title: Effects of sphingosine-1-phosphate receptor 1 phosphorylation in response to FTY720 during neuroinflammation.
abstract: Fingolimod (FTY720, Gilenya), a sphingosine-1-phosphate receptor (S1PR) modulator, is one of the first-line immunomodulatory therapies for treatment of relapsing-remitting multiple sclerosis (MS). HumanS1PR1variants have been reported to have functional heterogeneity in vitro, suggesting that S1PR1 function may influence FTY720 efficacy. In this study, we examined the influence of S1PR1 phosphorylation on response to FTY720 in neuroinflammation. We found that mice carrying a phosphorylation-defectiveS1pr1gene [S1PR1(S5A) mice] were refractory to FTY720 treatment in MOG35-55-immunized and Th17-mediated experimental autoimmune encephalomyelitis (EAE) models. Long-term treatment with FTY720 induced significant lymphopenia and suppressed Th17 response in the peripheral immune system via downregulating STAT3 phosphorylation in both WT and S1PR1(S5A) mice. However, FTY720 did not effectively prevent neuroinflammation in the S1PR1(S5A) EAE mice as a result of encephalitogenic cells expressing C-C chemokine receptor 6 (CCR6). Combined treatment with FTY720 and anti-CCR6 delayed disease progression in S1PR1(S5A) EAE mice, suggesting that CCR6-mediated cell trafficking can overcome the effects of FTY720. This work may have translational relevance regarding FTY720 efficacy in MS patients and suggests that cell type-specific therapies may enhance therapeutic efficacy in MS.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.
authors.forename: Hsing-Chuan
authors.initials: HC
authors.lastname: Tsai
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.|Department of Medicine, Division of Biomedical Informatics, University of California, San Diego, California, USA.
authors.forename: Yingxiang
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Graduate Program in Immunology, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Garris
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.
authors.forename: Monica A
authors.initials: MA
authors.lastname: Moreno
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.
authors.forename: Christina W
authors.initials: CW
authors.lastname: Griffin
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.
authors.forename: May H
authors.initials: MH
authors.lastname: Han
mesh_terms: D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D000068876:Fingolimod Hydrochloride / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis; D010766:Phosphorylation; D054399:Receptors, CCR6 / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000737:chemistry*; D000081025:Sphingosine-1-Phosphate Receptors
chemical_list: C498126:CCR6 protein, mouse; D007166:Immunosuppressive Agents; D054399:Receptors, CCR6; D049349:Receptors, Lysosphingolipid; C556330:S1pr1 protein, mouse; D000081025:Sphingosine-1-Phosphate Receptors; D000068876:Fingolimod Hydrochloride