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  • Review Article
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Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network

Key Points

  • Sphingosine 1-phosphate (S1P) and lysophosphatidic acid (LPA) are phospholipids that are mainly present in the extracellular fluid and are produced in the immune system by mast cells, platelets and macrophages.

  • S1P and LPA mediate their effects through two related families of G-protein-coupled receptors (GPCRs) that have different patterns of expression, and the expression of these GPCRs by immune cells is regulated in a manner that depends on developmental stage and activation status.

  • S1P and LPA affect immune-cell differentiation, proliferation, survival, migration, receptor expression, and protein synthesis and secretion.

  • The expression of the S1P receptor S1P1 by thymocytes late in their development is required for emigration from the thymus.

  • At the surface of T cells, S1P1 is the quantitatively dominant S1P receptor. It is expressed even in the presence of saturating concentrations of S1P, and it is downregulated by T-cell activation. Signalling through S1P1 leads to all of the effects of S1P on trafficking of immune cells and migration of T cells within tissues.

  • Thymocytes from S1P1-deficient mice or mice that have been treated with drugs that downregulate the expression of S1P1 fail to emigrate from the thymus to the blood.

  • T cells from S1P1-deficient mice or mice treated with S1P1-downregulating drugs rapidly leave the blood and are sequestered in the lymph nodes. These T cells show diminished recruitment to immune challenges in the peripheral tissues.

  • Mice that have S1p1-transgenic T cells show increased persistence and numbers of T cells in the blood, increased chemotaxis of T cells to S1P, diminished homing of T cells to lymph nodes and decreased proliferative responses after T-cell-receptor ligation. Consequently, these mice show diminished delayed-type hypersensitivity responses, reduced production of IgG and increased production of IgE.

  • The S1P–S1P1 axis also influences the distribution of B cells in the white pulp of spleen.

  • S1P–S1P-receptor axes in dendritic cells and T cells enhance the production of IgE.

  • LPA promotes mast-cell development, and the binding of S1P to S1P1 increases mast-cell chemotaxis to antigen. By contrast, the binding of S1P to S1P2, the expression of which is upregulated by IgE, inhibits mast-cell chemotaxis but augments IgE-mediated generation and/or release of allergic mediators.

Abstract

Sphingosine 1-phosphate (S1P) is a biologically active lysophospholipid that transmits signals through a family of G-protein-coupled receptors to control cellular differentiation and survival, as well as the vital functions of several types of immune cell. In this Review article, we discuss recent results that indicate that S1P and its receptors are required for the emigration of thymocytes from the thymus, the trafficking of lymphocytes in secondary lymphoid organs and the migration of B cells into splenic follicles. In an autocrine manner, through interactions with different G-protein-coupled receptors, S1P also enhances optimal mast-cell migration and release of pro-inflammatory mediators in allergic reactions. S1P–S1P-receptor regulatory systems might therefore be novel targets for the therapy of diverse immunological diseases.

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Figure 1: Sources of lysophospholipids in the immune system.
Figure 2: S1P1 pathways of intracellular trafficking and signalling.
Figure 3: Effects of S1P1 signalling on lymphocyte trafficking and tissue distribution.
Figure 4: S1P–S1P-receptor systems in the regulation of IgE production and mast-cell activation.
Figure 5: Postulated contributions of lymphocytes and endothelial cells to control of lymphocyte trafficking by the S1P–S1P1 system.

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Acknowledgements

This research was supported by grants from the National Institutes of Health (United States) to H.R. and E.J.G. and from Kyorin Pharmaceutical Company, Ltd (Japan) to H.R.

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DATABASES

Entrez Gene

AKT

AP1

ERK

IFN-γ

IL-4

IL-10

IL-12

protein kinase C-ε

S1P1

S1P4

Glossary

LYSOPHOSPHOLIPID

A phospholipid with a free hydroxyl group that is not conjugated to a fatty acid. Examples of lysophospholipids are lysosphingophospholipids, such as sphingosine 1-phosphate (S1P), and lysoglycerophospholipids, such as lysophosphatidic acid (LPA).

SPHINGOSINE KINASE

An enzyme that phosphorylates sphingosine to generate sphingosine 1-phosphate (S1P). This is the rate-limiting step in the synthesis of S1P.

G-PROTEIN-COUPLED RECEPTOR

(GPCR). A receptor that is composed of seven membrane-spanning helical segments, which are connected by extracellular and intracellular loops. These receptors associate with G proteins, which are a family of trimeric intracellular-signalling proteins with common β- and γ-chains, and one of several α-chains. The α-chain determines the nature of the signal that is transmitted from a ligand-occupied GPCR to downstream effector systems.

AMPHIPATHIC

A biophysical term that can be used to describe phospholipids because they have a hydrophobic (fatty acid) end and a charged or polar (phosphate) end.

ZWITTERION

A molecule or ion that has physically separate positively and negatively charged groups.

FTY720

A sphingosine-like drug that is phosphorylated intracellularly by sphingosine kinases to become a sphingosine 1-phosphate (S1P)-receptor agonist and has immunosuppressive activity. Both non-agonist FTY720 and agonist phospho-FTY720 function as downregulators of the S1P receptor S1P1 and other S1P receptors.

LCK–CRE CONDITIONAL-KNOCKOUT TECHNOLOGY

The Cre (cyclization recombinase) protein from bacteriophage P1 excises DNA that is flanked by recombination sequences known as loxP sites. These sequences can be introduced at either end of a gene by homologous recombination. Animals carrying loxP-flanked genes can be made transgenic for the Cre gene, which can be placed under a tissue-specific promoter (in this case, Lck, which is expressed by T cells). In the cells that express Cre, the loxP sites are recognized, and the DNA between them is excised, leading to tissue-specific deletion of the gene of interest.

VASCULAR ENDOTHELIAL CADHERIN

An endothelial-cell-specific cadherin (that is, a type of adhesion protein) that is present in adherens junctions, which are located between endothelial cells.

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Rosen, H., Goetzl, E. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol 5, 560–570 (2005). https://doi.org/10.1038/nri1650

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