Key Points
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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.
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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.
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S1P and LPA affect immune-cell differentiation, proliferation, survival, migration, receptor expression, and protein synthesis and secretion.
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The expression of the S1P receptor S1P1 by thymocytes late in their development is required for emigration from the thymus.
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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.
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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.
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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.
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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.
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The S1P–S1P1 axis also influences the distribution of B cells in the white pulp of spleen.
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S1P–S1P-receptor axes in dendritic cells and T cells enhance the production of IgE.
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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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References
Tigyi, G. & Goetzl, E. J. Lysolipid mediators in cell signaling and disease. Biochim. Biophys. Acta 1582, vii (2002).
Hla, T. Signaling and biological actions of sphingosine 1-phosphate. Pharmacol. Res. 47, 401–407 (2003).
Mills, G. B. & Moolenaar, W. H. The emerging role of lysophosphatidic acid in cancer. Nature Rev. Cancer 3, 582–591 (2003).
Anliker, B. & Chun, J. Lysophospholipid G protein-coupled receptors. J. Biol. Chem. 279, 20555–20558 (2004).
Siess, W. & Tigyi, G. Thrombogenic and atherogenic activities of lysophosphatidic acid. J. Cell. Biochem. 92, 1086–1094 (2004).
Karliner, J. S. Mechanisms of cardioprotection by lysophospholipids. J. Cell. Biochem. 92, 1095–1103 (2004).
Goetzl, E. J. & Rosen, H. Regulation of immunity by lysosphingolipids and their G protein-coupled receptors. J. Clin. Invest. 114, 1531–1537 (2004).
Eichholtz, T., Jalink, K., Fahrenfort, I. & Moolenaar, W. H. The bioactive phospholipid lysophosphatidic acid is released from activated platelets. Biochem. J. 291, 677–680 (1993).
Spiegel, S. & Milstien, S. Sphingolipid metabolites: members of a new class of lipid second messengers. J. Membr. Biol. 146, 225–237 (1995).
Fourcade, O. et al. Secretory phospholipase A2 generates the novel lipid mediator lysophosphatidic acid in membrane microvesicles shed from activated cells. Cell 80, 919–927 (1995). This was the first study to show the pathway in which lysophosphatidic acid is generated extracellularly by leukocytes and platelets.
Stunff, H. L., Milstien, S. & Spiegel, S. Generation and metabolism of bioactive sphingosine-1-phosphate. J. Cell. Biochem. 92, 882–899 (2004). This is the best recent summary of the cellular biochemistry of the generation and degradation of lysosphingolipids.
Goetzl, E. J. & Tigyi, G. Lysophospholipids and their G protein-coupled receptors in biology and diseases. J. Cell. Biochem. 92, 867–868 (2004).
Nava, V. E. et al. Functional characterization of human sphingosine kinase-1. FEBS Lett. 473, 81–84 (2000).
Mandala, S. M. et al. Sphingoid base 1-phosphate phosphatase: a key regulator of sphingolipid metabolism and stress response. Proc. Natl Acad. Sci. USA 95, 150–155 (1998).
Brindley, D. N., English, D., Pilquil, C., Buri, K. & Ling, Z. -C. Lipid phosphate phosphatases regulate signal transduction through glycerolipids and sphingolipids. Biochim. Biophys. Acta 1582, 33–44 (2002).
Olivera, A. & Rivera, J. Sphingolipids and the balancing of immune cell function: lessons from the mast cell. J. Immunol. 174, 1153–1158 (2005). This is a brief, recent summary of the role of lysosphingolipids in mast-cell biology and immunology.
Memon, R. A. et al. Endotoxin and cytokines increase hepatic sphingolipid biosynthesis and produce lipoproteins enriched in ceramides and sphingomyelin. Arterioscler. Thromb. Vasc. Biol. 18, 1257–1265 (1998).
Delon, C. et al. Sphingosine kinase 1 is an intracellular effector of phosphatidic acid. J. Biol. Chem. 279, 44763–44774 (2004).
Choi, O. H., Kim, J. H. & Kinet, J. P. Calcium mobilization via sphingosine kinase in signalling by the FcεRI antigen receptor. Nature 380, 634–636 (1996).
Jolly, P. S. et al. Transactivation of sphingosine-1-phosphate receptors by FcεRI triggering is required for normal mast cell degranulation and chemotaxis. J. Exp. Med. 199, 959–970 (2004).
Olivera, A. & Spiegel, S. Sphingosine kinase: a mediator of vital cellular functions. Prostaglandins Other Lipid Mediat. 64, 123–134 (2001).
Gaits, F. et al. Lysophosphatidic acid as a phospholipid mediator: pathways of synthesis. FEBS Lett. 410, 54–58 (1997).
Goetzl, E. J., Wang, W., McGiffert, C., Huang, M. C. & Graler, M. H. Sphingosine 1-phosphate and its G protein-coupled receptors constitute a multifunctional immunoregulatory system. J. Cell. Biochem. 92, 1104–1114 (2004).
Goetzl, E. J., Kong, Y. & Voice, J. K. Differential constitutive expression of functional receptors for lysophosphatidic acid by human blood lymphocytes. J. Immunol. 164, 4996–4999 (2000).
Zheng, Y., Voice, J. K., Kong, Y. & Goetzl, E. J. Altered expression and functional profile of lysophosphatidic acid receptors in mitogen-activated human blood T lymphocytes. FASEB J. 14, 2387–2389 (2000).
Rosen, H., Alfonso, C., Surh, C. D. & McHeyzer-Williams, M. G. Rapid induction of medullary thymocyte phenotypic maturation and egress inhibition by nanomolar sphingosine 1-phosphate receptor agonist. Proc. Natl Acad. Sci. USA 100, 10907–10912 (2003). This was the first pharmacological study to show the capacity of an S1P-receptor agonist to facilitate terminal differentiation of thymocytes and to regulate their emigration.
Allende, M. L., Dreier, J. L., Mandala, S. & Proia, R. L. Expression of the sphingosine 1-phosphate receptor, S1P1, on T-cells controls thymic emigration. J. Biol. Chem. 279, 15396–15401 (2004). This paper, together with reference 60, reports the discovery of the requirement for S1P 1 in the emigration of thymocytes.
Graeler, M. H., Kong, Y., Karliner, J. S. & Goetzl, E. J. Protein kinase Cε dependence of the recovery from down-regulation of S1P1 G protein-coupled receptors of T lymphocytes. J. Biol. Chem. 278, 27737–27741 (2003).
Lo, C. G., Xu, Y., Proia, R. L. & Cyster, J. G. Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. J. Exp. Med. 201, 291–301 (2005).
Graeler, M. & Goetzl, E. J. Activation-regulated expression and chemotactic function of sphingosine 1-phosphate receptors in mouse splenic T cells. FASEB J. 16, 1874–1878 (2002). This paper and reference 37 were the first papers to describe S1P receptors at the surface of lymphocytes, showing that S1P 1 and S1P 4 are the most abundant. They also provided the initial proof that S1P 1 mediates inhibition of lymphocyte chemotaxis to chemokines, as well as stimulation of chemotaxis.
Wang, W., Graeler, M. H. & Goetzl, E. J. Physiological sphingosine 1-phosphate requirement for optimal activity of mouse CD4+ regulatory T cells. FASEB J. 18, 1043–1045 (2004).
Cinamon, G. et al. Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nature Immunol. 5, 713–720 (2004).
Kaneider, N. C. et al. The immune modulator FTY720 targets sphingosine-kinase-dependent migration of human monocytes in response to amyloid β-protein and its precursor. FASEB J. 18, 1309–1311 (2004).
Idzko, M. et al. Sphingosine 1-phosphate induces chemotaxis of immature and modulates cytokine-release in mature human dendritic cells for emergence of TH2 immune responses. FASEB J. 16, 625–627 (2002).
Kveberg, L., Bryceson, Y., Inngjerdingen, M., Rolstad, B. & Maghazachi, A. A. Sphingosine 1 phosphate induces the chemotaxis of human natural killer cells. Role for heterotrimeric G proteins and phosphoinositide 3 kinases. Eur. J. Immunol. 32, 1856–1864 (2002).
Roviezzo, F. et al. Human eosinophil chemotaxis and selective in vivo recruitment by sphingosine 1-phosphate. Proc. Natl Acad. Sci. USA 101, 11170–11175 (2004).
Graeler, M., Shankar, G. & Goetzl, E. Suppression of T cell chemotaxis by sphingosine 1-phosphate. J. Immunol. 169, 4084–4087 (2002).
Dorsam, G. et al. Transduction of multiple effects of sphingosine 1-phosphate (S1P) on T cell functions by the S1P1 G protein-coupled receptor. J. Immunol. 171, 3500–3507 (2003). This is the initial proof that S1P 1 transduces most of the immune effects of S1P on T-cell function.
Bautista, D. L. et al. Dynamic modeling of EDG1 receptor structural changes induced by site-directed mutations. J. Mol. Struct. 529, 219–224 (2000).
Parrill, A. L. W. et al. Identification of EDG1 receptor residues that recognize sphingosine 1-phosphate. J. Biol. Chem. 275, 39379–39384 (2000).
Wang, D. A. et al. A single amino acid determines lysophospholipid specificity of the S1P1 (EDG1) and LPA1 (EDG2) phospholipid growth factor receptors. J. Biol. Chem. 276, 49213–49220 (2001).
Sardar, V. M. et al. Molecular basis for the lysophosphatidic acid receptor agonist selectivity. Biochim. Biophys. Acta 1582, 309–317 (2002).
Forrest, M. et al. Immune cell regulation and cardiovascular effects of sphingosine 1-phosphate receptor agonists in rodents are mediated via distinct receptor subtypes. J. Pharmacol. Exp. Ther. 309, 758–768 (2004).
Sanna, M. G. et al. Sphingosine 1-phosphate (S1P) receptor subtypes S1P1 and S1P3, respectively, regulate lymphocyte recirculation and heart rate. J. Biol. Chem. 279, 13839–13848 (2004).
Hale, J. J. et al. Potent S1P receptor agonists replicate the pharmacologic actions of the novel immune modulator FTY720. Bioorg. Med. Chem. Lett. 14, 3351–3355 (2004).
Bannert, N. et al. Sialylated O-glycans and sulfated tyrosines in the NH2-terminal domain of CC chemokine receptor 5 contribute to high affinity binding of chemokines. J. Exp. Med. 194, 1661–1673 (2001).
Farzan, M. et al. The role of post-translational modifications of the CXCR4 amino terminus in stromal-derived factor 1α association and HIV-1 entry. J. Biol. Chem. 277, 29484–29489 (2002).
Fieger, C. B., Huang, M. C., Van Brocklyn, J. R. & Goetzl, E. J. Type 1 sphingosine 1-phosphate G protein-coupled receptor signaling of lymphocyte functions requires sulfation of its extracellular amino-terminal tyrosines. FASEB J. (in the press).
Dohlman, H. G., Caron, M. G. & Lefkowitz, R. J. A family of receptors coupled to guanine nucleotide regulatory proteins. Biochemistry 26, 2657–2664 (1987).
Ishii, I., Fukushima, N., Ye, X. & Chun, J. Lysophospholipid receptors: signaling and biology. Annu. Rev. Biochem. 73, 321–354 (2004).
Peng, X. et al. Protective effects of sphingosine 1-phosphate in murine endotoxin-induced inflammatory lung injury. Am. J. Respir. Crit. Care Med. 169, 1245–1251 (2004).
McVerry, B. J. et al. Sphingosine 1-phosphate reduces vascular leak in murine and canine models of acute lung injury. Am. J. Respir. Crit. Care Med. 170, 987–993 (2004).
McVerry, B. J. & Garcia, J. G. In vitro and in vivo modulation of vascular barrier integrity by sphingosine 1-phosphate: mechanistic insights. Cell Signal. 17, 131–139 (2005).
Halin, C. et al. The S1P-analog FTY720 differentially modulates T cell homing via HEV: T cell-expressed S1P1 amplifies integrin activation in peripheral lymph nodes but not in Peyer's patches. Blood 3 May 2005 (10.1182/blood-2004-09-3687).
Goetzl, E. J., Kong, Y. & Mei, B. Lysophosphatidic acid and sphingosine 1-phosphate protection of T cells from apoptosis in association with suppression of Bax. J. Immunol. 162, 2049–2056 (1999).
Wang, W., Graeler, M. H. & Goetzl, E. J. Type 4 sphingosine 1-phosphate G protein-coupled receptor (S1P4) transduces S1P effects on T cell proliferation and cytokine secretion without signaling migration. FASEB J. (in the press).
Baumruker, T. & Prieschl, E. E. The role of sphingosine kinase in the signaling initiated at the high-affinity receptor for IgE (FcεRI) in mast cells. Int. Arch. Allergy Immunol. 122, 85–90 (2000).
Prieschl, E. E., Csonga, R., Novotny, V., Kikuchi, G. E. & Baumruker, T. The balance between sphingosine and sphingosine-1-phosphate is decisive for mast cell activation after Fcε receptor I triggering. J. Exp. Med. 190, 1–8 (1999).
Bagga, S. et al. Lysophosphatidic acid accelerates the development of human mast cells. Blood 104, 4080–4087 (2004).
Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004). This report of the discovery of the requirement for S1P 1 in the emigration of thymocytes shows that it is required for lymphocyte transmigration and egress from lymph nodes.
Girkontaite, I. et al. The sphingosine-1-phosphate (S1P) lysophospholipid receptor S1P3 regulates MAdCAM-1+ endothelial cells in splenic marginal sinus organization. J. Exp. Med. 200, 1491–1501 (2004).
Jo, E. et al. S1P1-selective in vivo-active agonists from high throughput screening: off-the-shelf chemical probes of receptor interactions, signaling and fate. Chem. Biol. (in the press).
Graler, M. H., Huang, M. C., Watson, S. & Goetzl, E. J. Immunological effects of transgenic constitutive expression of the type 1 sphingosine 1-phosphate receptor by mouse lymphocytes. J. Immunol. 174, 1997–2003 (2005). This study shows the defects in cellular immune responses and antibody responses, as well as in lymphocyte trafficking, in mice with S1p1 -transgenic T cells.
Chi, H. & Flavell, R. A. Regulation of T cell trafficking and primary immune responses by sphingosine 1-phosphate receptor 1. J. Immunol. 174, 2485–2488 (2005).
Liu, Y. et al. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J. Clin. Invest. 106, 951–961 (2000).
Allende, M. L., Yamashita, T. & Proia, R. L. G-protein coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation. Blood 102, 3665–3667 (2003).
Tolle, M. et al. Immunomodulator FTY720 induces eNOS-dependent arterial vasodilatation via the lysophospholipid receptor S1P3 . Circ. Res. 96, 913–920 (2005).
Mandala, S. et al. Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296, 346–349 (2002).
Garcia, J. G. N. et al. Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement. J. Clin. Invest. 108, 689–701 (2001).
Sanchez, T. et al. Phosphorylation and action of the immunomodulator FTY720 inhibits vascular endothelial cell growth factor-induced vascular permeability. J. Biol. Chem. 278, 47281–47290 (2003). References 69 and 70 are the definitive studies of the involvement of S1P and the effects of phospho-FTY720 in endothelial barrier integrity.
Chiba, K. et al. FTY720, a novel immunosuppressant possessing unique mechanisms. I. Prolongation of skin allograft survival and synergistic effect in combination with cyclosporine in rats. Transplant. Proc. 28, 1056–1059 (1996). This report and reference 73 were the first to show the immunosuppressive effects of the S1P 1 -receptor-binding compound FTY720.
Chiba, K. et al. FTY720, a novel immunosuppressant, induces sequestration of circulating lymphocytes by acceleration of lymphocyte homing. Transplant. Proc. 31, 1230–1233 (1999).
Fujita, T. et al. Potent immunosuppressants, 2-alkyl-2-aminopropane-1,3-diols. J. Med. Chem. 39, 4451–4459 (1996).
Fujita, T. et al. 2-Substituted 2-aminoethanol: minimum essential structure for immunosuppressive activity of ISP-I (myriocin). Bioorg. Med. Chem. Lett. 5, 1857–1860 (1995).
Pinschewer, D. D. et al. FTY720 immunosuppression impairs effector T-cell peripheral homing without affecting induction, expansion, and memory. J. Immunol. 164, 5761–5770 (2000).
Arnold, C. N., Butcher, E. C. & Campbell, D. J. Antigen-specific lymphocyte sequestration in lymphoid organs: lack of essential roles for αL and α4 integrin-dependent adhesion or Gαi protein-coupled receptor signaling. J. Immunol. 173, 866–873 (2004).
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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Glossary
- LYSOPHOSPHOLIPID
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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
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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
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(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
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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
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A molecule or ion that has physically separate positively and negatively charged groups.
- FTY720
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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
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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
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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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DOI: https://doi.org/10.1038/nri1650
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