Regulation of immunity by lysosphingolipids and their G protein–coupled receptors

Abstract

T and B lymphocytes, as well as endothelial cells, express distinctive profiles of G protein-coupled receptors for sphingosine 1-phosphate, which is a major regulator of T cell development, B and T cell recirculation, tissue homing patterns, and chemotactic responses to chemokines. The capacity of drugs that act on type 1 sphingosine 1-phosphate receptors to suppress organ graft rejection in humans and autoimmunity in animal models without apparent impairment of host defenses against infections suggests that this system is a promising target for new forms of immunotherapy. Lysosphingolipids in the constellation of immunoregulatory lipidsLysophospholipids (LPLs) with biological mediator activity include lysoglycero-phospholipids, epitomized by lysophosphatidic acid (LPA), and lysosphingophospholipids, such as sphingosine 1-phosphate (S1P). The defining property of each LPL is an absence of 1 fatty acid from 1 of the 2 possible positions of acylation on the glycerol backbone. Both classes of LPLs share 3 important characteristics. First, their structures have a lipid domain and 1 or more polar charged substituents, and they are bound extensively in vivo by albumin and other plasma proteins. Second, they affect numerous functions of many types of cells, from proliferation and survival to migration and secretion. There is solid evidence for involvement of LPLs in processes as diverse as oxidative metabolism, angiogenesis, and carcinogenesis. Third, they all signal cells predominantly through structurally related G protein-coupled receptors (GPCRs). Of the known lipid biomediators, only leukotriene B 4 (LTB4), derived by 5-lipoxygenation of arachidonic acid, and S1P are considered major immune cytokines. As the effects of both S1P and LTB4 are transduced by GPCRs that are prime targets for drug development, normal and pathological contributions of the S1P and LTB4 systems are expected to be highly susceptible to pharmaceutical intervention.All immunoregulatory lipid mediators are produced predominantly by cells of the innate immune system, such as mast cells, macrophages, and granulocytes, and act on T and B cells of the adaptive immune system, as well as phagocytes and endothelial cells, through their respective GPCRs. Arachidonic acid-derived lipid mediators, such as COX-generated prostaglandin E2 and thromboxane A2, affect some aspects of B cell and T cell development and survival, as well as cytokine secretion with low to moderate potency (1). LTB4 is a potent and selective chemotactic factor for subsets of effector T cells, but not for naive T cells, and does not effect other lymphocyte functions (2, 3). The phospholipid platelet-activating factor (PAF) and PAF-like fragments of oxidized phosphatidylcholine are potent inflammatory mediators but have modest or restricted suppressive immune effects on adaptive immunity that have been recognized only in very specialized settings (4). In contrast, profound effects of S1P, LPA, and other LPLs are seen on diverse aspects of differentiation, survival, migration, tissue...

Cutting Edge: Alternative Signaling of Th17 Cell Development by Sphingosine 1-Phosphate

“…In particular, the extension of NF-B involvement to S1P-enhancement of both Th17 cell development and IL-17 generation broadens the spectrum of NF-B contributions to immunological cytokinemediated chronic inflammation (21). The potential involvement of the S1P-S1P 1 axis in several autoimmune diseases had been considered to be attributable solely to the effects on lymphocyte trafficking in lymphoid organs and lymphocyte migration in nonlymphoid target organs (22). However, the present and other recent findings imply that the S1P-S1P 1 axis has major roles in the control of T cell proliferation (23) and the mediation of target organ-specific chronic inflammation through the Th17 cell-IL-17 system.…”

“…In many rodent models of human autoimmunity that are clearly T cell-dependent, FTY720 also suppresses immunopathology and diminishes clinical signs of disease (22). It has become increasingly evident that the proven ability of FTY720 to disrupt the lymphoid organ traffic of T cells, induce blood lymphopenia, and minimize T cell infiltration of target organs by effects on the S1P-S1P 1 axis are only one set of mechanisms for its potent immunosuppression.…”

Selective Activation of Sphingosine 1-Phosphate Receptors 1 and 3 Promotes Local Microvascular Network Growth

“…12 The activation of these different G proteins, including G i for proliferation, G 12 for cytoskeletal remodeling, and G q for cellular effects, is elicited by S1P binding to its receptors on vascular cells. 13,14 To this end, a general paradigm has emerged that S1P 1 /S1P 3 signaling promotes SMC proliferation and migration, whereas S1P 2 has opposing actions. Activating and/or antagonizing specific combinations of these three S1P receptors on ECs and SMCs may be an effective strategy for promoting arteriogenesis in ischemic tissues by inducing SMC proliferation and the growth of functional arteriolar microvessels (Table 1).…”

FTY720 Ameliorates Th1-Mediated Colitis in Mice by Directly Affecting the Functional Activity of CD4+CD25+ Regulatory T Cells

“…FTY720-phosphate (FTY720-P) exhibits a potency comparable to S1P itself as an agonist at four of the five known G-protein-coupled S1PRs (S1P 1,3,4,5 ). Interference of FTY720 with S1P signaling hampers entry of lymphocytes into efferent lymphatics within lymph nodes, thereby delaying their subsequent return into circulation (7,8). S1P 1 and S1P 4 are the main S1PRs on T and B cells.…”