Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy

Abstract

Membrane sphingolipids are metabolized to sphingosine-1-phosphate (S1P), a bioactive lipid mediator that regulates many processes in vertebrate development, physiology, and pathology. Once exported out of cells by cell-specific transporters, chaperone-bound S1P is spatially compartmentalized in the circulatory system. Extracellular S1P interacts with five GPCRs that are widely expressed and transduce intracellular signals to regulate cellular behavior, such as migration, adhesion, survival, and proliferation. While many organ systems are affected, S1P signaling is essential for vascular development, neurogenesis, and lymphocyte trafficking. Recently, a pharmacological S1P receptor antagonist has won approval to control autoimmune neuroinflammation in multiple sclerosis. The availability of pharmacological tools as well as mouse genetic models has revealed several physiological actions of S1P and begun to shed light on its pathological roles. The unique mode of signaling of this lysophospholipid mediator is providing novel opportunities for therapeutic intervention, with possibilities to target not only GPCRs but also transporters, metabolic enzymes, and chaperones.

Figure 3. Functions of S1P in vascular development and hematopoietic cell trafficking.

(A) During embryogenesis, rbc-derived S1P plays an essential role in the stabilization of the developing vascular system. In the postnatal period, both rbc and the endothelium release S1P into circulation to maintain vascular homeostasis. Plasma S1P is associated with ApoM⁺ HDL and albumin. S1P signaling regulates blood flow, endothelial integrity, barrier function, and antiinflammatory functions. (B) There is a steep S1P gradient between vascular and extravascular compartments. This is essential for trafficking of T cells from thymus and secondary lymphoid organs into blood and lymph, respectively. In the bone marrow sinusoids, S1P signaling is important for the release of megakaryocyte proplatelet extensions into the circulation.

Figure 2. Cellular sources of plasma S1P.

Endothelial cells and rbc release S1P, which is picked up and chaperoned by ApoM on the HDL particles and albumin. Chaperone-bound S1P interacts with S1P₁ on the endothelial cells to promote vascular barrier function. When endothelial cells are damaged, platelet activation and aggregation release S1P, which leads to local release of S1P that aids in the repair of vascular injury.

Figure 1. S1P synthesis, metabolism, and export.

Sphingomyelin (SM) and glycosphingolipids (GSL) are localized to plasma membrane microdomains. Degradation of plasma membrane sphingolipids into ceramide (Cer) and then ultimately to sphingosine (Sph) occurs in lysosomes and at the plasma membrane. Phosphorylation mediated by sphingosine kinases leads to the formation of S1P, which follows one of three pathways: (a) S1P is exported by transporters, such as SPNS2, where it can interact with its GPCRs (S1P₁–S1P₅) on the cell surface; (b) S1P is degraded by S1P lyase into hexadecenal (Hex) and phosphoethanolamine (PE), which are shunted into the glycerolipid biosynthetic pathway; or (c) S1P is dephosphorylated by S1P phosphatase for recycling of sphingosine into ceramide synthesis. S1PR, S1P receptor; S1Pase, S1P phosphatase.