Targeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis

Abstract

Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Because lymphocytes live long (which is critical for adaptive immunity) and recirculate thousands of times, the S1P-S1PR pathway is involved in the pathogenesis of immune-mediated diseases. The S1PR1 modulators lead to receptor internalization, subsequent ubiquitination, and proteasome degradation, which renders lymphocytes incapable of following the S1P gradient and prevents their access to inflammation sites. These drugs might also block lymphocyte egress from lymph nodes by inhibiting transendothelial migration. Targeting S1PRs as a therapeutic strategy was first employed for multiple sclerosis (MS), and four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) are currently approved for its treatment. New S1PR modulators are under clinical development for MS, and their uses are being evaluated to treat other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. A clinical trial in patients with COVID-19 treated with ozanimod is ongoing. Ozanimod and etrasimod have shown promising results in IBD; while in phase 2 clinical trials, ponesimod has shown improvement in 77% of the patients with psoriasis. Cenerimod and amiselimod have been tested in SLE patients. Fingolimod, etrasimod, and IMMH001 have shown efficacy in RA preclinical studies. Concerns relating to S1PR modulators are leukopenia, anemia, transaminase elevation, macular edema, teratogenicity, pulmonary disorders, infections, and cardiovascular events. Furthermore, S1PR modulators exhibit different pharmacokinetics; a well-established first-dose event associated with S1PR modulators can be mitigated by gradual up-titration. In conclusion, S1P modulators represent a novel and promising therapeutic strategy for immune-mediated diseases.

Fig. 1

S1P synthesis, degradation, export, and intracellular signaling [, –16]. (a) Ceramide is broken down by ceramidases into sphingosine, which is phosphorylated by two sphingosine kinases (SphK1, SphK2), generating S1P within lysosomes and the endoplasmic reticulum (ER). SphK1 is mainly cytosolic and is translocated to the plasma membrane upon activation. SPHK2 is located within the mitochondria, nucleus, and ER. At the ER, S1P might be dephosphorylated by S1P phosphatase (SPP1,2) to sphingosine, which can be used for ceramide synthesis or irreversibly degraded by S1P lyases. S1P is also produced in the mitochondria and nucleus by SPHK2 with intracellular targets such as prohibitin 2 (PHB2) and histone deacetylases (HDACs) [1]. PHB2 stabilizes cytochrome c oxidases (COX), whereas HDACs remove acetyl groups from histones, altering gene transcription. S1P is transported out of the cell by specific ATP-binding cassette transporters like ABCA1, ABCC1, ABCG2, and Spinter Homolog 2 (SPNS2) protein [1]. Extracellular S1P can act in a paracrine or autocrine fashion binding to S1PRs and initiating downstream signaling. (b) S1P generated by SPHK1 in response to TNF binds to the TNF-receptor-associated factor 2 (TRAF2), an E3 ubiquitin ligase, enhancing its activity and leading to lysine-63-linked polyubiquitination of the receptor-interacting protein 1 (RIP1) and activating the nuclear factor “kappa-light-chain-enhancer” within the NF-κB pathway, favoring transcription of proinflammatory cytokines [14, 21]. TRAF2 may alternatively bind to TRAF-interacting protein (TRIP), blocking S1P binding to TRAF2 and suppressing downstream signaling. (c) In response to IL-1, SPHK1 and the cellular inhibitor of apoptosis 2 (cIAP2) form a complex with interferon-regulatory factor 1 (IRF1) leading to its polyubiquitination and activation. Consequently, IRF1 enhances the expression of the chemokine CXCL10 and CCL5, which are important for mononuclear cell recruitment to sites of inflammation [15, 16]