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Sphingosine 1-Phosphate Modulation in Inflammatory Bowel Diseases: Keeping Lymphocytes Out of the Intestine

ABSTRACT: Inflammatory bowel diseases (IBDs) are chronic and disabling conditions that, uncontrolled, lead to irreversible bowel damage and associated comorbidities. Despite the new era of biological therapies, IBDs remain not curative. The treatment purpose is to induce endoscopic remission, reduce the progression of the disease and improve the quality of life. Optimal and early treatment could enable the prevention of their complications. Small molecules, administrated as oral agents, have the capacity of overcoming the limitations of biologic agents (i.e., parenteral administration, rapidity of action and primary and secondary non-responsiveness). Of special interest are results from the use of oral sphingosine 1-phosphate (S1P) receptor modulators (ozanimod, etrasimod, fingolimod and laquinimod), based on S1P activities to target lymphocyte recirculation in the mucosa, acting as immunosuppressive agents. Most S1P modulators are reported to be safe and effective in the treatment of both UC and CD. High and satisfactory rates of clinical remission as well as endoscopic improvement and remission can be achieved with these molecules. Safety alarms remain rather low, although the S1P binding to two of its G protein-coupled receptors, 2 and 3 (S1PR2 and S1PR3), may be associated with cardiovascular risks. Cost-effectiveness studies and head-to-head trials are needed to better define their place in therapy. This review summarizes these emerging data published by PubMed and EMBASE databases and from ongoing clinical trials on the safety and efficacy of selectivity of S1P modulators in the treatment of IBD.

SUBMITTER: Dal Buono A

PROVIDER: S-EPMC9313037 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Review article: the sphingosine 1 phosphate/sphingosine 1 phosphate receptor axis - a unique therapeutic target in inflammatory bowel disease.

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| S-EPMC8766911 | biostudies-literature

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

Project description: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.

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Transcriptional modulation of SLC26A3 (DRA) by sphingosine-1-phosphate.

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Sphingosine-1-Phosphate Signaling and Metabolism Gene Signature in Pediatric Inflammatory Bowel Disease: A Matched-case Control Pilot Study.

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| S-EPMC6912289 | biostudies-literature

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