The alliance of sphingosine-1-phosphate and its receptors in immunity

Key Points

  • 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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Sphingolipid synthesis and degradation.
Figure 2: Regulation of S1P levels in vivo.
Figure 3: S1PR1-mediated lymphocyte egress from lymph nodes.
Figure 4: Effects of S1P on immune-cell function.


  1. 1

    Hannun, Y. A. & Obeid, L. M. Principles of bioactive lipid signalling: lessons from sphingolipids. Nature Rev. Mol. Cell. Biol. 9, 139–150 (2008). This is a comprehensive overview of the cellular regulation and function of sphingolipid metabolism.

    CAS  Article  Google Scholar 

  2. 2

    Rivera, J. & Olivera, A. Src family kinases and lipid mediators in control of allergic inflammation. Immunol. Rev. 217, 255–268 (2007).

    CAS  PubMed  Article  Google Scholar 

  3. 3

    Sanchez, T. & Hla, T. Structural and functional characteristics of S1P receptors. J. Cell. Biochem. 92, 913–922 (2004).

    CAS  PubMed  Article  Google Scholar 

  4. 4

    Brinkmann, V. et al. The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J. Biol. Chem. 277, 21453–21457 (2002).

    CAS  PubMed  Article  Google Scholar 

  5. 5

    Matloubian, M. et al. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427, 355–360 (2004).

    CAS  PubMed  Article  Google Scholar 

  6. 6

    Kunisawa, J. et al. Sphingosine 1-phosphate-dependent trafficking of peritoneal B cells requires functional NFκB-inducing kinase in stromal cells. Blood 111, 4646–4652 (2008).

    CAS  PubMed  Article  Google Scholar 

  7. 7

    Graler, M. H. & Goetzl, E. J. The immunosuppressant FTY720 down-regulates sphingosine 1-phosphate G-protein-coupled receptors. FASEB J. 18, 551–553 (2004).

    CAS  PubMed  Article  Google Scholar 

  8. 8

    Mechtcheriakova, D. et al. Sphingosine 1-phosphate phosphatase 2 is induced during inflammatory responses. Cell Signal. 19, 748–760 (2007).

    CAS  PubMed  Article  Google Scholar 

  9. 9

    Peest, U. et al. S1P-lyase independent clearance of extracellular sphingosine 1-phosphate after dephosphorylation and cellular uptake. J. Cell. Biochem. 104, 756–772 (2008).

    CAS  PubMed  Article  Google Scholar 

  10. 10

    Zhao, Y. et al. Intracellular generation of sphingosine 1-phosphate in human lung endothelial cells: role of lipid phosphate phosphatase-1 and sphingosine kinase 1. J. Biol. Chem. 282, 14165–14177 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11

    Pappu, R. et al. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 316, 295–298 (2007).

    CAS  Article  Google Scholar 

  12. 12

    Schwab, S. R. et al. Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 309, 1735–1739 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13

    Yatomi, Y. Plasma sphingosine 1-phosphate metabolism and analysis. Biochim. Biophys. Acta 1780, 606–611 (2008).

    CAS  PubMed  Article  Google Scholar 

  14. 14

    Venkataraman, K. et al. Vascular endothelium as a contributor of plasma sphingosine 1-phosphate. Circ. Res. 102, 669–676 (2008). This study indicates that endothelial cells can be a source of S1P in plasma.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15

    Olivera, A. et al. The sphingosine kinase-sphingosine-1-phosphate axis is a determinant of mast cell function and anaphylaxis. Immunity 26, 287–297 (2007). This paper shows that deficiency of SPHK2 in mast cells impairs antigen-induced calcium influx and PKC activation, and results in a broad defect in mast-cell effector functions. It also reveals a previously unrecognized role for circulating S1P in mast-cell responsiveness.

    CAS  Article  Google Scholar 

  16. 16

    Mizugishi, K. et al. Essential role for sphingosine kinases in neural and vascular development. Mol. Cell. Biol. 25, 11113–11121 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17

    Boujaoude, L. C. et al. Cystic fibrosis transmembrane regulator regulates uptake of sphingoid base phosphates and lysophosphatidic acid: modulation of cellular activity of sphingosine 1-phosphate. J. Biol. Chem. 276, 35258–35264 (2001).

    CAS  PubMed  Article  Google Scholar 

  18. 18

    Kobayashi, N. et al. Sphingosine 1-phosphate is released from the cytosol of rat platelets in a carrier-mediated manner. J. Lipid Res. 47, 614–621 (2006).

    CAS  PubMed  Article  Google Scholar 

  19. 19

    Mitra, P. et al. Role of ABCC1 in export of sphingosine-1-phosphate from mast cells. Proc. Natl Acad. Sci. USA 103, 16394–16399 (2006). This report identifies, for the first time in an immune cell, an ABC1 transporter as a transporter of S1P from mast cells.

    CAS  PubMed  Article  Google Scholar 

  20. 20

    Anada, Y., Igarashi, Y. & Kihara, A. The immunomodulator FTY720 is phosphorylated and released from platelets. Eur. J. Pharmacol. 568, 106–111 (2007).

    CAS  PubMed  Article  Google Scholar 

  21. 21

    Hanel, P., Andreani, P. & Graler, M. H. Erythrocytes store and release sphingosine 1-phosphate in blood. FASEB J. 21, 1202–1209 (2007).

    PubMed  Article  CAS  Google Scholar 

  22. 22

    Hla, T. & Maciag, T. An abundant transcript induced in differentiating human endothelial cells encodes a polypeptide with structural similarities to G-protein-coupled receptors. J. Biol. Chem. 265, 9308–9313 (1990).

    CAS  PubMed  Google Scholar 

  23. 23

    Spiegel, S. Sphingosine 1-phosphate: a ligand for the EDG-1 family of G-protein- coupled receptors. Ann. N. Y. Acad. Sci. 905, 54–60 (2000).

    CAS  PubMed  Article  Google Scholar 

  24. 24

    Walzer, T. et al. Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor. Nature Immunol. 8, 1337–1344 (2007). This paper shows the participation of S1PR5 in the trafficking of NK cells.

    CAS  Article  Google Scholar 

  25. 25

    Czeloth, N. et al. Sphingosine-1 phosphate signaling regulates positioning of dendritic cells within the spleen. J. Immunol. 179, 5855–5863 (2007).

    CAS  PubMed  Article  Google Scholar 

  26. 26

    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).

    CAS  PubMed  Article  Google Scholar 

  27. 27

    Jolly, P. S. et al. Transactivation of sphingosine-1-phosphate receptors by FcɛRI triggering is required for normal mast cell degranulation and chemotaxis. J. Exp. Med. 199, 959–970 (2004).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28

    Yokoo, E. et al. Sphingosine 1-phosphate inhibits migration of RBL-2H3 cells via S1P2: cross-talk between platelets and mast cells. J. Biochem. 135, 673–681 (2004).

    CAS  PubMed  Article  Google Scholar 

  29. 29

    Okamoto, H. et al. Inhibitory regulation of Rac activation, membrane ruffling, and cell migration by the G protein-coupled sphingosine-1-phosphate receptor EDG5 but not EDG1 or EDG3. Mol. Cell. Biol. 20, 9247–9261 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30

    Sugimoto, N., Takuwa, N., Okamoto, H., Sakurada, S. & Takuwa, Y. Inhibitory and stimulatory regulation of Rac and cell motility by the G12/13-Rho and Gi pathways integrated downstream of a single G protein-coupled sphingosine-1-phosphate receptor isoform. Mol. Cell. Biol. 23, 1534–1545 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  31. 31

    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 patches. Blood 106, 1314–1322 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. 32

    Yopp, A. C. et al. FTY720-enhanced T cell homing is dependent on CCR2, CCR5, CCR7, and CXCR4: evidence for distinct chemokine compartments. J. Immunol. 173, 855–865 (2004).

    CAS  PubMed  Article  Google Scholar 

  33. 33

    Schwab, S. R. & Cyster, J. G. Finding a way out: lymphocyte egress from lymphoid organs. Nature Immunol. 8, 1295–1301 (2007).

    CAS  Article  Google Scholar 

  34. 34

    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 study, together with references 5 and 11, shows that lymphocyte egress into the blood depends on a gradient of S1P from tissue (low concentration) to blood (high concentration) and on lymphocyte S1PR1. It also shows that plasma S1P is mostly generated by erythrocytes.

    CAS  PubMed  Article  Google Scholar 

  35. 35

    Allende, M. L. et al. S1P1 receptor expression regulates emergence of NKT cells in peripheral tissues. FASEB J. 22, 307–315 (2008).

    CAS  PubMed  Article  Google Scholar 

  36. 36

    Kabashima, K. et al. Plasma cell S1P1 expression determines secondary lymphoid organ retention versus bone marrow tropism. J. Exp. Med. 203, 2683–2690 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37

    Gohda, M. et al. Sphingosine 1-phosphate regulates the egress of IgA plasmablasts from Peyer's patches for intestinal IgA responses. J. Immunol. 180, 5335–5343 (2008).

    CAS  PubMed  Article  Google Scholar 

  38. 38

    Kurashima, Y. et al. Sphingosine 1-phosphate-mediated trafficking of pathogenic Th2 and mast cells for the control of food allergy. J. Immunol. 179, 1577–1585 (2007).

    CAS  PubMed  Article  Google Scholar 

  39. 39

    Cinamon, G. et al. Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone. Nature Immunol. 5, 713–720 (2004).

    CAS  Article  Google Scholar 

  40. 40

    Cinamon, G., Zachariah, M. A., Lam, O. M., Foss, F. W. Jr & Cyster, J. G. Follicular shuttling of marginal zone B cells facilitates antigen transport. Nature Immunol. 9, 54–62 (2008).

    CAS  Article  Google Scholar 

  41. 41

    Ledgerwood, L. G. et al. The sphingosine 1-phosphate receptor 1 causes tissue retention by inhibiting the entry of peripheral tissue T lymphocytes into afferent lymphatics. Nature Immunol. 9, 42–53 (2008).

    CAS  Article  Google Scholar 

  42. 42

    Massberg, S. et al. Immunosurveillance by hematopoietic progenitor cells trafficking through blood, lymph, and peripheral tissues. Cell 131, 994–1008 (2007). This study shows that S1PR1 functions in the trafficking of HSPCs through non-lymphoid tissues, which has a role in immunosurveillance.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43

    Bai, A., Hu, H., Yeung, M. & Chen, J. Kruppel-like factor 2 controls T cell trafficking by activating L-selectin (CD62L) and sphingosine-1-phosphate receptor 1 transcription. J. Immunol. 178, 7632–7639 (2007).

    CAS  PubMed  Article  Google Scholar 

  44. 44

    Carlson, C. M. et al. Kruppel-like factor 2 regulates thymocyte and T-cell migration. Nature 442, 299–302 (2006).

    CAS  PubMed  Article  Google Scholar 

  45. 45

    Sebzda, E., Zou, Z., Lee, J. S., Wang, T. & Kahn, M. L. Transcription factor KLF2 regulates the migration of naive T cells by restricting chemokine receptor expression patterns. Nature Immunol. 9, 292–300 (2008).

    CAS  Article  Google Scholar 

  46. 46

    Gonzalez-Cabrera, P. J., Hla, T. & Rosen, H. Mapping pathways downstream of sphingosine 1-phosphate subtype 1 by differential chemical perturbation and proteomics. J. Biol. Chem. 282, 7254–7264 (2007).

    CAS  PubMed  Article  Google Scholar 

  47. 47

    Oo, M. L. et al. Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor. J. Biol. Chem. 282, 9082–9089 (2007).

    CAS  PubMed  Article  Google Scholar 

  48. 48

    Pham, T. H., Okada, T., Matloubian, M., Lo, C. G. & Cyster, J. G. S1P1 receptor signaling overrides retention mediated by G α i-coupled receptors to promote T cell egress. Immunity 28, 122–133 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49

    Alfonso, C., McHeyzer-Williams, M. G. & Rosen, H. CD69 down-modulation and inhibition of thymic egress by short- and long-term selective chemical agonism of sphingosine 1-phosphate receptors. Eur. J. Immunol. 36, 149–159 (2006).

    CAS  PubMed  Article  Google Scholar 

  50. 50

    Shiow, L. R. et al. CD69 acts downstream of interferon-α/β to inhibit S1P1 and lymphocyte egress from lymphoid organs. Nature 440, 540–544 (2006).

    CAS  Article  PubMed  Google Scholar 

  51. 51

    Rosen, H., Sanna, M. G., Cahalan, S. M. & Gonzalez-Cabrera, P. J. Tipping the gatekeeper: S1P regulation of endothelial barrier function. Trends Immunol. 28, 102–107 (2007).

    CAS  PubMed  Article  Google Scholar 

  52. 52

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53

    Sanna, M. G. et al. Enhancement of capillary leakage and restoration of lymphocyte egress by a chiral S1P1 antagonist in vivo. Nature Chem. Biol. 2, 434–441 (2006).

    CAS  Article  Google Scholar 

  54. 54

    Wei, S. H. et al. Sphingosine 1-phosphate type 1 receptor agonism inhibits transendothelial migration of medullary T cells to lymphatic sinuses. Nature Immunol. 6, 1228–1235 (2005).

    CAS  Article  Google Scholar 

  55. 55

    Foss, F. W. Jr et al. Synthesis and biological evaluation of γ-aminophosphonates as potent, subtype-selective sphingosine 1-phosphate receptor agonists and antagonists. Bioorg. Med. Chem. 15, 663–677 (2007).

    CAS  PubMed  Article  Google Scholar 

  56. 56

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  57. 57

    Allende, M. L., Yamashita, T. & Proia, R. L. G-protein-coupled receptor S1P1 acts within endothelial cells to regulate vascular maturation. Blood 102, 3665–3677 (2003).

    CAS  PubMed  Article  Google Scholar 

  58. 58

    Singer, I. I. et al. Sphingosine-1-phosphate agonists increase macrophage homing, lymphocyte contacts, and endothelial junctional complex formation in murine lymph nodes. J. Immunol. 175, 7151–7161 (2005).

    CAS  PubMed  Article  Google Scholar 

  59. 59

    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).

    CAS  PubMed  Article  Google Scholar 

  60. 60

    Idzko, M. et al. Local application of FTY720 to the lung abrogates experimental asthma by altering dendritic cell function. J. Clin. Invest. 116, 2935–2944 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61

    Maeda, Y. et al. Migration of CD4 T cells and dendritic cells toward sphingosine 1-phosphate (S1P) is mediated by different receptor subtypes: S1P regulates the functions of murine mature dendritic cells via S1P receptor type 3. J. Immunol. 178, 3437–3446 (2007).

    CAS  PubMed  Article  Google Scholar 

  62. 62

    Lan, Y. Y. et al. The sphingosine-1-phosphate receptor agonist FTY720 modulates dendritic cell trafficking in vivo. Am. J. Transplant. 5, 2649–2659 (2005).

    CAS  PubMed  Article  Google Scholar 

  63. 63

    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).

    CAS  PubMed  Article  Google Scholar 

  64. 64

    Muller, H. et al. The immunomodulator FTY720 interferes with effector functions of human monocyte-derived dendritic cells. Eur. J. Immunol. 35, 533–545 (2005).

    PubMed  Article  CAS  Google Scholar 

  65. 65

    Niessen, F. et al. Dendritic cell PAR1–S1P3 signalling couples coagulation and inflammation. Nature 452, 654–658 (2008). This paper describes a new role for DCs in the dissemination of inflammation and coagulation during severe sepsis, and reveals the involvement of SPHK1 and S1PR3 activation by PAR1 in this process.

    CAS  PubMed  Article  Google Scholar 

  66. 66

    Riewald, M. & Ruf, W. Science review: role of coagulation protease cascades in sepsis. Crit. Care 7, 123–129 (2003).

    PubMed  Article  Google Scholar 

  67. 67

    Kaneider, N. C. et al. 'Role reversal' for the receptor PAR1 in sepsis-induced vascular damage. Nature Immunol. 8, 1303–1312 (2007).

    CAS  Article  Google Scholar 

  68. 68

    Choi, O., H., Kim, J.-H. & Kinet, J.-P. Calcium mobilization via sphingosine kinase in signalling by the FcɛRI antigen receptor. Nature 380, 634–636 (1996).

    CAS  Article  Google Scholar 

  69. 69

    Melendez, A. J. & Khaw, A. K. Dichotomy of Ca2+ signals triggered by different phospholipid pathways in antigen stimulation of human mast cells. J. Biol. Chem. 277, 17255–17262 (2002).

    CAS  Article  Google Scholar 

  70. 70

    Olivera, A. et al. IgE-dependent activation of sphingosine kinases 1 and 2 and secretion of sphingosine 1-phosphate requires Fyn kinase and contributes to mast cell responses. J. Biol. Chem. 281, 2515–2525 (2006).

    CAS  Article  Google Scholar 

  71. 71

    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 FcɛRI triggering. J. Exp. Med. 190, 1–8 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72

    Olivera, A. & Rivera, J. Sphingolipids and the balancing of immune cell function: lessons from the mast cell. J. Immunol. 174, 1153–1158 (2005).

    CAS  PubMed  Article  Google Scholar 

  73. 73

    Oskeritzian, C. A. et al. Distinct roles of sphingosine kinases 1 and 2 in human mast cell functions. Blood 111, 4193–4200 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74

    Fueller, M., Wang, D. A., Tigyi, G. & Siess, W. Activation of human monocytic cells by lysophosphatidic acid and sphingosine-1-phosphate. Cell Signal. 15, 367–375 (2003).

    CAS  PubMed  Article  Google Scholar 

  75. 75

    Hughes, J. E. et al. Sphingosine-1-phosphate induces an antiinflammatory phenotype in macrophages. Circ. Res. 102, 950–958 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76

    Jiang, L. I. et al. Use of a cAMP BRET sensor to characterize a novel regulation of cAMP by the sphingosine 1-phosphate/G13 pathway. J. Biol. Chem. 282, 10576–10584 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77

    Nofer, J. R. et al. FTY720, a synthetic sphingosine 1 phosphate analogue, inhibits development of atherosclerosis in low-density lipoprotein receptor-deficient mice. Circulation 115, 501–508 (2007).

    CAS  PubMed  Article  Google Scholar 

  78. 78

    Dueñas, A. I. et al. Selective attenuation of Toll-like receptor 2 signaling may explain the atheroprotective effect of sphingosine 1-phosphate. Cardiovasc. Res. 79, 537–544 (2008).

    PubMed  Article  CAS  Google Scholar 

  79. 79

    Weigert, A. et al. Tumor cell apoptosis polarizes macrophages — role of sphingosine-1-phosphate. Mol. Biol. Cell 18, 3810–3819 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80

    Weigert, A. et al. Apoptotic cells promote macrophage survival by releasing the antiapoptotic mediator sphingosine-1-phosphate. Blood 108, 1635–1642 (2006).

    CAS  PubMed  Article  Google Scholar 

  81. 81

    Gude, D. R. et al. Apoptosis induces expression of sphingosine kinase 1 to release sphingosine-1-phosphate as a “come-and-get-me” signal. FASEB J., 22, 2629–2638 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82

    Rosen, H. & Goetzl, E. J. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nature Rev. Immunol. 5, 560–570 (2005).

    CAS  Article  Google Scholar 

  83. 83

    Jin, Y. et al. Sphingosine 1-phosphate is a novel inhibitor of T-cell proliferation. Blood 101, 4909–4915 (2003).

    CAS  PubMed  Article  Google Scholar 

  84. 84

    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).

    PubMed  Article  Google Scholar 

  85. 85

    Song, J. et al. A novel sphingosine 1-phosphate receptor agonist, 2-amino-2-propanediol hydrochloride (KRP-203), regulates chronic colitis in interleukin-10 gene-deficient mice. J. Pharmacol. Exp. Ther. 324, 276–283 (2008).

    CAS  PubMed  Article  Google Scholar 

  86. 86

    Huang, M. C., Watson, S. R., Liao, J. J. & Goetzl, E. J. Th17 augmentation in OTII TCR plus T cell-selective type 1 sphingosine 1-phosphate receptor double transgenic mice. J. Immunol. 178, 6806–6813 (2007).

    CAS  PubMed  Article  Google Scholar 

  87. 87

    Wang, W., Huang, M. C. & Goetzl, E. J. Type 1 sphingosine 1-phosphate G protein-coupled receptor (S1P1) mediation of enhanced IL-4 generation by CD4 T cells from S1P1 transgenic mice. J. Immunol. 178, 4885–4890 (2007).

    CAS  Article  PubMed  Google Scholar 

  88. 88

    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. 19, 1731–1733 (2005).

    CAS  PubMed  Article  Google Scholar 

  89. 89

    Sekiguchi, M. et al. Role of sphingosine 1-phosphate in the pathogenesis of Sjögren's syndrome. J. Immunol. 180, 1921–1928 (2008).

    CAS  PubMed  Article  Google Scholar 

  90. 90

    Liao, J. J., Huang, M. C. & Goetzl, E. J. Cutting Edge: Alternative signaling of Th17 cell development by sphingosine 1-phosphate. J. Immunol. 178, 5425–5428 (2007). This study, together with reference 86, shows that S1P–S1PR1 activation can provide an alternative pathway to IL-23 stimulation for the differentiation of CD4+ T cells into IL-17-producing cells.

    CAS  PubMed  Article  Google Scholar 

  91. 91

    Jacobson, J. R. & Garcia, J. G. Novel therapies for microvascular permeability in sepsis. Curr. Drug Targets. 8, 509–514 (2007).

    CAS  PubMed  Article  Google Scholar 

  92. 92

    Deutschman, D. H. et al. Predicting obstructive coronary artery disease with serum sphingosine-1-phosphate. Am. Heart J. 146, 62–68 (2003).

    CAS  PubMed  Article  Google Scholar 

  93. 93

    Ammit, A. J. et al. Sphingosine 1-phosphate modulates human airway smooth muscle cell functions that promote inflammation and airway remodeling in asthma. FASEB J. 15, 1212–1214 (2001).

    CAS  Article  Google Scholar 

  94. 94

    Kitano, M. et al. Sphingosine 1-phosphate/sphingosine 1-phosphate receptor 1 signaling in rheumatoid synovium: regulation of synovial proliferation and inflammatory gene expression. Arthritis Rheum. 54, 742–753 (2006).

    CAS  Article  PubMed  Google Scholar 

  95. 95

    Yamashita, Y. et al. Cutting Edge: genetic variation influences FcɛRI-induced mast cell activation and allergic responses. J. Immunol. 179, 740–743 (2007).

    CAS  PubMed  Article  Google Scholar 

  96. 96

    Rivera, J. & Tessarollo, L. Genetic background and the dilema of translating mouse studies to humans. Immunity 28, 1–4 (2008).

    CAS  PubMed  Article  Google Scholar 

  97. 97

    Maki, T., Gottschalk, R., Ogawa, N. & Monaco, A. P. Prevention and cure of autoimmune diabetes in nonobese diabetic mice by continuous administration of FTY720. Transplantation 79, 1051–1055 (2005).

    CAS  PubMed  Article  Google Scholar 

  98. 98

    Srinivasan, S. et al. Sphingosine-1-phosphate reduces CD4+ T-cell activation in type 1 diabetes through regulation of hypoxia-inducible factor short isoform I.1 and CD69. Diabetes 57, 484–493 (2008).

    CAS  PubMed  Article  Google Scholar 

  99. 99

    Marino, E. et al. Marginal-zone B-cells of nonobese diabetic mice expand with diabetes onset, invade the pancreatic lymph nodes, and present autoantigen to diabetogenic T-cells. Diabetes 57, 395–404 (2008).

    CAS  PubMed  Article  Google Scholar 

  100. 100

    Kahan, B. D. Frontiers in immunosuppression. Transplant. Proc. 40, 11–15 (2008).

    CAS  PubMed  Article  Google Scholar 

  101. 101

    Kappos, L. et al. Oral fingolimod (FTY720) for relapsing multiple sclerosis. N. Engl. J. Med. 355, 1124–1140 (2006).

    CAS  PubMed  Article  Google Scholar 

  102. 102

    Foster, C. A. et al. FTY720 rescue therapy in the dark agouti rat model of experimental autoimmune encephalomyelitis: expression of central nervous system genes and reversal of blood-brain-barrier damage. Brain Pathol. 6 June 2008 (doi: 0.1111/j.1750-3639.2008.0018).

  103. 103

    Aranami, T. & Yamamura, T. Th17 cells and autoimmune encephalomyelitis (EAE/MS). Allergol. Int. 57, 115–120 (2008).

    CAS  PubMed  Article  Google Scholar 

  104. 104

    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).

    CAS  PubMed  Article  Google Scholar 

  105. 105

    Matsuyuki, H. et al. Involvement of sphingosine 1-phosphate (S1P) receptor type 1 and type 4 in migratory response of mouse T cells toward S1P. Cell. Mol. Immunol. 3, 429–437 (2006).

    CAS  PubMed  Google Scholar 

Download references


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.

Author information



Corresponding author

Correspondence to Juan Rivera.

Related links

Related links


Juan Rivera's laboratory


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.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Rivera, J., Proia, R. & Olivera, A. The alliance of sphingosine-1-phosphate and its receptors in immunity. Nat Rev Immunol 8, 753–763 (2008).

Download citation

Further reading