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

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Abstract
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.