Role of Sphingosine 1-Phosphate (S1P) Receptor 1 in Experimental Autoimmune Encephalomyelitis —I

Noriyasu Seki, Yasuhiro Maeda, Hirotoshi Kataoka, Kunio Sugahara, Kenji Chiba

Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan.
Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan;.
Pharmacology Research Laboratories I, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan; Advanced Medical Research Laboratories, Research Division, Mitsubishi Tanabe Pharma Corporation, Yokohama, Japan..

DOI: 10.4236/pp.2013.48089                

Abstract

Infiltration of myelin-specific helper T (Th) cells into the central nervous system (CNS) plays a key role in pathogenesis of experimental autoimmune encephalomyelitis (EAE). In this study, we investigated the involvement of sphingosine 1-phosphate (S1P)-S1P receptor 1 (S1P1) axis in lymphocytes for EAE development when C57BL/6 mice were immunized with myelin oliogodendrocyte glycoprotein (MOG). The expression of S1P1 mRNA and S1P responsiveness of lymphocytes in draining lymph nodes (DLN) were down-regulated markedly after MOG immunization until onset of EAE. Accompanying with reacquisition of down-regulated S1P1 transcript and S1P responsiveness in DLN lymphocytes, MOG-immunized mice developed EAE symptoms with significant infiltration of Th1 and Th17 cells into the CNS and a marked elevation of IFN-γ, T-bet, IL-17, and RORγt mRNA expressions. Prophylactic administration of an S1P1 functional antagonist, fingolimod hydrochloride (FTY720, 0.3 mg/kg, orally) significantly inhibited EAE development and almost completely prevented infiltration of Th1 and Th17 cells into the CNS with a marked reduction of IFN-γ, T-bet, IL-17, and RORγt mRNA expressions. Similar results were obtained by treatment with an S1P1-selective agonist, SEW2871 or an S1P lyase inhibitor, 2-acetyl-4-tetrahydroxybutylimidazole. Moreover, FTY720-phosphate and SEW2871 inhibited in vitro migration of Th1 and Th17 cells toward S1P but did not affect cytokine production or generation of Th1 or Th17 cells. These results suggest that reacquisition of S1P1 expression in DLN lymphocytes plays a major role in trafficking of myelin antigen-specific Th1/Th17 cells from DLN to the CNS in EAE and that prophylactic effect of FTY720 on EAE is predominantly caused by functional antagonism via lymphocytic S1P1.

Keywords

Sphingosine 1-Phosphosphate Receptor 1; Fingolimod Hydrochloride (FTY720); Experimental Autoimmune Encephalomyelitis; Th1 Cells; Th17 Cells

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	G. D. A. Hafler, “Multiple Sclerosis,” Journal of Clinical Investigation, Vol. 113, No. 6, 2004, pp. 788-794.
[2]	V. K. Kuchroo, A. C. Anderson, H. Waldner, M. Munder, E. Bettelli and L. B. Nicholson, “T Cell Response in Experimental Autoimmune Encephalomyelitis (EAE): Role of Self and Cross-Reactive Antigens in Shaping, Tuning, and Regulating the Autopathogenic T Cell Repertoire,” Annual Review of Immunology, Vol. 20, 2002, pp. 101-123. http://dx.doi.org/10.1146/annurev.immunol.20.081701.141316
[3]	R. Martin and H. F. McFarland, “Immunological Aspects of Experimental Allergic Encephalomyelitis and Multiple Sclerosis,” Critical Reviews in Clinical Laboratory Sciences, Vol. 32, No. 2, 1995, pp. 121-182. http://dx.doi.org/10.3109/10408369509084683
[4]	L. Steinman, “Assessment of Animal Models for MS and Demyelinating Disease in the Design of Rational Therapy,” Neuron, Vol. 24, No. 3, 1999, pp. 511-514. http://dx.doi.org/10.1016/S0896-6273(00)81107-1
[5]	S. D. Miller and W. J. Karpus, “The Immunopathogenesis and Regulation of T-Cell-Mediated Demyelinating Diseases,” Immunology Today, Vol. 15, No. 8, 1994, pp. 356-361. http://dx.doi.org/10.1016/0167-5699(94)90173-2
[6]	V. K. Kuchroo, C. A. Martin, J. M. Greer, S. T. Ju, R. A. Sobel and M. E. Dorf, “Cytokines and Adhesion Molecules Contribute to the Ability of Myelin Proteolipid Protein-Specific T Cell Clones to Mediate Experimental Allergic Encephalomyelitis,” Journal of Immunology, Vol. 151, No. 8, 1993, pp. 4371-4382.
[7]	M. K. Kennedy, D. S. Torrance, K. S. Picha and K. M. Mohler, “Analysis of Cytokine mRNA Expression in the Central Nervous System of Mice with Experimental Autoimmune Encephalomyelitis Reveals that IL-10 mRNA Expression Correlates with Recovery,” Journal of Immunology, Vol. 149, No. 7, 1992, pp. 2496-2505.
[8]	L. Steinman, R. Martin, C. Bernard, P. Conlon and J. R. Oksenberg, “Multiple Sclerosis: Deeper Understanding of Its Pathogenesis Reveals New Targets for Therapy,” Annual Review of Neuroscience, Vol. 25, 2002, pp. 491-505. http://dx.doi.org/10.1146/annurev.neuro.25.112701.142913
[9]	J. J. Lafaille, F. V. Keere, A. L. Hsu, J. L. Baron, W. Haas, C. S. Raine and S. Tonegawa, “Myelin Basic Protein-Specific T Helper 2 (Th2) Cells Cause Experimental Autoimmune Encephalomyelitis in Immunodeficient Hosts Rather than Protect Them from the Disease,” Journal of Experimental Medicine, Vol. 186, No. 2, 1997, pp. 307-312. http://dx.doi.org/10.1084/jem.186.2.307
[10]	C. L. Langrish, Y. Chen, W. M. Blumenschein, J. Mattson, B. Basham, J. D. Sedgwick, T. McClanahan, R. A. Kastelein and D. J. Cua, “IL-23 Drives a Pathogenic T Cell Population That Induces Autoimmune Inflammation,” Journal of Experimental Medicine, Vol. 201, No. 2, 2005, pp. 233-240. http://dx.doi.org/10.1084/jem.20041257
[11]	E. Bettelli, Y. Carrier, W. Gao, T. Korn, T. B. Strom, M. Oukka, H. L. Weiner and V. K. Kuchroo, “Reciprocal Developmental Pathways for the Generation of Pathogenic Effector TH17 and Regulatory T Cells,” Nature, Vol. 441, No. 7090, 2006, pp. 235-238. http://dx.doi.org/10.1038/nature04753
[12]	Y. Komiyama, S. Nakae, T. Matsuki, A. Nambu, H. Ishigame, S. Kakuta, K. Sudo and Y. Iwakura, “IL-17 Plays an Important Role in the Development of Experimental Autoimmune Encephalomyelitis,” Journal of Immunology, Vol. 177, No. 1, 2006, pp. 566-573.
[13]	H. Park, Z. Li, X. O. Yang, S. H. Chang, R. Nurieva, Y. H. Wang, Y. Wang, L. Hood, Z. Zhu, Q. Tian and C. Dong, “A Distinct Lineage of CD4 T Cells Regulates Tissue Inflammation by Producing Interleukin 17,” Nature Immunology, Vol. 6, No. 11, 2005, pp. 1133-1141. http://dx.doi.org/10.1038/ni1261
[14]	P. Ye, P. B. Garvey, P. Zhang, S. Nelson, G. Bagby, W. R. Summer, P. Schwarzenberger, J. E. Shellito and J. K. Kolls, “Interleukin-17 and Lung Host Defense against Klebsiella Pneumoniae Infection,” American Journal of Respiratory Cell and Molecular Biology, Vol. 25, No. 3, 2001, pp. 335-340. http://dx.doi.org/10.1165/ajrcmb.25.3.4424
[15]	T. Chitnis, N. Najafian, C. Benou, A. D. Salama, M. J. Grusby, M. H. Sayegh and S. J. Khoury, “Effect of Targeted Disruption of STAT4 and STAT6 on the Induction of Experimental Autoimmune Encephalomyelitis,” Journal of Clinical Investigation, Vol. 108, No. 5, 2001, pp. 739-747.
[16]	M. Falcone, A. J. Rajan, B. R. Bloom and C. F. Brosnan, “A Critical Role for IL-4 in Regulating Disease Severity in Experimental Allergic Encephalomyelitis as Demonstrated in IL-4-deficient C57BL/6 Mice and BALB/c Mice,” Journal of Immunology, Vol. 160, No. 10, 1998, pp. 4822-4830.
[17]	A. P. Kohm, P. A. Carpentier, H. A. Anger and S. D. Miller, “Cutting Edge: CD4+CD25+ Regulatory T Cells Suppress Antigen-Specific Autoreactive Immune Responses and Central Nervous System Inflammation during Active Experimental Autoimmune Encephalomyelitis,” Journal of Immunology, Vol. 169, No. 9, 2002, pp. 4712-4716.
[18]	S. Mandala, R. Hajdu, J. Bergstrom, E. Quackenbush, J. Xie, J. Milligan, R. Thornton, G. J. Shei, D. Card, C. Keohane, M. Rosenbach, J. Hale, C. L. Lynch, K. Rupprecht, W. Parsons and H. Rosen, “Alteration of Lymphocyte Trafficking by Sphingosine-1-Phosphate Receptor Agonists,” Science, Vol. 296, No. 5566, 2002, pp. 346-349. http://dx.doi.org/10.1126/science.1070238
[19]	M. Matloubian, C. G. Lo, G. Cinamon, M. J. Lesneski, Y. Xu, V. Brinkmann, M. L. Allende, R. L. Proia and J. G. Cyster, “Lymphocyte Egress from Thymus and Peripheral Lymphoid Organs Is Dependent on S1P Receptor 1,” Nature, Vol. 427, No. 6972, 2004, pp. 355-360. http://dx.doi.org/10.1038/nature02284
[20]	J. G. Cyster, “Chemokines, Sphingosine-1-Phosphate, and Cell Migration in Secondary Lymphoid Organs,” Annual Review of Immunology, Vol. 23, 2005, pp. 127-159. http://dx.doi.org/10.1146/annurev.immunol.23.021704.115628
[21]	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,” Journal of Experimental Medicine, Vol. 201, No. 2, 2005, pp. 291-301. http://dx.doi.org/10.1084/jem.20041509
[22]	T. H. Pham, T. Okada, M. Matloubian, C. G. Lo and J. G. Cyster, “S1P1 Receptor Signaling Overrides Retention Mediated by G Alpha i-Coupled Receptors to Promote T Cell Egress,” Immunity, Vol. 28, No. 1, 2008, pp. 122-133. http://dx.doi.org/10.1016/j.immuni.2007.11.017
[23]	K. Adachi, T. Kohara, N. Nakao, M. Arita, K. Chiba, T. Mishina, S. Sasaki and T. Fujita, “Design, Synthesis, and Structure Activity Relationships of 2-Substitued-2-Amino-1,3-Propanediols: Discovery of a Novel Immunosuppressant, FTY720,” Bioorganic & Medicinal Chemistry Letters, Vol. 5, 1995, pp. 853-856. http://dx.doi.org/10.1016/0960-894X(95)00127-F
[24]	K. Chiba, “FTY720, a New Class of Immunomodulator, Inhibits Lymphocyte Egress from Secondary Lymphoid Tissues and Thymus by Agonistic Activity at Sphingosine 1-Phosphate Receptors,” Pharmacology and Therapeutics, Vol. 108, No. 3, 2005, pp. 308-319. http://dx.doi.org/10.1016/j.pharmthera.2005.05.002
[25]	V. Brinkmann, M. D. Davis, C. E. Heise, R. Albert, S. Cottens, R. Hof, C. Bruns, E. Prieschl, T. Baumruker, P. Hiestand, C. A. Foster, M. Zollinger and K. R. Lynch, “The Immune Modulator FTY720 Targets Sphingosine 1-Phosphate Receptors,” Journal of Biological Chemistry, Vol. 277, No. 24, 2002, pp. 21453-21457. http://dx.doi.org/10.1074/jbc.C200176200
[26]	M. Kiuchi, K. Adachi, A. Tomatsu, M. Chino, S. Takeda, Y. Tanaka, Y. Maeda, N. Sato, N. Mitsutomi, K. Sugahara and K. Chiba, “Asymmetric Synthesis and Biological Evaluation of the Enantiomeric Isomers of the Immunosuppressive FTY720-Phosphate,” Bioorganic and Medicinal Chemistry, Vol. 13, No. 2, 2005, pp. 425-432. http://dx.doi.org/10.1016/j.bmc.2004.10.008
[27]	K. Chiba, H. Matsuyuki, Y. Maeda and K. Sugahara, “Role of Sphingosine 1-Phosphate Receptor Type 1 in Lymphocyte Egress from Secondary Lymphoid Tissues and Thymus,” Cellular & Molecular Immunology, Vol. 3, No. 1, 2006, pp. 11-19.
[28]	K. Chiba, “Sphingosine 1-Phosphate Receptor Type 1 as a Novel Target for the Therapy of Autoimmune Diseases,” Inflammation and Regeneration, Vol. 30, 2010, pp. 160-168. http://dx.doi.org/10.2492/inflammregen.30.160
[29]	L. Kappos, J. Antel, G. Comi, X. Montalban, P. O’Connor, C. H. Polman, T. Haas, A. A. Korn, G. Karlsson and E. W. Radue, “Oral Fingolimod (FTY720) for Relapsing Multiple Sclerosis,” New England Journal of Medicine, Vol. 355, No. 11, 2006, pp. 1124-1140. http://dx.doi.org/10.1056/NEJMoa052643
[30]	J. A. Cohen, F. Barkhof, G. Comi, H. P. Hartung, B. O. Khatri, X. Montalban, J. Pelletier, R. Capra, P. Gallo, G. Izquierdo, K. Tiel-Wilck, A. de Vera, J. Jin, T. Stites, S. Wu, S. Aradhye and L. Kappos, “Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis,” New England Journal of Medicine, Vol. 362, No. 5, 2010, pp. 402-415. http://dx.doi.org/10.1056/NEJMoa0907839
[31]	G. Comi, P. O’Connor, X. Montalban, J. Antel, E. W. Radue, G. Karlsson, H. Pohlmann, S. Aradhye and L. Kappos, “Phase II Study of Oral Fingolimod (FTY720) in Multiple Sclerosis: 3-Year Results,” Multiple Sclerosis, Vol. 16, No. 2, 2010, pp. 197-207. http://dx.doi.org/10.1177/1352458509357065
[32]	L. Kappos, E. W. Radue, P. O’Connor, C. Polman, R. Hohlfeld, P. Calabresi, K. Selmaj, C. Agoropoulou, M. Leyk, L. Zhang-Auberson and P. Burtin, “A PlaceboControlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis,” New England Journal of Medicine, Vol. 362, No. 5, 2010, pp. 387-401. http://dx.doi.org/10.1056/NEJMoa0909494
[33]	B. Khatri, F. Barkhof, G. Comi, H. P. Hartung, L. Kappos, X. Montalban, J. Pelletier, T. Stites, S. Wu, F. Holdbrook, L. Zhang-Auberson, G. Francis and J. A. Cohen, “Comparison of Fingolimod with Interferon Beta-1a in Relapsing-Remitting Multiple Sclerosis: A Randomised Extension of the TRANSFORMS Study,” The Lancet Neurology, Vol. 10, No. 6, 2011, pp. 520-529. http://dx.doi.org/10.1016/S1474-4422(11)70099-0
[34]	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,” Journal of Immunology, Vol. 178, No. 6, 2007, pp. 3437-3446.
[35]	S. Thangada, K. M. Khanna, V. A. Blaho, M. L. Oo, D. S. Im, C. Guo, L. Lefrancois and T. Hla, “Cell-Surface Residence of Sphingosine 1-Phosphate Receptor 1 on Lymphocytes Determines Lymphocyte Egress Kinetics,” Journal of Experimental Medicine, Vol. 207, No. 7, 2010, pp. 1475-1483. http://dx.doi.org/10.1084/jem.20091343
[36]	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, 2009, pp. 428-434. http://dx.doi.org/10.1038/nchembio.173
[37]	M. Fujino, N. Funeshima, Y. Kitazawa, H. Kimura, H. Amemiya, S. Suzuki and X. K. Li, “Amelioration of Experimental Autoimmune Encephalomyelitis in Lewis Rats by FTY720 Treatment,” Journal of Pharmacology and Experimental Therapeutics, Vol. 305, No. 1, 2003, pp. 70-77. http://dx.doi.org/10.1124/jpet.102.045658
[38]	M. Webb, C. S. Tham, F. F. Lin, K. Lariosa-Willingham, N. Yu, J. Hale, S. Mandala, J. Chun and T. S. Rao, “Sphingosine 1-Phosphate Receptor Agonists Attenuate Relapsing-Remitting Experimental Autoimmune Encephalitis in SJL mice,” Journal of Neuroimmunology, Vol. 153, No. 1-2, 2004, pp. 108-121. http://dx.doi.org/10.1016/j.jneuroim.2004.04.015
[39]	H. Kataoka, K. Sugahara, K. Shimano, K. Teshima, M. Koyama, A. Fukunari and K. Chiba, “FTY720, Sphingosine 1-Phosphate Receptor Modulator, Ameliorates Experimental Autoimmune Encephalomyelitis by Inhibition of T Cell Infiltration,” Cellular & Molecular Immunology, Vol. 2, No. 6, 2005, pp. 439-448.
[40]	C. A. Foster, L. M. Howard, A. Schweitzer, E. Persohn, P. C. Hiestand, B. Balatoni, R. Reuschel, C. Beerli, M. Schwartz and A. Billich, “Brain Penetration of the Oral Immunomodulatory Drug FTY720 and Its Phosphorylation in the Central Nervous System during Experimental Autoimmune Encephalomyelitis: Consequences for Mode of Action in Multiple Sclerosis,” Journal of Pharmacology and Experimental Therapeutics, Vol. 323, No. 2, 2007, pp. 469-475. http://dx.doi.org/10.1124/jpet.107.127183
[41]	B. Balatoni, M. K. Storch, E. M. Swoboda, V. Schonborn, A. Koziel, G. N. Lambrou, P. C. Hiestand, R. Weissert and C. A. Foster, “FTY720 Sustains and Restores Neuronal Function in the DA Rat Model of MOG-Induced Experimental Autoimmune Encephalomyelitis,” Brain Research Bulletin, Vol. 74, No. 5, 2007, pp. 307-316. http://dx.doi.org/10.1016/j.brainresbull.2007.06.023
[42]	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, 2005, pp. 1735-1739. http://dx.doi.org/10.1126/science.1113640
[43]	M. G. Sanna, J. Liao, E. Jo, C. Alfonso, M. Y. Ahn, M. S. Peterson, B. Webb, S. Lefebvre, J. Chun, N. Gray and H. Rosen, “Sphingosine 1-Phosphate (S1P) Receptor Subtypes S1P1 and S1P3, Respectively, Regulate Lymphocyte Recirculation and Heart Rate,” Journal of Biological Chemistry, Vol. 279, No. 14, 2004, pp. 13839-13848. http://dx.doi.org/10.1074/jbc.M311743200
[44]	M. Veldhoen, R. J. Hocking, C. J. Atkins, R. M. Locksley and B. Stockinger, “TGFbeta in the Context of an Inflammatory Cytokine Milieu Supports de Novo Differentiation of IL-17-Producing T Cells,” Immunity, Vol. 24, No. 2, 2006, pp. 179-189. http://dx.doi.org/10.1016/j.immuni.2006.01.001
[45]	M. O. Li, Y. Y. Wan and R. A. Flavell, “T Cell-Produced Transforming Growth Factor-beta1 Controls T Cell Tolerance and Regulates Th1and Th17-Cell Differentiation,” Immunity, Vol. 26, No. 5, 2007, pp. 579-591. http://dx.doi.org/10.1016/j.immuni.2007.03.014
[46]	Y. Maeda, N. Seki, N. Sato, K. Sugahara and K. Chiba, “Sphingosine 1-Phosphate Receptor Type 1 Regulates Egress of Mature T Cells from Mouse Bone Marrow,” International Immunology, Vol. 22, No. 6, 2010, pp. 515-525. http://dx.doi.org/10.1093/intimm/dxq036
[47]	C. Alfonso, M. G. McHeyzer-Williams and H. Rosen, “CD69 Down-Modulation and Inhibition of Thymic Egress by Shortand Long-Term Selective Chemical Agonism of Sphingosine 1-Phosphate Receptors,” European Journal of Immunology, Vol. 36, No. 1, 2006, pp. 149-159. http://dx.doi.org/10.1002/eji.200535127
[48]	M. A. Kroenke, T. J. Carlson, A. V. Andjelkovic and B. M. Segal, “IL-12-and IL-23-Modulated T Cells Induce Distinct Types of EAE Based on Histology, CNS Chemokine Profile, and Response to Cytokine Inhibition,” Journal of Experimental Medicine, Vol. 205, No. 7, 2008, pp. 1535-1541. http://dx.doi.org/10.1084/jem.20080159
[49]	I. M. Stromnes, L. M. Cerretti, D. Liggitt, R. A. Harris and J. M. Goverman, “Differential Regulation of Central Nervous System Autoimmunity by T(H)1 and T(H)17 Cells,” Nature Medicine, Vol. 14, No. 3, 2008, pp. 337-342. http://dx.doi.org/10.1038/nm1715
[50]	L. Steinman, “Mixed Results with Modulation of TH-17 Cells in Human Autoimmune Diseases,” Nature Immunology, Vol. 11, No. 1, 2010, pp. 41-44. http://dx.doi.org/10.1038/ni.1803
[51]	J. J. Liao, M. C. Huang and E. J. Goetzl, “Cutting Edge: Alternative Signaling of Th17 Cell Development by Sphingosine 1-Phosphate,” Journal of Immunology, Vol. 178, No. 9, 2007, pp. 5425-5428.