Sphingosine 1-phosphate (S1P), a product of membrane sphingolipid metabolism, is secreted and acts through G protein–coupled S1P receptors (S1PRs) in vertebrates. S1PR isoforms mediate complex cellular actions either alone or in combination in most organ systems. This stable lysolipid circulates as a complex with protein chaperones that not only enables aqueous solubility but also helps facilitate specific modes of receptor signaling. However, differential concentration gradients of S1P are normally present in various compartments and are perturbed under disease conditions. The abundance of circulatory S1P and the high expression of S1PRs in exposed cells—that is, vascular and hematopoietic cells—poses a key question of how this signaling axis is regulated. This question is of clinical relevance because the first S1PR-targeted drug, fingolimod, has been approved for the treatment of multiple sclerosis since 2010. Recent findings from basic research as well as insights gleaned from clinical and translational studies have enriched our understanding of how this simple lysolipid evolved as a complex regulator of multiple physiological systems and, when dysregulated, contributes to numerous diseases.

Extracellular spatial gradients of S1P, demonstrated by using S1P reporters, are tightly regulated and control fundamental processes such as hematopoietic cell trafficking, immune cell fate, and vascular integrity. The gradients are formed through location-specific function of metabolic enzymes, S1P transporters, and chaperones. Such physiological S1P gradients are altered in diseases, thus contributing to conditions such as inflammation, autoimmunity, and vascular dysfunction. S1P complexed to chaperone proteins—for example, high-density lipoprotein–bound apolipoprotein M—mediate distinct modes of receptor activation, resulting in biased receptor signaling and specific biological outcomes. S1PRs are also regulated tightly through endocytic mechanisms and receptor modulators that enhance or inhibit signal strength and duration. Various signaling mechanisms of this simple lysolipid mediator has helped reveal its multiple actions in the immune system, which include adaptive immune cell localization in various compartments (egress versus retention), fate switching, survival, and activation that influences both cell-mediated and humoral immunity. In the cardiovascular system, high expression of multiple S1PR isoforms in various cell types regulate development, homeostasis, and physiology. Current S1PR-targeted drugs that aim to tame autoimmunity exhibit considerable cardiovascular-adverse events. In the central nervous system (CNS), widespread application of S1PR-targeted drugs in autoimmune neuroinflammatory diseases has stimulated research that revealed the broad but poorly understood effects of S1P signaling in neurodevelopment, the neurovascular unit, neurons, and glia. Furthermore, in addition to the involvement of pathological S1P signaling in acute ischemic conditions of various organs, chronic dysregulated S1P signaling has been implicated in fibrotic diseases of lung, heart, liver, and kidney.

Considerable challenges remain to fully harness the new knowledge in S1P pathobiology to translational utility in clinical medicine. Approaches that mimic S1P chaperones, S1P neutralizing agents, modulation of transporters, biased agonists and antagonists of S1PR isotypes, and sphingolipid metabolic enzyme modulators provide viable pathways to therapy. Focusing on the immune system, such approaches may widen the autoimmunity therapeutic landscape and provide new …