Sphingosine-1-phosphate receptor-1 (S1P₁) is expressed by lymphocytes, dendritic cells, and endothelium and modulated...

The sphingosine-1-phosphate receptor-1 (S1P₁) agonist ozanimod ameliorates ulcerative colitis, yet its mechanism of action is unknown. Here, we examine the cell subsets that express S1P₁ in intestine using S1P₁-eGFP mice, the regulation of S1P₁ 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 S1P₁-eGFP mice. We then assayed the expression of enzymes that regulate intestinal S1P levels, and the effect of FTY720 on lymphocyte behavior and S1P₁ expression. We found that not only T and B cells express S1P₁, but also dendritic (DC) and endothelial cells. Furthermore, chronic but not acute inflammatory signals increased S1P₁ 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 S1P₁ degradation and retention of Naïve but not effector T cells. Our data demonstrate that chronic inflammation modulates S1P₁ 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.