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

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dc.contributor.authorPerez-Jeldres, Tamara
dc.contributor.authorAlvarez-Lobos, Manuel
dc.contributor.authorRivera-Nieves, Jesus
dc.date.accessioned2025-01-20T23:50:56Z
dc.date.available2025-01-20T23:50:56Z
dc.date.issued2021
dc.description.abstractSphingosine-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.
dc.description.funderNational Institute of Allergy and Infectious Diseases
dc.fuente.origenWOS
dc.identifier.doi10.1007/s40265-021-01528-8
dc.identifier.eissn1179-1950
dc.identifier.issn0012-6667
dc.identifier.urihttps://doi.org/10.1007/s40265-021-01528-8
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/94751
dc.identifier.wosidWOS:000650143500002
dc.issue.numero9
dc.language.isoen
dc.pagina.final1002
dc.pagina.inicio985
dc.revistaDrugs
dc.rightsacceso restringido
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleTargeting Sphingosine-1-Phosphate Signaling in Immune-Mediated Diseases: Beyond Multiple Sclerosis
dc.typeartículo
dc.volumen81
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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