Sphingosine-1-phosphate receptor-1 (S1P 1) is expressed by lymphocytes, dendritic cells, and endothelium and modulated during inflammatory bowel disease

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Abstract

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 Naïve 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.

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Karuppuchamy, T., Behrens, E. H., González-Cabrera, P., Sarkisyan, G., Gima, L., Boyer, J. D., … Rivera-Nieves, J. (2017). Sphingosine-1-phosphate receptor-1 (S1P 1) is expressed by lymphocytes, dendritic cells, and endothelium and modulated during inflammatory bowel disease. Mucosal Immunology, 10(1), 162–171. https://doi.org/10.1038/mi.2016.35

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