TITLE:
Role of Sphingosine 1-Phosphate (S1P) Receptor 1 in Experimental Autoimmune Encephalomyelitis —I
AUTHORS:
Noriyasu Seki, Yasuhiro Maeda, Hirotoshi Kataoka, Kunio Sugahara, Kenji Chiba
KEYWORDS:
Sphingosine 1-Phosphosphate Receptor 1; Fingolimod Hydrochloride (FTY720); Experimental Autoimmune Encephalomyelitis; Th1 Cells; Th17 Cells
JOURNAL NAME:
Pharmacology & Pharmacy,
Vol.4 No.8,
November
26,
2013
ABSTRACT:
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 immunized 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
lymphocytes, MOG-immunized mice developed EAE symptoms with significant
infiltration of Th1 and Th17 cells into the CNS and a marked elevation of IFN-γ,
T-bet, IL-17, and RORγt mRNA expressions. Prophylactic administration of
an S1P1 functional antagonist, fingolimod hydrochloride (FTY720, 0.3 mg/kg,
orally) significantly inhibited EAE development and almost completely prevented
infiltration of Th1 and Th17 cells into the CNS with a marked reduction of IFN-γ,
T-bet, IL-17, and RORγt 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 generation 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.