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

Abstract

Background: Ozanimod, a high selective sphingosine 1 phosphate (S1P) receptor (S1PR) 1/5 modulator was approved by the Food and Drug Administration for the treatment of adult patients with moderately to severely active ulcerative colitis. Additional S1PR modulators are being tested in clinical development programmes for both ulcerative colitis and Crohn's disease.

Aim: To provide an overview of advances in understanding S1PRs biology and summarise preclinical and clinical investigations of S1P receptor modulators in chronic inflammatory disease with special emphasis on inflammatory bowel diseases (IBD).

Methods: We performed a narrative review using PubMed and ClinicalTrials.gov.

Results: Through S1PRs, S1P regulates multiple cellular processes, including proliferation, migration, survival, and vascular barrier integrity. The S1PRs function of regulating lymphocyte trafficking is well known, but new functions of S1PRs expand our knowledge of S1PRs biology. Several S1PR modulators are in clinical development for both ulcerative colitis and Crohn's disease and have shown promise in phase II and III studies with ozanimod now being approved for ulcerative colitis.

Conclusions: S1P receptor modulators constitute a novel, promising, safe, and convenient strategy for the treatment of IBD.

Figure 1. S1P/S1PRs signaling pathways.

Intracellular S1P synthesis is catalyzed by SPHK1 and SPHK2. The degradation of S1P is catalyzed by S1PP and SPL. S1P signals primarily through five G protein-coupled receptor subtypes named S1PR1-5.

Figure 2. S1PR modulators regulate sequestration of T lymphocytes.

Treatment with an S1PR1 modulator, which induces downregulation and attenuates signaling through this receptor, blocks lymphocyte trafficking.