The alliance of sphingosine-1-phosphate and its receptors in immunity

Abstract

Sphingosine-1-phosphate (S1P) is a biologically active metabolite of plasma-membrane sphingolipids that is essential for immune-cell trafficking. Its concentration is increased in many inflammatory conditions, such as in asthma and autoimmunity. Much of the immune function of S1P results from engagement of a family of G-protein-coupled receptors (S1PR1-S1PR5). Recent findings on the role of S1P in immunosurveillance, the discovery of regulatory mechanisms in S1P-mediated immune-cell trafficking, and new advances in understanding how S1P affects immune-cell function indicate that the alliance between S1P and its receptors has a fundamental role in immunity.Sphingolipids are essential plasma-membrane lipids that concentrate in liquid-ordered domains (commonly known as lipid rafts or cholesterol-enriched membrane microdomains). These lipids can be rapidly metabolized upon stimulation of various plasma-membrane receptors through the activation of an enzymatic cascade (FIG. 1), which converts sphingolipids, such as sphingomyelin or complex glycosphingolipids, to ceramide and subsequently to sphingosine. Two sphingosine kinases (SPHK1 and SPHK2) then phosphorylate sphingosine to generate the lysosphingolipid sphingosine-1-phosphate (S1P) 1 . This sphingolipid metabolite has both cell intrinsic and extrinsic activity, affecting cell homeostasis and function 2 . Here, we focus on its cell-extrinsic function in the immune system as a ligand for a family of five G-protein-coupled receptors (GPCRs), known as S1PR1-S1PR5 3 .The fundamental physiological role of the interaction between S1P and S1PRs in immune-cell function was recognized through studies of the immunosuppressant FTY720. This compound rapidly induces lymphopenia through the sequestration of lymphocytes in lymph nodes and by blocking the egress of mature thymocytes from the thymus. A breakthrough in the understanding of its mechanism, together with a link to S1PR signalling, came with the realization that FTY720 is a sphingosine analogue that could be phosphorylated by SPHKs to produce a S1PR ligand 4 with potent effects including S1PR agonism and downregulation of S1PR expression 5-7 .In this article, we discuss the recent advances towards understanding how S1P and its receptors regulate immune-cell trafficking and function. New data have emerged demonstrating a role for S1P-S1PR in immunosurveillance, immune cell-differentiation and immune responses. The recent flurry of research activity in this area has shown that the interplay between S1P metabolism and receptor function has broad effects on the immune system. The evolving paradigm is that the alliance of S1P-S1PR is an essential regulatory circuit in immunity.

The S1P1 receptor-selective agonist CYM-5442 reduces the severity of acute GVHD by inhibiting macrophage recruitment

“…Establishment of an aGVHD model On day 0, BALB/c (H2 d ) recipients were lethally irradiated with 750 cGy total body irradiation from a 60 Co source and were infused with 1310 7 C57BL/6 (H2 b ) bone marrow cells and 5310 6 whole splenocytes 4 h later. CYM (3 mg/kg), 5,27,28 control water, or FTY720 was intraperitoneally injected daily from day 21 to day 3 post allogeneic bone marrow transplantation (BMT).…”

“…[4][5][6][7] S1P is mainly produced by erythrocytes and endothelial cells. S1P binds to five known G protein-coupled receptors, S1P [1][2][3][4][5] , and acts as a second messenger during cell signaling.…”

The Role of Sphingosine 1-Phosphate in Migration of Osteoclast Precursors; an Application of Intravital Two-Photon Microscopy

“…In this review, we summarize the bidirectional regulation of osteoclast precursor migration by S1P and briefly describe intravital bone imaging in living animals. S1P and its receptors S1P is a bioactive sphingolipid metabolite that regulates diverse biological functions including cell proliferation, motility, and survival (Cyster, 2005;Rivera et al, 2008;Rosen et al, 2005;. Sphingolipids are essential plasma membrane constituents composed of a serine head group and one or two fatty acid tails.…”

“…In addition, because S1P is an amphiphilic molecule that cannot easily cross membranes, an S1P gradient between the blood and tissues is maintained. S1P signals via five 7-transmembrane receptors or G proteincoupled receptors (GPCRs), S1PR1 to S1PR5, previously referred to as endothelial differentiation gene (Edg) receptors (Rivera et al, 2008;Rosen et al, 2007). Because of the different distribution of these receptors and their different coupling to signal-transducing G proteins, S1P shows a broad range of Table 1.…”

Fragile privileges: autoimmunity in brain and eye

“…Intriguingly, KLF-2, a master gene controlling T cell migration and quiescence [34] was among the elevated genes, suggesting a regulatory role for this gene. Interestingly, KLF-2 controls the transcription of sphingosin-1-phosphate receptors, which are not only centrally involved in regulating T cell egress from lymphoid organs, but have also [35] . In fact, although without experimental proof so far, the KLF-2/sphingosin-posphate receptor axis may contribute to the signals triggering the mass exodus of reshaped migratory effector T cells from the spleen 3-4 days after transfer.…”