Platelet-Derived S1P and Its Relevance for the Communication with Immune Cells in Multiple Human Diseases

Abstract

Sphingosine-1-phosphate (S1P) is a versatile signaling lipid involved in the regulation of numerous cellular processes. S1P regulates cellular proliferation, migration, and apoptosis as well as the function of immune cells. S1P is generated from sphingosine (Sph), which derives from the ceramide metabolism. In particular, high concentrations of S1P are present in the blood. This originates mainly from erythrocytes, endothelial cells (ECs), and platelets. While erythrocytes function as a storage pool for circulating S1P, platelets can rapidly generate S1P de novo, store it in large quantities, and release it when the platelet is activated. Platelets can thus provide S1P in a short time when needed or in the case of an injury with subsequent platelet activation and thereby regulate local cellular responses. In addition, platelet-dependently generated and released S1P may also influence long-term immune cell functions in various disease processes, such as inflammation-driven vascular diseases. In this review, the metabolism and release of platelet S1P are presented, and the autocrine versus paracrine functions of platelet-derived S1P and its relevance in various disease processes are discussed. New pharmacological approaches that target the auto- or paracrine effects of S1P may be therapeutically helpful in the future for pathological processes involving S1P.

Keywords: S1P; S1P receptors; immune cells; platelets; sphingosine-1-phosphate.

Figure 1

Metabolism of S1P, its cellular release, and binding partners. Sphingosine is formed via CDase from ceramides, which in turn can be formed de novo from serine and palmitoyl-CoA or sphingomyelin and glycosphingolipids. S1P is then formed intracellularly via SphK1/2 from sphingosine and transported out of the cell by ATP-binding cassette transporters (particularly ABCC4/MRP4) or the sphingolipid transporter 2 (Spns2) and the major facilitator superfamily transporter Mfsd2b. S1P can exert either paracrine or autocrine effects by binding to one of its G-protein-coupled receptors, S1PR1-5. Alb, albumin; apoM, apolipoprotein M; CDase, ceramidase; HDL, high-density lipoprotein; LDL, low-density lipoprotein; S1P, sphingosine-1-phosphate; SMase, sphingomyelinase; SMS, sphingomyelin synthase; SphK1/2, sphingosine kinase 1/2; SPL, S1P lyase; SPP, S1P phosphatase; S1PR1–5, S1P receptors 1–5; VLDL, very low-density lipoprotein.

Figure 2

Release of S1P from resting and activated platelets. Platelets rapidly take up sphingosine from the serum and convert it into S1P. S1P is then stored within the platelet membrane and is released at a basal level in a calcium-dependent manner. After the activation of platelets with various agonists, such as thrombin or TxA₂, S1P is released in bulk via de novo synthesis or from intracellular reservoirs in granules. The transporter MRP4, which is located mainly in the plasma membrane in activated platelets, has been shown to be capable of active S1P transmembrane transport. While both processes of degranulation and S1P secretion are linked to PKC, it is currently unclear how MRP4 is involved in the granule-dependent S1P release or if the secretion of S1P by MRP4 occurs independently. In addition, other mechanisms have been suggested to be involved in platelet S1P release, including the transporter Mfsd2b. For references, see Section 2.2. Alb, albumin; COX-1, cyclooxygenase 1; G, granules; MRP4, multidrug resistance protein 4; PAR-1, protease-activated receptor 1; PKC, protein kinase C; S1P, sphingosine-1-phosphate; SphK2, sphingosine kinase 2; TP, thromboxane receptor; TxA₂, thromboxane A₂; ?, unclear to date.

Figure 3

Effects of S1P on megakaryocytes and platelets. At present, the expression of S1PR1, 2, 3, and 4 on MKs has been detected. S1P regulates thrombopoiesis through S1PR1. However, thrombopoiesis is suppressed by the activation of S1PR2. Different autocrine effects on platelet activation are discussed. Evidence suggests the possible involvement of S1PR1, 2, 4, and 5 in platelet responses, indicating that presumably all members of the S1PR family are present in MKs/platelets. In addition to no effect or even inhibitory effects on platelet activation, a platelet-activating or aggregation-promoting effect of S1P on platelets when combined with thrombin, epinephrine, NA, ADP, or collagen has been described. In addition, an increase in cellular Ca²⁺ levels after S1P stimulation is under discussion. ADP, adenosine diphosphate; MK, megakaryocytes; NA, noradrenalin; Ca²⁺, calcium; S1P, sphingosine-1-phosphate; S1PR1–5, S1P receptors 1–5; ?, unclear to date.

Figure 4

Paracrine effects of S1P on endothelial and immune cells. S1P released from platelets (in bulk during platelet activation 🗲) can affect various cells and cell functions. The focus in this scheme is on the S1P effects on EC or platelets as well as on immune cells, which are attracted by S1P and then release pro- and anti-inflammatory mediators. S1P thus has a direct or indirect influence on various diseases, such as diabetes, atherosclerosis, and MS. EC, endothelial cell; GBM, glioblastoma; MS, multiple sclerosis; S1P, sphingosine-1-phosphate; TF, tissue factor.