Sphingosine-1-phosphate receptor-1 (S1P1) is expressed by lymphocytes, dendritic cells, and endothelium and modulated during inflammatory bowel disease

The sphingosine-1-phosphate receptor-1 (S1P(1)) agonist ozanimod ameliorates ulcerative colitis, yet its mechanism of action is unknown. Here, we examine the cell subsets that express S1P(1) in intestine using S1P(1)-eGFP mice, the regulation of S1P(1) expression in lymphocytes after administration of dextran sulfate sodium (DSS), after colitis induced by transfer of CD4(+) CD45RB(hi) cells, and by crossing a mouse with TNF-driven ileitis with S1P(1)-eGFP mice. We then assayed the expression of enzymes that regulate intestinal S1P levels, and the effect of FTY720 on lymphocyte behavior and S1P(1) expression. We found that not only T and B cells express S1P(1), but also dendritic (DC) and endothelial cells. Furthermore, chronic but not acute inflammatory signals increased S1P(1) 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(1) degradation and retention of Naive but not effector T cells. Our data demonstrate that chronic inflammation modulates S1P(1) 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.