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Sphingosine-1-phosphate receptor-1 (S1P 1 ) is expressed by lymphocytes, dendritic cells, and endothelium and modulated during inflammatory bowel disease
The sphingosine-1-phosphate receptor-1 (S1P
) agonist ozanimod ameliorates ulcerative colitis, yet its mechanism of action is unknown. Here, we examine the cell subsets that express S1P
in intestine using S1P
-eGFP mice, the regulation of S1P
expression in lymphocytes after administration of dextran sulfate sodium (DSS), after colitis induced by transfer of CD4
CD45RB
cells, and by crossing a mouse with TNF-driven ileitis with S1P
-eGFP mice. We then assayed the expression of enzymes that regulate intestinal S1P levels, and the effect of FTY720 on lymphocyte behavior and S1P
expression. We found that not only T and B cells express S1P
, but also dendritic (DC) and endothelial cells. Furthermore, chronic but not acute inflammatory signals increased S1P
expression, while the enzymes that control tissue S1P levels in mice and humans with inflammatory bowel disease (IBD) were uniformly dysregulated, favoring synthesis over degradation. Finally, we observed that FTY720 reduced T-cell velocity and induced S1P
degradation and retention of Naïve but not effector T cells. Our data demonstrate that chronic inflammation modulates S1P
expression and tissue S1P levels and suggests that the anti-inflammatory properties of S1PR agonists might not be solely due to their lymphopenic effects, but also due to potential effects on DC migration and vascular barrier function.