Sphingosine 1-phosphate in coagulation and inflammation

Abstract

Sphingosine 1-phosphate (S1P) is a lipid mediator produced from sphingomyelin by the sequential enzymatic actions of sphingomyelinase, ceramidase, and sphingosine kinase. Five subtypes of cell surface G-protein-coupled receptors, S1P(1-5), mediate the actions of S1P in various organs systems, most notably cardiovascular, immune, and central nervous systems. S1P is enriched in blood and lymph but is present at much lower concentrations in interstitial fluids of tissues. This vascular S1P gradient is important for the regulation of trafficking of various immune cells. FTY720, which was recently approved for the treatment of relapsing-remitting multiple sclerosis, potently sequesters lymphocytes into lymph nodes by functionally antagonizing the activity of the S1P(1) receptor. S1P also plays critical roles in the vascular barrier integrity, thereby regulating inflammation, tumor metastasis, angiogenesis, and atherosclerosis. Recent studies have also revealed the involvement of S1P signaling in coagulation and in tumor necrosis factor α-mediated signaling. This review highlights the importance of S1P signaling in these inflammatory processes as well as the contribution of each receptor subtype, which exhibits both cooperative and redundant functions.

Fig. 1

Metabolic pathways, transport, and receptors of S1P. a De novo sphingolipid metabolism starts at the endoplasmic reticulum where serine palmitoyltransferase condesates serine and palmitate into 3-keto-dihydrosphingosine, followed by sequential conversion to dihydrosphingosine, dihydroceramide, and ceramide by the action of 3-keto-dihydrosphingosine reductase, dihydroceramide synthases, and dihydroceramide desaturase, respectively. Ceramide, generated either from the de novo pathway or from degradation of complex sphingolipids such as sphingomyelin and glycosphingolipids, is deacylated by ceramidase to sphingosine, followed by phosphorylation by sphingosine kinase to produce S1P. S1P is dephosphorylated to sphingosine by S1P phosphatase or by lipid phosphate phosphatases, or is irreversibly degraded to phosphoethanolamine and hexadecenal by S1P lyase. b S1P produced intracellularly is transported by specific transporters such as Spns2 and carried by carrier proteins such as HDL-associated apoM and albumin. c S1P activates S1P receptors, S1P_1–5, which transmit diverse intracellular signals depending on the coupled Gα subunit of heterotrimeric G protein and the expression pattern of each receptors in a given cell type

Fig. 2

Regulation of lymphocyte trafficking by S1P. Lymphocytes in circulation have their S1P₁ mostly internalized due to the high S1P concentration in plasma. Upon entrance in secondary lymphoid organs where S1P concentration is low, they gradually recover the surface expression of S1P₁ and regain ability to egress from the lymphoid organs toward S1P in circulation. FTY720 is phosphorylated by sphingosine kinase 2 and induces the internalization and degradation of S1P₁ and thereby inhibits the lymphocyte egress

Fig. 3

Regulation of vascular permeability by S1P and crosstalk with PAR1 signaling. a In endothelial cells, S1P₁ induces Rac-mediated formation of cortical actin and adherens junctions and decreases vascular permeability, whereas S1P₂ and S1P₃ induce Rho-mediated increases in vascular permeability. b PAR1, when activated by the complex of endothelial protein C receptor (EPCR) and activated protein C (aPC), potently inhibits thrombin-induced vascular permeability. This barrier-protective activity of aPC is partly dependent on cross-activation of S1P₁ either by SphK1-mediated S1P production or by EPCR-mediated trans-activation of S1P₁. c Thrombin-activated PAR1 increases vascular permeability partly via trans-activation of S1P₃. PAR1-S1P₃ coupling in dendritic cells leads to the systemic inflammation in the late stage of severe sepsis