Sphingosine-1-phosphate (S1P) is a pleiotropic lysosphingolipid derived from the metabolism of plasma membrane
lipids. The interaction between S1P and its ubiquitously expressed
G-protein-coupled receptors (S1PR1-5) is crucial in many pathophysiological processes. Emerging evidence suggested a potential role for S1P receptors in
anti-neutrophil cytoplasmic antibody (
ANCA)-associated vasculitis (AAV). In the present study, we investigated the effects of three different S1P receptors modulators (
FTY720,
SEW2871 and
TY52156) in a recognized rat model of experimental autoimmune
vasculitis (EAV). The effects of treatments were evaluated with clinico-pathological parameters including
hematuria,
proteinuria, crescent formation, pulmonary
hemorrhage, etc. In vitro functional studies were performed in a Jurkat T-cell line following stimulations of serum from
myeloperoxidase-AAV patients. We found that only the
FTY720 treatment significantly alleviated
hematuria and
proteinuria, and diminished glomerular crescent formation, renal tubulointerstitial lesions and pulmonary
hemorrhage in EAV. The attenuation was accompanied by less renal T-cell infiltration, up-regulated
mRNA of S1PR1 and down-regulated IL-1β in kidneys, but not altered circulating
ANCA levels, suggesting that the
therapeutic effects of
FTY720 were B-cell independent. Further in vitro studies demonstrated that
FTY720 incubation could significantly inhibit the proliferation, adhesion, and migration, and increase apoptosis of T cells. In conclusion, the S1P modulator
FTY720 could attenuate EAV through the reduction and inhibition of T cells, which might become a novel treatment of
ANCA-associated vasculitis.