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Mediators of Inflammation
Volume 2016, Article ID 8606878, 11 pages
http://dx.doi.org/10.1155/2016/8606878
Review Article

Sphingosine-1-Phosphate Signaling in Immune Cells and Inflammation: Roles and Therapeutic Potential

1Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine and Massey Cancer Center, West Hospital 7-402, 1200 East Broad Street, P.O. Box 980011, Richmond, VA 23298-0011, USA
2Department of Biochemistry & Molecular Biology, Virginia Commonwealth University School of Medicine and Massey Cancer Center, West Hospital 7-402, 1200 East Broad Street, P.O. Box 980011, Richmond, VA 23298-0011, USA
3Breast Surgery, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA

Received 18 October 2015; Accepted 3 January 2016

Academic Editor: Laura Riboni

Copyright © 2016 Masayo Aoki et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. K. Takabe, S. W. Paugh, S. Milstien, and S. Spiegel, “‘Inside-out’ signaling of sphingosine-1-phosphate: therapeutic targets,” Pharmacological Reviews, vol. 60, no. 2, pp. 181–195, 2008. View at Publisher · View at Google Scholar · View at Scopus
  2. K. Takabe and S. Spiegel, “Export of sphingosine-1-phosphate and cancer progression,” Journal of Lipid Research, vol. 55, no. 9, pp. 1839–1846, 2014. View at Publisher · View at Google Scholar · View at Scopus
  3. M. Nagahashi, S. Ramachandran, E. Y. Kim et al., “Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis,” Cancer Research, vol. 72, no. 3, pp. 726–735, 2012. View at Publisher · View at Google Scholar · View at Scopus
  4. R. L. Proia and T. Hla, “Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy,” The Journal of Clinical Investigation, vol. 125, no. 4, pp. 1379–1387, 2015. View at Publisher · View at Google Scholar
  5. K. Takabe, A. Yamada, O. M. Rashid et al., “Twofer anti-vascular therapy targeting sphingosine-1-phosphate for breast cancer,” Gland Surgery, vol. 1, no. 2, pp. 80–83, 2012. View at Publisher · View at Google Scholar
  6. S. Spiegel and S. Milstien, “The outs and the ins of sphingosine-1-phosphate in immunity,” Nature Reviews Immunology, vol. 11, no. 6, pp. 403–415, 2011. View at Publisher · View at Google Scholar · View at Scopus
  7. W. Huang, M. Nagahashi, K. Terracina, and K. Takabe, “Emerging role of sphingosine-1-phosphate in inflammation, cancer, and lymphangiogenesis,” Biomolecules, vol. 3, no. 3, pp. 408–434, 2013. View at Publisher · View at Google Scholar
  8. M. H. Bolli, S. Abele, C. Binkert et al., “2-Imino-thiazolidin-4-one derivatives as potent, orally active S1P1 receptor agonists,” Journal of Medicinal Chemistry, vol. 53, no. 10, pp. 4198–4211, 2010. View at Publisher · View at Google Scholar · View at Scopus
  9. Y. Maeda, N. Seki, H. Kataoka et al., “IL-17-producing Vγ4+ γδ T cells require sphingosine 1-phosphate receptor 1 for their egress from the lymph nodes under homeostatic and inflammatory conditions,” The Journal of Immunology, vol. 195, no. 4, pp. 1408–1416, 2015. View at Publisher · View at Google Scholar
  10. P. Keul, S. Lucke, K. Von Wnuck Lipinski et al., “Sphingosine-1-phosphate receptor 3 promotes recruitment of monocyte/macrophages in inflammation and atherosclerosis,” Circulation Research, vol. 108, no. 3, pp. 314–323, 2011. View at Publisher · View at Google Scholar · View at Scopus
  11. N. C. Hait, C. A. Oskeritzian, S. W. Paugh, S. Milstien, and S. Spiegel, “Sphingosine kinases, sphingosine 1-phosphate, apoptosis and diseases,” Biochimica et Biophysica Acta—Biomembranes, vol. 1758, no. 12, pp. 2016–2026, 2006. View at Publisher · View at Google Scholar · View at Scopus
  12. C. E. Chalfant and S. Spiegel, “Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling,” Journal of Cell Science, vol. 118, no. 20, pp. 4605–4612, 2005. View at Publisher · View at Google Scholar · View at Scopus
  13. M. Maceyka and S. Spiegel, “Sphingolipid metabolites in inflammatory disease,” Nature, vol. 510, no. 7503, pp. 58–67, 2014. View at Publisher · View at Google Scholar · View at Scopus
  14. S. E. Alvarez, K. B. Harikumar, N. C. Hait et al., “Sphingosine-1-phosphate is a missing cofactor for the E3 ubiquitin ligase TRAF2,” Nature, vol. 465, no. 7301, pp. 1084–1088, 2010. View at Publisher · View at Google Scholar · View at Scopus
  15. E.-S. Park, S. Choi, B. Shin et al., “Tumor necrosis factor (TNF) receptor-associated factor (TRAF)-interacting protein (TRIP) negatively regulates the TRAF2 ubiquitin-dependent pathway by suppressing the TRAF2-sphingosine 1-phosphate (S1P) interaction,” The Journal of Biological Chemistry, vol. 290, no. 15, pp. 9660–9673, 2015. View at Publisher · View at Google Scholar
  16. K. B. Harikumar, J. W. Yester, M. J. Surace et al., “K63-linked polyubiquitination of transcription factor IRF1 is essential for IL-1-induced production of chemokines CXCL10 and CCL5,” Nature Immunology, vol. 15, no. 3, pp. 231–238, 2014. View at Publisher · View at Google Scholar · View at Scopus
  17. Y. Xiong, H. J. Lee, B. Mariko et al., “Sphingosine kinases are not required for inflammatory responses in macrophages,” The Journal of Biological Chemistry, vol. 288, no. 45, pp. 32563–32573, 2013. View at Publisher · View at Google Scholar · View at Scopus
  18. M. Maceyka, H. Sankala, N. C. Hait et al., “SphK1 and SphK2, sphingosine kinase isoenzymes with opposing functions in sphingolipid metabolism,” The Journal of Biological Chemistry, vol. 280, no. 44, pp. 37118–37129, 2005. View at Publisher · View at Google Scholar · View at Scopus
  19. N. C. Hait, J. Allegood, M. Maceyka et al., “Regulation of histone acetylation in the nucleus by sphingosine-1-phosphate,” Science, vol. 325, no. 5945, pp. 1254–1257, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. D.-H. Nguyen-Tran, N. C. Hait, H. Sperber et al., “Molecular mechanism of sphingosine-1-phosphate action in Duchenne muscular dystrophy,” DMM Disease Models and Mechanisms, vol. 7, no. 1, pp. 41–54, 2014. View at Publisher · View at Google Scholar · View at Scopus
  21. G. M. Strub, M. Paillard, J. Liang et al., “Sphingosine-1-phosphate produced by sphingosine kinase 2 in mitochondria interacts with prohibitin 2 to regulate complex IV assembly and respiration,” The FASEB Journal, vol. 25, no. 2, pp. 600–612, 2011. View at Publisher · View at Google Scholar · View at Scopus
  22. E. Studer, X. Zhou, R. Zhao et al., “Conjugated bile acids activate the sphingosine-1-phosphate receptor 2 in primary rodent hepatocytes,” Hepatology, vol. 55, no. 1, pp. 267–276, 2012. View at Publisher · View at Google Scholar · View at Scopus
  23. M. Nagahashi, K. Takabe, R. Liu et al., “Conjugated bile acid-activated S1P receptor 2 is a key regulator of sphingosine kinase 2 and hepatic gene expression,” Hepatology, vol. 61, no. 4, pp. 1216–1226, 2015. View at Publisher · View at Google Scholar
  24. M. M. Adada, K. Alexa Orr-Gandy, A. J. Snider et al., “Sphingosine kinase 1 regulates tumor necrosis factor-mediated RANTES induction through p38 mitogen-activated protein kinase but independently of nuclear factor κB activation,” The Journal of Biological Chemistry, vol. 288, no. 38, pp. 27667–27679, 2013. View at Publisher · View at Google Scholar · View at Scopus
  25. N. M. Grin'kina, E. E. Karnabi, D. Damania, S. Wadgaonkar, I. A. Muslimov, and R. Wadgaonkar, “Sphingosine kinase 1 deficiency exacerbates LPS-induced neuroinflammation,” PloS ONE, vol. 7, no. 5, Article ID e36475, 2012. View at Publisher · View at Google Scholar · View at Scopus
  26. M. A. Hanson, C. B. Roth, E. Jo et al., “Crystal structure of a lipid G protein-coupled receptor,” Science, vol. 335, no. 6070, pp. 851–855, 2012. View at Publisher · View at Google Scholar · View at Scopus
  27. S. Spiegel and S. Milstien, “Functions of the multifaceted family of sphingosine kinases and some close relatives,” The Journal of Biological Chemistry, vol. 282, no. 4, pp. 2125–2129, 2007. View at Publisher · View at Google Scholar · View at Scopus
  28. H. Okamoto, N. Takuwa, T. Yokomizo 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,” Molecular and Cellular Biology, vol. 20, no. 24, pp. 9247–9261, 2000. View at Publisher · View at Google Scholar · View at Scopus
  29. D. J. Swan, J. A. Kirby, and S. Ali, “Vascular biology: the role of sphingosine 1-phosphate in both the resting state and inflammation,” Journal of Cellular and Molecular Medicine, vol. 14, no. 9, pp. 2211–2222, 2010. View at Publisher · View at Google Scholar · View at Scopus
  30. M. L. Allende, M. Bektas, B. G. Lee et al., “Sphingosine-1-phosphate lyase deficiency produces a pro-inflammatory response while impairing neutrophil trafficking,” The Journal of Biological Chemistry, vol. 286, no. 9, pp. 7348–7358, 2011. View at Publisher · View at Google Scholar · View at Scopus
  31. D.-S. Im, C. E. Heise, N. Ancellin et al., “Characterization of a novel sphingosine 1-phosphate receptor, Edg-8,” The Journal of Biological Chemistry, vol. 275, no. 19, pp. 14281–14286, 2000. View at Publisher · View at Google Scholar · View at Scopus
  32. C. Jaillard, S. Harrison, B. Stankoff et al., “Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival,” The Journal of Neuroscience, vol. 25, no. 6, pp. 1459–1469, 2005. View at Publisher · View at Google Scholar · View at Scopus
  33. A. S. Novgorodov, M. El-Alwani, J. Bielawski, L. M. Obeid, and T. I. Gudz, “Activation of sphingosine-1-phosphate receptor S1P5 inhibits oligodendrocyte progenitor migration,” The FASEB Journal, vol. 21, no. 7, pp. 1503–1514, 2007. View at Publisher · View at Google Scholar · View at Scopus
  34. E. Debien, K. Mayol, V. Biajoux et al., “S1PR5 is pivotal for the homeostasis of patrolling monocytes,” European Journal of Immunology, vol. 43, no. 6, pp. 1667–1675, 2013. View at Publisher · View at Google Scholar · View at Scopus
  35. E. J. Goetzl and H. Rosen, “Regulation of immunity by lysosphingolipids and their G protein-coupled receptors,” The Journal of Clinical Investigation, vol. 114, no. 11, pp. 1531–1537, 2004. View at Publisher · View at Google Scholar · View at Scopus
  36. N. D. Lewis, S. A. Haxhinasto, S. M. Anderson et al., “Circulating monocytes are reduced by sphingosine-1-phosphate receptor modulators independently of S1P3,” The Journal of Immunology, vol. 190, no. 7, pp. 3533–3540, 2013. View at Publisher · View at Google Scholar · View at Scopus
  37. Y. Maeda, H. Matsuyuki, K. Shimano, H. Kataoka, K. Sugahara, and K. Chiba, “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,” The Journal of Immunology, vol. 178, no. 6, pp. 3437–3446, 2007. View at Publisher · View at Google Scholar · View at Scopus
  38. I. I. Singer, M. Tian, L. A. Wickham et al., “Sphingosine-1-phosphate agonists increase macrophage homing, lymphocyte contacts, and endothelial junctional complex formation in murine lymph nodes,” The Journal of Immunology, vol. 175, no. 11, pp. 7151–7161, 2005. View at Publisher · View at Google Scholar · View at Scopus
  39. M. M. Price, C. A. Oskeritzian, Y. T. Falanga et al., “A specific sphingosine kinase 1 inhibitor attenuates airway hyperresponsiveness and inflammation in a mast cell-dependent murine model of allergic asthma,” Journal of Allergy and Clinical Immunology, vol. 131, no. 2, pp. 501.e1–511.e1, 2013. View at Publisher · View at Google Scholar · View at Scopus
  40. J. G. Juarez, N. Harun, M. Thien et al., “Sphingosine-1-phosphate facilitates trafficking of hematopoietic stem cells and their mobilization by CXCR4 antagonists in mice,” Blood, vol. 119, no. 3, pp. 707–716, 2012. View at Publisher · View at Google Scholar · View at Scopus
  41. R. Pappu, S. R. Schwab, I. Cornelissen et al., “Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate,” Science, vol. 316, no. 5822, pp. 295–298, 2007. View at Publisher · View at Google Scholar · View at Scopus
  42. M. Kurano, K. Tsukamoto, R. Ohkawa et al., “Liver involvement in sphingosine 1-phosphate dynamism revealed byadenoviral hepatic overexpression of apolipoprotein M,” Atherosclerosis, vol. 229, no. 1, pp. 102–109, 2013. View at Publisher · View at Google Scholar · View at Scopus
  43. M. Liu, J. Seo, J. Allegood et al., “Hepatic apolipoprotein M (ApoM) overexpression stimulates formation of larger ApoM/sphingosine 1-phosphate-enriched plasma high density lipoprotein,” The Journal of Biological Chemistry, vol. 289, no. 5, pp. 2801–2814, 2014. View at Publisher · View at Google Scholar · View at Scopus
  44. V. A. Blaho, S. Galvani, E. Engelbrecht et al., “HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation,” Nature, vol. 523, no. 7560, pp. 342–346, 2015. View at Publisher · View at Google Scholar
  45. S. R. Schwab and J. G. Cyster, “Finding a way out: lymphocyte egress from lymphoid organs,” Nature Immunology, vol. 8, no. 12, pp. 1295–1301, 2007. View at Publisher · View at Google Scholar · View at Scopus
  46. J. Rivera, R. L. Proia, and A. Olivera, “The alliance of sphingosine-1-phosphate and its receptors in immunity,” Nature Reviews Immunology, vol. 8, no. 10, pp. 753–763, 2008. View at Publisher · View at Google Scholar · View at Scopus
  47. H. Rosen and E. J. Goetzl, “Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network,” Nature Reviews Immunology, vol. 5, no. 7, pp. 560–570, 2005. View at Publisher · View at Google Scholar · View at Scopus
  48. T. Willinger, S. M. Ferguson, J. P. Pereira, P. De Camilli, and R. A. Flavell, “Dynamin 2-dependent endocytosis is required for sustained S1PR1 signaling,” The Journal of Experimental Medicine, vol. 211, no. 4, pp. 685–700, 2014. View at Publisher · View at Google Scholar · View at Scopus
  49. C. S. Garris, V. A. Blaho, T. Hla, and M. H. Han, “Sphingosine-1-phosphate receptor 1 signalling in T cells: trafficking and beyond,” Immunology, vol. 142, no. 3, pp. 347–353, 2014. View at Publisher · View at Google Scholar · View at Scopus
  50. C. G. Lo, Y. Xu, R. L. Proia, and J. G. Cyster, “Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit,” The Journal of Experimental Medicine, vol. 201, no. 2, pp. 291–301, 2005. View at Publisher · View at Google Scholar · View at Scopus
  51. J.-J. Liao, M.-C. Huang, M. Graler, Y. Huang, H. Qiu, and E. J. Goetzl, “Distinctive T cell-suppressive signals from nuclearized type 1 sphingosine 1-phosphate G protein-coupled receptors,” The Journal of Biological Chemistry, vol. 282, no. 3, pp. 1964–1972, 2007. View at Publisher · View at Google Scholar · View at Scopus
  52. A. E. Denton, E. W. Roberts, M. A. Linterman, and D. T. Fearon, “Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8+ T cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 33, pp. 12139–12144, 2014. View at Publisher · View at Google Scholar · View at Scopus
  53. L. R. Shiow, D. B. Rosen, N. Brdičková et al., “CD69 acts downstream of interferon-α/β to inhibit S1P1 and lymphocyte egress from lymphoid organs,” Nature, vol. 440, no. 7083, pp. 540–544, 2006. View at Publisher · View at Google Scholar · View at Scopus
  54. C. A. Oskeritzian, N. C. Hait, P. Wedman et al., “The sphingosine-1-phosphate/sphingosine-1-phosphate receptor 2 axis regulates early airway T-cell infiltration in murine mast cell-dependent acute allergic responses,” Journal of Allergy and Clinical Immunology, vol. 135, no. 4, pp. 1008–1018, 2014. View at Publisher · View at Google Scholar · View at Scopus
  55. M. Chimen, H. M. McGettrick, B. Apta et al., “Homeostatic regulation of T cell trafficking by a B cell-derived peptide is impaired in autoimmune and chronic inflammatory disease,” Nature Medicine, vol. 21, no. 5, pp. 467–475, 2015. View at Publisher · View at Google Scholar
  56. L. G. Ledgerwood, G. Lal, N. Zhang et al., “The sphingosine 1-phosphate receptor 1 causes tissue retention by inhibiting the entry of peripheral tissue T lymphocytes into afferent lymphatics,” Nature Immunology, vol. 9, no. 1, pp. 42–53, 2008. View at Publisher · View at Google Scholar · View at Scopus
  57. T. I. Arnon, Y. Xu, C. Lo et al., “GRK2-dependent S1PR1 desensitization is required for lymphocytes to overcome their attraction to blood,” Science, vol. 333, no. 6051, pp. 1898–1903, 2011. View at Publisher · View at Google Scholar · View at Scopus
  58. C. N. Skon, J.-Y. Lee, K. G. Anderson, D. Masopust, K. A. Hogquist, and S. C. Jameson, “Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells,” Nature Immunology, vol. 14, no. 12, pp. 1285–1293, 2013. View at Publisher · View at Google Scholar · View at Scopus
  59. L. K. Mackay, A. Braun, B. L. Macleod et al., “Cutting edge: CD69 interference with sphingosine-1-phosphate receptor function regulates peripheral T cell retention,” The Journal of Immunology, vol. 194, no. 5, pp. 2059–2063, 2015. View at Publisher · View at Google Scholar
  60. M. Bot, P. P. Van Veldhoven, S. C. A. de Jager et al., “Hematopoietic sphingosine 1-phosphate lyase deficiency decreases atherosclerotic lesion development in LDL-receptor deficient mice,” PLoS ONE, vol. 8, no. 5, Article ID e63360, 2013. View at Publisher · View at Google Scholar · View at Scopus
  61. S. R. Schwab, J. P. Pereira, M. Matloubian, Y. Xu, Y. Huang, and J. G. Cyster, “Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients,” Science, vol. 309, no. 5741, pp. 1735–1739, 2005. View at Publisher · View at Google Scholar · View at Scopus
  62. S. M. Park, C. E. Angel, J. D. Mcintosh et al., “Sphingosine-1-phosphate lyase is expressed by CD68+ cells on the parenchymal side of marginal reticular cells in human lymph nodes,” European Journal of Immunology, vol. 44, no. 8, pp. 2425–2436, 2014. View at Publisher · View at Google Scholar · View at Scopus
  63. M. Ohtoyo, M. Tamura, N. Machinaga, F. Muro, and R. Hashimoto, “Sphingosine 1-phosphate lyase inhibition by 2-acetyl-4-(tetrahydroxybutyl)imidazole (THI) under conditions of vitamin B6 deficiency,” Molecular and Cellular Biochemistry, vol. 400, no. 1-2, pp. 125–133, 2014. View at Publisher · View at Google Scholar · View at Scopus
  64. J. P. Pereira, J. G. Cyster, and Y. Xu, “A role for S1P and S1P1 in immature-B cell egress from mouse bone marrow,” PLoS ONE, vol. 5, no. 2, Article ID e9277, 2010. View at Publisher · View at Google Scholar · View at Scopus
  65. M. L. Allende, G. Tuymetova, B. G. Lee, E. Bonifacino, Y.-P. Wu, and R. L. Proia, “S1P1 receptor directs the release of immature B cells from bone marrow into blood,” The Journal of Experimental Medicine, vol. 207, no. 5, pp. 1113–1124, 2010. View at Publisher · View at Google Scholar · View at Scopus
  66. G. Cinamon, M. Matloubian, M. J. Lesneski et al., “Sphingosine 1-phosphate receptor 1 promotes B cell localization in the splenic marginal zone,” Nature Immunology, vol. 5, no. 7, pp. 713–720, 2004. View at Publisher · View at Google Scholar · View at Scopus
  67. T. I. Arnon, R. M. Horton, I. L. Grigorova, and J. G. Cyster, “Visualization of splenic marginal zone B-cell shuttling and follicular B-cell egress,” Nature, vol. 493, no. 7434, pp. 684–688, 2013. View at Publisher · View at Google Scholar · View at Scopus
  68. R. K. Sinha, C. Park, I.-Y. Hwang, M. D. Davis, and J. H. Kehrl, “B lymphocytes exit lymph nodes through cortical lymphatic sinusoids by a mechanism independent of sphingosine-1-phosphate-mediated chemotaxis,” Immunity, vol. 30, no. 3, pp. 434–446, 2009. View at Publisher · View at Google Scholar · View at Scopus
  69. J. A. Green, K. Suzuki, B. Cho et al., “The sphingosine 1-phosphate receptor S1P2 maintains the homeostasis of germinal center B cells and promotes niche confinement,” Nature Immunology, vol. 12, no. 7, pp. 672–680, 2011. View at Publisher · View at Google Scholar · View at Scopus
  70. J. R. Muppidi, R. Schmitz, J. A. Green et al., “Loss of signalling via Gα13 in germinal centre B-cell-derived lymphoma,” Nature, vol. 516, no. 7530, pp. 254–258, 2014. View at Publisher · View at Google Scholar · View at Scopus
  71. H. Sic, H. Kraus, J. Madl et al., “Sphingosine-1-phosphate receptors control B-cell migration through signaling components associated with primary immunodeficiencies, chronic lymphocytic leukemia, and multiple sclerosis,” Journal of Allergy and Clinical Immunology, vol. 134, no. 2, pp. 420.e15–428.e15, 2014. View at Publisher · View at Google Scholar · View at Scopus
  72. L. Kveberg, Y. Bryceson, M. Inngjerdingen, B. Rolstad, and A. A. Maghazachi, “Sphingosine 1 phosphate induces the chemotaxis of human natural killer cells. Role for heterotrimeric G proteins and phosphoinositide 3 kinases,” European Journal of Immunology, vol. 32, no. 7, pp. 1856–1864, 2002. View at Google Scholar · View at Scopus
  73. M. L. Allende, D. Zhou, D. N. Kalkofen et al., “S1P1 receptor expression regulates emergence of NKT cells in peripheral tissues,” The FASEB Journal, vol. 22, no. 1, pp. 307–315, 2008. View at Publisher · View at Google Scholar · View at Scopus
  74. C. N. Jenne, A. Enders, R. Rivera et al., “T-bet-dependent S1P5 expression in NK cells promotes egress from lymph nodes and bone marrow,” The Journal of Experimental Medicine, vol. 206, no. 11, pp. 2469–2481, 2009. View at Publisher · View at Google Scholar · View at Scopus
  75. T. Walzer, L. Chiossone, J. Chaix et al., “Natural killer cell trafficking in vivo requires a dedicated sphingosine 1-phosphate receptor,” Nature Immunology, vol. 8, no. 12, pp. 1337–1344, 2007. View at Publisher · View at Google Scholar · View at Scopus
  76. T. A. Johnson, B. L. Evans, B. A. Durafourt et al., “Reduction of the peripheral blood CD56bright NK lymphocyte subset in FTY720-treated multiple sclerosis patients,” The Journal of Immunology, vol. 187, no. 1, pp. 570–579, 2011. View at Publisher · View at Google Scholar · View at Scopus
  77. A. Kawahara, T. Nishi, Y. Hisano, H. Fukui, A. Yamaguchi, and N. Mochizuki, “The sphingolipid transporter Spns2 functions in migration of zebrafish myocardial precursors,” Science, vol. 323, no. 5913, pp. 524–527, 2009. View at Publisher · View at Google Scholar · View at Scopus
  78. N. Osborne, K. Brand-Arzamendi, E. A. Ober et al., “The spinster homolog, two of hearts, is required for sphingosine 1-phosphate signaling in zebrafish,” Current Biology, vol. 18, no. 23, pp. 1882–1888, 2008. View at Publisher · View at Google Scholar · View at Scopus
  79. K. Takabe, R. H. Kim, J. C. Allegood et al., “Estradiol induces export of sphingosine 1-phosphate from breast cancer cells via ABCC1 and ABCG2,” The Journal of Biological Chemistry, vol. 285, no. 14, pp. 10477–10486, 2010. View at Publisher · View at Google Scholar · View at Scopus
  80. M. Nagahashi, E. Y. Kim, A. Yamada et al., “Spns2, a transporter of phosphorylated sphingoid bases, regulates their blood and lymph levels, and the lymphatic network,” The FASEB Journal, vol. 27, no. 3, pp. 1001–1011, 2013. View at Publisher · View at Google Scholar · View at Scopus
  81. M. A. Zachariah and J. G. Cyster, “Neural crest-derived pericytes promote egress of mature thymocytes at the corticomedullary junction,” Science, vol. 328, no. 5982, pp. 1129–1135, 2010. View at Publisher · View at Google Scholar · View at Scopus
  82. B. Bréart, W. D. Ramos-Perez, A. Mendoza et al., “Lipid phosphate phosphatase 3 enables efficient thymic egress,” The Journal of Experimental Medicine, vol. 208, no. 6, pp. 1267–1278, 2011. View at Publisher · View at Google Scholar · View at Scopus
  83. A. Nijnik, S. Clare, C. Hale et al., “The role of sphingosine-1-phosphate transporter Spns2 in immune system function,” The Journal of Immunology, vol. 189, no. 1, pp. 102–111, 2012. View at Publisher · View at Google Scholar
  84. A. Mendoza, B. Bréart, W. D. Ramos-Perez et al., “The transporter Spns2 is required for secretion of lymph but not plasma sphingosine-1-phosphate,” Cell Reports, vol. 2, no. 5, pp. 1104–1110, 2012. View at Publisher · View at Google Scholar · View at Scopus
  85. S. Fukuhara, S. Simmons, S. Kawamura et al., “The sphingosine-1-phosphate transporter Spns2 expressed on endothelial cells regulates lymphocyte trafficking in mice,” The Journal of Clinical Investigation, vol. 122, no. 4, pp. 1416–1426, 2012. View at Publisher · View at Google Scholar · View at Scopus
  86. M. S. Donoviel, N. C. Hait, S. Ramachandran et al., “Spinster 2, a sphingosine-1-phosphate transporter, plays a critical role in inflammatory and autoimmune diseases,” The FASEB Journal, vol. 29, no. 12, pp. 5018–5028, 2015. View at Publisher · View at Google Scholar
  87. V. Brinkmann, A. Billich, T. Baumruker et al., “Fingolimod (FTY720): discovery and development of an oral drug to treat multiple sclerosis,” Nature Reviews Drug Discovery, vol. 9, no. 11, pp. 883–897, 2010. View at Publisher · View at Google Scholar · View at Scopus
  88. S. Mandala, R. Hajdu, J. Bergstrom et al., “Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists,” Science, vol. 296, no. 5566, pp. 346–349, 2002. View at Publisher · View at Google Scholar · View at Scopus
  89. B. Prager, S. F. Spampinato, and R. M. Ransohoff, “Sphingosine 1-phosphate signaling at the blood–brain barrier,” Trends in Molecular Medicine, vol. 21, no. 6, pp. 354–363, 2015. View at Publisher · View at Google Scholar
  90. J. G. Cyster, “Chemokines, sphingosine-1-phosphate, and cell migration in secondary lymphoid organs,” Annual Review of Immunology, vol. 23, pp. 127–159, 2005. View at Publisher · View at Google Scholar · View at Scopus
  91. Y. Hisano, N. Kobayashi, A. Kawahara, A. Yamaguchi, and T. Nishi, “The sphingosine 1-phosphate transporter, SPNS2, functions as a transporter of the phosphorylated form of the immunomodulating agent FTY720,” The Journal of Biological Chemistry, vol. 286, no. 3, pp. 1758–1766, 2011. View at Publisher · View at Google Scholar · View at Scopus
  92. F. Mullershausen, F. Zecri, C. Cetin, A. Billich, D. Guerini, and K. Seuwen, “Persistent signaling induced by FTY720-phosphate is mediated by internalized S1P1 receptors,” Nature Chemical Biology, vol. 5, no. 6, pp. 428–434, 2009. View at Publisher · View at Google Scholar · View at Scopus
  93. L. M. Healy, G. K. Sheridan, A. J. Pritchard, A. Rutkowska, F. Mullershausen, and K. K. Dev, “Pathway specific modulation of S1P1 receptor signalling in rat and human astrocytes,” British Journal of Pharmacology, vol. 169, no. 5, pp. 1114–1129, 2013. View at Publisher · View at Google Scholar · View at Scopus
  94. M. L. Oo, S. Thangada, M.-T. Wu et al., “Immunosuppressive and anti-angiogenic sphingosine 1-phosphate receptor-1 agonists induce ubiquitinylation and proteasomal degradation of the receptor,” The Journal of Biological Chemistry, vol. 282, no. 12, pp. 9082–9089, 2007. View at Publisher · View at Google Scholar · View at Scopus
  95. D. A. Sykes, D. M. Riddy, C. Stamp et al., “Investigating the molecular mechanisms through which FTY720-P causes persistent S1P1 receptor internalization,” British Journal of Pharmacology, vol. 171, no. 21, pp. 4797–4807, 2014. View at Publisher · View at Google Scholar · View at Scopus
  96. C. S. Garris, L. Wu, S. Acharya et al., “Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation,” Nature Immunology, vol. 14, no. 11, pp. 1166–1172, 2013. View at Publisher · View at Google Scholar · View at Scopus
  97. A. Nomachi, M. Yoshinaga, J. Liu et al., “Moesin controls clathrin-mediated S1PR1 internalization in T cells,” PLoS ONE, vol. 8, no. 12, Article ID e82590, 2013. View at Publisher · View at Google Scholar · View at Scopus
  98. Z.-Y. Song, R. Yamasaki, Y. Kawano et al., “Peripheral blood T cell dynamics predict relapse in multiple sclerosis patients on fingolimod,” PLoS ONE, vol. 10, no. 4, Article ID e0124923, 2015. View at Publisher · View at Google Scholar
  99. A. Ntranos, O. Hall, D. P. Robinson et al., “FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway,” Journal of Neuroimmunology, vol. 270, no. 1-2, pp. 13–21, 2014. View at Publisher · View at Google Scholar · View at Scopus
  100. J. W. Choi, S. E. Gardell, D. R. Herr et al., “FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 2, pp. 751–756, 2011. View at Publisher · View at Google Scholar · View at Scopus
  101. N. C. Hait, D. Avni, A. Yamada et al., “The phosphorylated prodrug FTY720 is a histone deacetylase inhibitor that reactivates ERα expression and enhances hormonal therapy for breast cancer,” Oncogenesis, vol. 4, article e156, 2015. View at Publisher · View at Google Scholar
  102. G. Liu, S. Burns, G. Huang et al., “The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR,” Nature Immunology, vol. 10, no. 7, pp. 769–777, 2009. View at Publisher · View at Google Scholar · View at Scopus
  103. S. J. Priceman, S. Shen, L. Wang et al., “S1PR1 is crucial for accumulation of regulatory T cells in tumors via STAT3,” Cell Reports, vol. 6, no. 6, pp. 992–999, 2014. View at Publisher · View at Google Scholar · View at Scopus
  104. N. Muls, H. A. Dang, C. J. M. Sindic, and V. van Pesch, “Fingolimod increases CD39-expressing regulatory T cells in multiple sclerosis patients,” PLoS ONE, vol. 9, no. 11, Article ID 0113025, 2014. View at Publisher · View at Google Scholar · View at Scopus
  105. G. Liu, Y. Bi, R. Wang et al., “Targeting S1P1 receptor protects against murine immunological hepatic injury through myeloid-derived suppressor cells,” The Journal of Immunology, vol. 192, no. 7, pp. 3068–3079, 2014. View at Publisher · View at Google Scholar · View at Scopus
  106. S. G. Ha, X. N. Ge, N. S. Bahaie et al., “ORMDL3 promotes eosinophil trafficking and activation via regulation of integrins and CD48,” Nature Communications, vol. 4, article 2479, 2013. View at Publisher · View at Google Scholar · View at Scopus
  107. D. K. Breslow, S. R. Collins, B. Bodenmiller et al., “Orm family proteins mediate sphingolipid homeostasis,” Nature, vol. 463, no. 7284, pp. 1048–1053, 2010. View at Publisher · View at Google Scholar · View at Scopus
  108. C. Oyeniran, J. L. Sturgill, N. C. Hait et al., “Aberrant ORM (yeast)–like protein isoform 3 (ORMDL3) expression dysregulates ceramide homeostasis in cells and ceramide exacerbates allergic asthma in mice,” Journal of Allergy and Clinical Immunology, vol. 136, no. 4, pp. 1035.e6–1046.e6, 2015. View at Publisher · View at Google Scholar
  109. C. Zecca, M. Caporro, S. Györik, and C. Gobbi, “Life-threatening asthma attack during prolonged fingolimod treatment: case report,” Patient Preference and Adherence, vol. 8, pp. 987–989, 2014. View at Publisher · View at Google Scholar · View at Scopus
  110. B. G. Bender, “Motivating patient adherence to allergic rhinitis treatments,” Current Allergy and Asthma Reports, vol. 15, article 10, 2015. View at Publisher · View at Google Scholar
  111. A. Kleinjan, M. van Nimwegen, K. Leman, H. C. Hoogsteden, and B. N. Lambrecht, “Topical treatment targeting sphingosine-1-phosphate and sphingosine lyase abrogates experimental allergic rhinitis in a murine model,” Allergy, vol. 68, no. 2, pp. 204–212, 2013. View at Publisher · View at Google Scholar · View at Scopus
  112. L. Japtok, W. Bäumer, and B. Kleuser, “Sphingosine-1-phosphate as signaling molecule in the skin,” Allergo Journal International, vol. 23, no. 2, pp. 54–59, 2014. View at Publisher · View at Google Scholar
  113. I. Reines, M. Kietzmann, R. Mischke et al., “Topical application of sphingosine-1-phosphate and FTY720 attenuate allergic contact dermatitis reaction through inhibition of dendritic cell migration,” The Journal of Investigative Dermatology, vol. 129, no. 8, pp. 1954–1962, 2009. View at Publisher · View at Google Scholar · View at Scopus
  114. K. Schaper, J. Dickhaut, L. Japtok et al., “Sphingosine-1-phosphate exhibits anti-proliferative and anti-inflammatory effects in mouse models of psoriasis,” Journal of Dermatological Science, vol. 71, no. 1, pp. 29–36, 2013. View at Publisher · View at Google Scholar · View at Scopus
  115. A. Vaclavkova, S. Chimenti, P. Arenberger et al., “Oral ponesimod in patients with chronic plaque psoriasis: a randomised, double-blind, placebo-controlled phase 2 trial,” The Lancet, vol. 384, no. 9959, pp. 2036–2045, 2014. View at Publisher · View at Google Scholar · View at Scopus
  116. J. Y. Niederkorn, “Immunology of corneal allografts: insights from animal models,” Journal of Clinical and Experimental Ophthalmology, vol. 6, no. 3, article 429, 2015. View at Publisher · View at Google Scholar
  117. Y. Liu, J. Jiang, H. Xiao et al., “Topical application of FTY720 and cyclosporin A prolong corneal graft survival in mice,” Molecular Vision, vol. 18, pp. 624–633, 2012. View at Google Scholar · View at Scopus
  118. L. Jia, Y. Liu, L. Wang, J. Zhu, and Y. Huang, “Effects of topical sphingosine-1-phosphate 1 receptor agonist on corneal allograft in mice,” Cornea, vol. 33, no. 4, pp. 398–404, 2014. View at Publisher · View at Google Scholar · View at Scopus
  119. J. Zhu, Y. Liu, and Y. Huang, “Topical application of sphingosine 1-phosphate receptor 1 prolongs corneal graft survival in mice,” Molecular Medicine Reports, vol. 11, no. 5, pp. 3800–3807, 2015. View at Publisher · View at Google Scholar · View at Scopus
  120. C. Stein and S. Küchler, “Targeting inflammation and wound healing by opioids,” Trends in Pharmacological Sciences, vol. 34, no. 6, pp. 303–312, 2013. View at Publisher · View at Google Scholar · View at Scopus
  121. K. R. Watterson, D. A. Lanning, R. F. Diegelmann, and S. Spiegel, “Regulation of fibroblast functions by lysophospholipid mediators: potential roles in wound healing,” Wound Repair and Regeneration, vol. 15, no. 5, pp. 607–616, 2007. View at Publisher · View at Google Scholar · View at Scopus
  122. H. Yu, L. Yuan, M. Xu, Z. Zhang, and H. Duan, “Sphingosine kinase 1 improves cutaneous wound healing in diabetic rats,” Injury, vol. 45, no. 7, pp. 1054–1058, 2014. View at Publisher · View at Google Scholar · View at Scopus