Sphingosine 1-phosphate receptor modulators for the treatment of inflammatory bowel disease and other immune-mediated diseases

Inflammatory bowel disease (IBD) is an idiopathic intestinal inflammatory disease involving the ileum, rectum, and colon. Clinical manifestations include diarrhea, abdominal pain, and bloody stool. The disease includes ulcerative colitis (UC) and Crohn’s disease (CD). Biological therapies, including anti-TNF, anti-IL-12/23, and anti-integrins, improved the treatment of IBD, but they lack universal effectiveness and uniform immunogenicity. The advantage of small molecules over biological therapies includes tolerance of low immunogenicity, oral administration, and low manufacturing cost. Sphingosine 1-phosphate (S1P), derived from membrane sphingolipids, is a signaling molecule that is involved in immunological, cardiovascular, and neurological processes through interaction with sphingosine 1-phosphate receptors (S1PRs). S1P binds to S1PRs on the cell surface, activating multiple downstream signaling pathways such as AKT, Rac, Rho, ERK and PKC, causing a wide range of biological effects. S1PR is a G protein-coupled receptor with five subtypes: S1PR1, S1PR2, S1PR3, S1PR4, and S1PR5. S1PR1 to 3 are expressed in various tissues, and S1PR4 is expressed in lymph nodes. S1PR5 is expressed in brain and skin. The S1PR agonists arise as new strategies for regulating downstream cytokine signaling in immune-mediated diseases. This article reviews the mechanisms of immune regulation by S1P/S1PRs, the pharmacokinetics of S1PR modulators (Fingolimod, Ozanimod, Etrasimod, Siponimod, among others), and the related clinical data. S1PR subtypes and the medications that functionally modulate them