regulated markedly after MOG immunization until onset of EAE. Accompanying with reacquisition of down-regulated S1P1 transcript and S1P responsiveness in DLN lympho- cytes, MOG-immunized mice developed EAE symptoms with significant infiltration of Th1 and Th17 cells into the CNS and a marked elevation of IFN-, T-bet, IL-17, and RORt mRNA expressions. Prophylactic administration of an S1P1 functional antagonist, fingolimod hydrochloride (FTY720, 0.3 mg/kg, orally) significantly inhibited EAE devel- opment and almost completely prevented infiltration of Th1 and Th17 cells into the CNS with a marked reduction of IFN-, T-bet, IL-17, and RORt mRNA expressions. Similar results were obtained by treatment with an S1P1-selective agonist, SEW2871 or an S1P lyase inhibitor, 2-acetyl-4-tetrahydroxybutylimidazole. Moreover, FTY720-phosphate and SEW2871 inhibited in vitro migration of Th1 and Th17 cells toward S1P but did not affect cytokine production or gen- eration of Th1 or Th17 cells. These results suggest that reacquisition of S1P1 expression in DLN lymphocytes plays a major role in trafficking of myelin antigen-specific Th1/Th17 cells from DLN to the CNS in EAE and that prophylactic effect of FTY720 on EAE is predominantly caused by functional antagonism via lymphocytic S1P1