The outs and the ins of sphingosine-1-phosphate in immunity

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Abstract
The bioactive lipid mediator sphingosine-1-phosphate (S1P) is produced by the sphingosine kinases SPHK1 and SPHK2, and has emerged as a crucial regulator of immunity. Erythrocytes and the lymphatic endothelium are the main contributors to the high levels of S1P in the plasma and lymph, respectively. Trafficking of immune cells relies on S1P receptors (S1PRs) to sense gradients of S1P within and between lymphoid tissues and the circulation. The expression of these receptors is tightly regulated temporally and spatially. Recent studies using pharmacological and genetic approaches combined with intravital staining explain how S1PR1 regulates the egress of newly formed T cells from the thymus and the exit of mature T and B cells from secondary lymphoid organs. Plasma S1P maintains vascular integrity. S1PRs have distinct roles in inflammation-induced vascular permeability. S1P ligation of S1PR1 on endothelial cells induces RAC-dependent adherens junction assembly to enhance barrier integrity, whereas S1PR2 and S1PR3 promote vascular permeability through activation of a RHO-dependent pathway. Many environmental cues, including cytokines and growth factors, stimulate SPHK1 to produce S1P, which is then exported out of cells by specific transporters to activate S1P receptors on the same cell or neighbouring cells. This process, called S1P inside-out signalling, regulates many processes that are important for immunity and inflammation. It has long been suspected that S1P has direct intracellular actions independent of its receptors. Recent studies have uncovered intriguing intracellular targets relevant to immunology, including TNF receptor-associated factor 2 (TRAF2), protein kinase Cδ (PKCδ) and histone deacetylases (HDACs). S1P binds to TRAF2, a key component in the nuclear factor-κB (NF-κB) signalling pathway that is triggered by tumour necrosis factor (TNF), and stimulates its E3 ubiquitin ligase activity. This suggests a novel paradigm for the regulation of K63-linked polyubiquitylation and provides a mechanistic explanation for the numerous observations of the importance of SPHK1 in inflammatory, anti-apoptotic and immune processes. Sepsis is an overwhelming multi-organ immune response to bacterial infections. Toll-like receptor 4 (TLR4) is a sensor of lipopolysaccharide (LPS), a component of bacterial cell walls. Signalling from TLR4 leads to the activation of SPHK1 and the production of S1P, which has important roles in sepsis-induced inflammatory responses. The SPHK1–S1P–S1PR3 axis downstream of protease-activated receptor 1 (PAR1) signalling in dendritic cells regulates late-phase amplification of inflammation during sepsis. In macrophages, S1P produced by SPHK1 stimulates PKCδ, leading to the activation of the IκB kinase (IKK) complex and NF-κB in response to LPS and bacterial lipoprotein. Histone deacetylases (HDACs) remove acetyl groups from the N-terminal tails of histones, and this represses gene transcription. S1P produced in the nucleus by SPHK2, which is present together with HDACs in repressor complexes, binds to and inhibits HDACs, allowing transcription of specific genes to occur. Preclinical and clinical studies suggest that diverse pharmacological agents that target the functions of S1P and its receptors have therapeutic potential for treating a wide range of inflammatory and autoimmune disorders. The sphingosine analogue FTY720 (fingolomod) is the first orally effective therapeutic for the treatment of multiple sclerosis.