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.

Sphingolipids in Lung Pathology in the Coronavirus Disease Era: A Review of Sphingolipid Involvement in the Pathogenesis of Lung Damage

“…In 2019, the FDA approved Siponimod, an inhibitor selective for S1PR1 and S1PR5, which has shown effectiveness in MS treatment (U.S. Food and Drug Administration, 2019;Fronza et al, 2021). Ozanimod was approved for use in MS in 2020, and is selective for S1PR1 and S1PR5 as well (U.S. Food and Drug Administration, 2020; Fauzyah et al, 2021;Perez-Jeldres et al, 2021). In March 2021, Ponesimod, a highly selective inhibitor of S1PR1, was approved for patients with relapsing MS (Fronza et al, 2021;U.S.…”

“…While S1P pathway modulators have been used in MS for some time, recent studies have begun to demonstrate efficacy in different pathologies such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis, and inflammatory bowel disease (IBD) including ulcerative colitis (UC), and Crohn's disease (CD) (Perez-Jeldres et al, 2021). A clinical trial with Ozanimod showed effectiveness in the treatment of moderate to severe UC (Sandborn et al, 2016;Perez-Jeldres et al, 2021). Other medications that are not currently approved have undergone trials in the treatment of IBD with varying degrees of success; these drugs include Mocravimod, Etrasimod, and Amiselimod (Perez-Jeldres et al, 2021).…”

“…A clinical trial with Ozanimod showed effectiveness in the treatment of moderate to severe UC (Sandborn et al, 2016;Perez-Jeldres et al, 2021). Other medications that are not currently approved have undergone trials in the treatment of IBD with varying degrees of success; these drugs include Mocravimod, Etrasimod, and Amiselimod (Perez-Jeldres et al, 2021). Ponesimod has shown potential in psoriasis treatment (Vaclavkova et al, 2014;Perez-Jeldres et al, 2021).…”

“…Other medications that are not currently approved have undergone trials in the treatment of IBD with varying degrees of success; these drugs include Mocravimod, Etrasimod, and Amiselimod (Perez-Jeldres et al, 2021). Ponesimod has shown potential in psoriasis treatment (Vaclavkova et al, 2014;Perez-Jeldres et al, 2021). Cenerimod, a selective S1PR1 modulator, demonstrated treatment potential and an acceptable safety profile in the treatment of SLE (Hermann et al, 2019;Perez-Jeldres et al, 2021).…”

The Gut-Brain Axis in Inflammatory Bowel Disease—Current and Future Perspectives

“…While this strategy is highly efficient in autoimmune CNS diseases such as MS, it may yield beneficial effects in inflammatory bowel diseases as well. Indeed, several preclinical studies have examined these modes of actions and may provide useful in future clinical approaches [40][41][42]. Neurodegeneration is a frequent consequence of severe neuroinflammation in MS.…”