New findings show that the homeostatic levels of circulating sphingosine-1-phosphate (S1P) are mainly determined by the secretion from erythocytes (blood) and probably from endothelial cells (lymph and blood). Tissue levels of S1P are low compared with lymph and blood, establishing a gradient that allows immune cells to traffic into the circulation, thereby influencing their differentiation and function.
The S1P receptor S1PR1 has a dominant role in immune-cell trafficking as a regulator of migration. However, other receptors, such as S1PR3 (in dendritic cells (DCs)) and S1PR5 (in natural killer cells), also regulate trafficking and tissue localization.
Tight control of the expression of S1PR1 is required for normal immune responses. S1PR1 expression by lymphocytes is transcriptionally regulated (through Kruppel-like factor 2), downregulated in the presence of high levels of S1P and also down-modulated through protein–protein interactions with CD69 (a C-type lectin that is expressed on lymphocyte activation).
Some immune cells can change or upregulate the type of S1PR that is expressed on their cell surface with differentiation (in DCs) or on activation (in mast cells and haematopoietic stem cells). These changes alter the functional role of these cells and/or result in increased immune responses.
S1P can increase the inflammatory response to both innate and adaptive immune challenges. This can occur directly by causing the production of inflammatory mediators (such as interleukin-1β (IL-1β) and tissue factor through stimulation of S1PR3 on DCs) or by increasing functional responses to the initial stimulus (such as the S1PR2-mediated augmentation of high-affinity Fc receptor for IgE (FcɛRI)-dependent mast-cell degranulation).
Increases in the levels of circulating S1P favour increased T helper 2 (TH2)-cell responses while dampening or, in some cases, not affecting TH1-cell responses. Under certain circumstances (such as in the presence of IL-1β, IL-6 and transforming growth factor-β) S1P results in increased TH17-cell differentiation while dampening both TH1-cell and TH2-cell responses.
The strategy of blocking T-cell egress (through the administration of the sphingosine analogue FTY720) has shown benefits in the treatment of patients with relapsing–remitting multiple sclerosis. Animal models also indicate that there might be clinical benefits in type 1 diabetes and Crohn's disease.
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.
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Our work is supported by the intramural research programmes of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, USA. We apologize to those authors whose work we could not cite owing to space constraints.
- Liquid-ordered domains
Regions of cell membrane with a high content of cholesterol and sphingolipids. Cholesterol and sphingolipids can form a liquid-ordered phase in membranes that is resistant to detergent solubilization. These detergent-resistant liquid-ordered domains are commonly known as lipid rafts.
A membrane lipid that is composed of one molecule of the long-chain amino alcohol sphingosine (4-sphingenine) or one of its derivatives, one molecule of a long-chain acid, a polar head alcohol and sometimes phosphoric acid in diester linkage at the polar head group.
- G-protein-coupled receptors
A family of receptors that is characterized by seven transmembrane segments. This class of receptor can respond to a wide range of agonists. Some agonists bind to the extracellular loops of the receptor, others can penetrate into the transmembrane region. Agonist binding causes coupling of these receptors to heterotrimeric GTP-binding proteins, which enable signal transmission.
- Serum albumin
The most abundant plasma protein in humans and other mammals. Albumin is essential for maintaining the osmotic pressure that is required for the proper distribution of body fluids between intravascular compartments and body tissues and it acts as a plasma carrier by nonspecifically binding bioactive molecules.
- High-density lipoprotein
(HDL). A type of lipoprotein that carries cholesterol from the body's tissues to the liver. HDL is referred to as 'good cholesterol' owing to its ability to effectively transport cholesterol out of tissues.
- Laminar shear stress
A mechanical force created by blood flow through a vessel that impinges on the endothelium by virtue of its unique location in the vessel wall.
A term describing a chemical compound with both hydrophilic and hydrophobic properties. Also known as amphipathic.
- ATP-binding cassette (ABC) family of transporters
A family of proteins that transport various molecules across extracellular and intracellular membranes by coupling ATP hydrolysis to the transport. Eukaryotic ABC genes are classified in seven families, from ABCA to ABCG, based on gene organization and primary sequence homology. Functional characterization can be made, in part, by differential sensitivity to inhibitory drugs.
- M1-type macrophage
A macrophage that is activated by Toll-like receptor ligands (such as LPS) and interferon-γ and that express, among others, inducible nitric-oxide synthase and nitric oxide.
- M2-type macrophage
A macrophage that is stimulated by interleukin-4 (IL-4) or IL-13 and that expresses arginase-1, the mannose receptor CD206 and the IL-4 receptor α-chain.
- Delayed-type hypersensitivity
A delayed (occurring days after challenge) antigen-specific, cell-mediated immune response. This response is mainly T-cell mediated and involves monocytes and/or macrophages as effector cells that mount an inflammatory response. The magnitude of the effector-cell response to antigen can be measured as an increase in swelling at the site of challenge.
- Sjögren's syndrome
An autoimmune disease that results in the chronic dysfunction of exocrine (salivary) glands that is manifested in dry eyes and dry mouth, and that might be combined with another disease of connective tissue, such as rheumatoid arthritis (most common), lupus, scleroderma or polymyositis.
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Rivera, J., Proia, R. & Olivera, A. The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat Rev Immunol 8, 753–763 (2008). https://doi.org/10.1038/nri2400
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