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+CD45RBhi 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.