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

The sphingosine-1-phosphate receptor-1 (S1P) agonist ozanimod ameliorates ulcerative colitis, yet its mechanism of action is unknown. Here, we examine the cell subsets that express S1P in intestine using S1P-eGFP mice, the regulation of S1P expression in lymphocytes after administration of dextran sulfate sodium (DSS), after colitis induced by transfer of CD4CD45RB cells, and by crossing a mouse with TNF-driven ileitis with S1P-eGFP mice. We then assayed the expression of enzymes that regulate intestinal S1P levels, and the effect of FTY720 on lymphocyte behavior and S1P expression.

S1P signaling: new therapies and opportunities.

Development of sphingosine-1-phosphate receptor 1 (S1P1) modulators to dampen inflammation and its sequelae is becoming increasingly promising for treating medical conditions characterized by significant immunopathology. As shown by the non-selective S1P receptor modulator FTY720 (fingolimod [Gilenya(®)]) in the treatment of relapsing-remitting multiple sclerosis (MS), the ability to use S1P1 modulation to precisely block immune cell traffic-immunomodulation-while maintaining immunosurveillance, has opened therapeutic opportunities in various other immune-derived chronic pathologies, including inflammatory bowel disease (IBD), lupus, psoriasis, as well as, potentially, in early acute viral respiratory infection. Proof-of-concept studies across validated animal models with S1P receptor modulators highly selective for S1P1, such as BAF-312 (Siponimod), KRP-203, ONO-4641 (Ceralifimod), ponesimod and RPC-1063, and emerging clinical trials for safety and efficacy in humans, particularly in MS, ulcerative colitis (UC) and psoriasis, have set the stage for us to consider additional testing in various other autoimmune diseases.

The organization of the sphingosine 1-phosphate signaling system.

The understanding of the role of the sphingosine 1-phosphate signaling system in immunology and host defense has deepened exponentially over the past 12 years since the discovery that lymphocyte egress was reversibly modulated by sphingosine 1-phosphate receptors, and with the development of fingolimod, a prodrug of a nonselective S1P receptor agonist, for therapeutic use in the treatment of relapsing, remitting multiple sclerosis. Innovative genetic and chemical approaches, together with structural biology, now provide a more detailed molecular understanding of a regulated lysophospholipid ligand with a variety of autocrine, paracrine, and systemic effects in physiology and pathology, based upon selective interactions with a high affinity and selective evolutionary cluster of G-protein-coupled receptors.

Sphingosine 1-phosphate receptor 1 (S1P(1)) upregulation and amelioration of experimental autoimmune encephalomyelitis by an S1P(1) antagonist.

Sphingosine 1-phosphate receptor 1 (S1P(1)) is a G protein-coupled receptor that is critical for proper lymphocyte development and recirculation. Agonists to S1P(1) are currently in use clinically for the treatment of multiple sclerosis, and these drugs may act on both S1P(1) expressed on lymphocytes and S1P(1) expressed within the central nervous system. Agonists to S1P(1) and deficiency in S1P(1) both cause lymphocyte sequestration in the lymph nodes.