Effects of sphingosine-1-phosphate receptor 1 phosphorylation in response to FTY720 during neuroinflammation

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). Human variants have been reported to have functional heterogeneity in vitro, suggesting that S1PR1 func...

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Bibliographic Details
Published in:JCI insight 2016-06, Vol.1 (9), p.e86462-e86462
Main Authors: Tsai, Hsing-Chuan, Huang, Yingxiang, Garris, Christopher S, Moreno, Monica A, Griffin, Christina W, Han, May H
Format: Article
Language:English
Subjects:
Animals
Encephalomyelitis, Autoimmune, Experimental - drug therapy
Fingolimod Hydrochloride - pharmacology
Immunosuppressive Agents - pharmacology
Mice
Mice, Inbred C57BL
Multiple Sclerosis
Phosphorylation
Receptors, CCR6 - metabolism
Receptors, Lysosphingolipid - chemistry
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Summary: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). Human variants 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-defective gene [S1PR1(S5A) mice] were refractory to FTY720 treatment in MOG -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.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.86462