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 asthma and autoimmunity. Much of the immune function of S1P results from the 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 the mechanism by which S1P affects immune-cell function indicate that the alliance between S1P and its receptors has a fundamental role in immunity.

FIGURE 1. Sphingolipid synthesis and degradation

- Stimulation of various tyrosine kinase, G-protein-coupled, cytokine and ITAM-bearing receptors activates sphingomyelinases (SMase) that cleave sphingomyelin (SM) to yield ceramide; ceramidases (CERase) then cleave ceramide to form sphingosine (SPH), and sphingosine kinases (SPHKS) phosphorylate SPH to form sphingosine-1-phosphate (S1P). The increase in S1P levels is short-lived due to re-synthesis of more complex sphingolipids, the degradation of S1P by S1P lyase and resynthesis of more complex sphingolipids, or its dephosphorylation by S1P phosphatases (SPPases). Both SPPases and S1P lyase are present in cell membranes and are crucial for the fine-tuning of S1P levels inside and outside cells. S1P can act as a second messenger inside cells and affect calcium fluxes, although the target/s are unknown. S1P is also exported outside cells by ABC-type or other transporters. Extracellular S1P can bind a family of five plasma-membrane G-protein-coupled receptors (known as S1PR1–S1PR5) that are differentially expressed by immune cells.

FIGURE 2. Regulation of S1P levels in vivo

Sphingosine-1-phosphate (S1P) levels in the blood are tightly regulated and are increased compared with the tissue interstitium. S1P in circulatory fluids is mostly bound to albumin or lipoproteins, particularly high-density lipoprotein (HDL). Erythrocytes express sphingosine kinases (SPHKs) responsible for the phosphorylation of sphingosine (SPH) to S1P, but they lack the enzymes necessary for S1P degradation (S1P lyase and S1P phosphatases); thus they can store and release large amounts of S1P. Endothelial cells exposed to shear laminar stress down-regulate the expression of S1P lyase and phosphatases by an unknown mechanism, which results in increased production and secretion of S1P in the circulation. Platelets and mast cells produce and secrete large amounts of S1P but only when stimulated and thus do not seem to influence the basal levels of circulating S1P. However, they probably contribute to the production of local S1P gradients in (patho)physiological settings. Activation of platelets by thrombin during clotting activates the transport of S1P into the extracellular space through an ABCA (ATP-binding cassette type A) transporter. The local secretion of S1P by platelets near the endothelium can affect endothelial responses by increasing the adhesion of multiple types of immune cell and inducing endothelial chemotaxis and differentiation, which promotes wound healing. S1P also synergizes with thrombin to induce the release of tissue factor from platelets, which promotes blood coagulation. Mast cells stimulated through their Fc receptors for IgE (FcεR) can secrete S1P in the tissues in which they reside and produce local S1P gradients. S1P gradients (shaded green) function to recruit inflammatory cells, cause immune-cell differentiation and increase immune-cell functions.

FIGURE 3. S1PR1-mediated lymphocyte egress from lymph nodes

The level of sphingosine-1-phosphate (S1P) in lymphoid tissues is normally relatively low compared with the lymph, thereby forming a S1P gradient (shaded green). S1PR1 expressed on T cells is responsive to the S1P gradient and promotes T-cell egress from the lymphoid organ through the endothelial barrier into lymph. Upon activation of the T cell in the lymphoid organ on encountering an antigen-expressing dendritic cell (DC) or by type I interferon stimulation, S1PR1 expression is decreased. Mechanisms include direct protein:protein interaction with CD69, which is induced upon type I interferon stimulation, and through down-regulation of the transcription factor KLF2, which is a direct activator of the S1PR1 gene. Effector T cells eventually re-express S1PR1 and thereby egress from the lymph node to the lymph and into the peripheral tissues. If the levels of S1P are increased in lymphoid tissues, by inhibition of S1P lyase or possibly by inflammation, or in the presence of synthetic S1PR1 ligands such as FTY720, T-cell egress might be blocked by several possible mechanisms: dissipation of the S1P gradient, down-modulation of S1PR1 on T cells by ligand-induced internalization and S1PR1-mediated closure of egress ports on the endothelium by enhancement of junctional contacts.

FIGURE 4. Effects of S1P on immune cell function

Sphingosine-1-phosphate (S1P) promotes increased numbers of T helper 2 (T_H2) cells and T_H17 over T_H1 cells, and it increases the ratio of M2-type to M1-type macrophages. In a sepsis model, PAR1 induces the autocrine production of S1P and activation of S1PR3 in dendritic cells (DCs), which leads to cytokine and tissue-factor production by these cells, thereby amplifying inflammation and coagulation. S1PR3 activation also results in increased endocytosis in mature dendritic cells. During DC maturation with lipopolysaccharide (LPS), S1P impairs the initiation of T_H1-cell responses by suppressing DC interleukin-12 (IL-12) production, but promotes T_H2-cell responses by increasing IL-4 and IL-10 production through an unknown mechanism. Activation of S1PR1 by S1P in activated T cells inhibits interferon-γ (IFNγ) production and overexpression of S1PR1 increases IL-4 production. The preferential T_H2-cell skewing by DCs, together with the suppression of T_H1-cell responses, also favours the production of IL-4. IL-4 is required for IgE production by B cells. Increased levels of IgE increase the expression of IgE receptors on mast cells and basophils, and upon antigen encounter, can result in increased degranulation responses and IL-4 production by these cells. S1P enhances the IL-4-mediated differentiation of monocytes into IL-10-producing macrophages (M2 type), while suppressing the production of IL-12 and other cytokines by M1-type macrophages, and it enhances mast-cell effector functions. The effects of S1P are not restricted to T_H1 and T_H2-cell responses as it substitutes for IL-23 in the induction of T_H17 cells, an effect that seems to be mediated by S1PR1.