Sphingosine-1-phosphate, its receptors, and their role in multiple sclerosis

Sphingosine-1-phosphate (S1P), via its G protein-coupled receptors, is a signaling molecule with important regulatory properties that are expressed on numerous, widely varied cell types. Five S1P receptors (S1PR1-5) have been identified, each with effects determined by the cell types upon which they are expressed and by their unique, and sometimes promiscuous, G protein-driven downstream pathways. The discovery that lymphocyte egress from peripheral lymphoid organs is promoted by S1P via S1PR1 stimulation, led to the development of pharmacological agents that are S1PR1 antagonists. These agents promote lymphocyte sequestration and reduce lymphocyte-driven inflammatory damage. Because these agents reduce inflammation-driven damage of the central nervous system (CNS) in preclinical experimental models, they have been extensively examined for efficacy in the treatment of multiple sclerosis (MS). Preclinical research has also demonstrated broadly based immunological regulation and modulation, as well as direct trophic and protective effects of S1PR modulation upon cells within the CNS, independent of effects caused by lymphocyte migration. As of April 2023, four of these agents, fingolimod, siponimod, ozanimod, and ponesimod, have been approved for the treatment of MS. In patients with MS, these agents reduce relapse risk, sustained disability progression, magnetic resonance imaging markers of disease activity, and whole brain and/or cortical and deep gray matter atrophy. Future development of more selective extracellular S1PR modulators and agents acting upon cytoplasmic and nuclear S1PR-driven pathways may greatly expand our understanding of S1P biology and offer widened opportunities to develop novel therapeutic agents for MS and for a wide range of other inflammatory and noninflammatory diseases.