Abstract
Sphingosine 1-phosphate (S1P) signaling regulates lymphocyte egress from lymphoid organs into systemic circulation. The sphingosine phosphate receptor 1 (S1P1) agonist FTY-720 (Gilenya) arrests immune trafficking and prevents multiple sclerosis (MS) relapses. However, alternative mechanisms of S1P-S1P1 signaling have been reported. Phosphoproteomic analysis of MS brain lesions revealed S1P1 phosphorylation on S351, a residue crucial for receptor internalization. Mutant mice harboring an S1pr1 gene encoding phosphorylation-deficient receptors (S1P1(S5A)) developed severe experimental autoimmune encephalomyelitis (EAE) due to autoimmunity mediated by interleukin 17 (IL-17)-producing helper T cells (TH17 cells) in the peripheral immune and nervous system. S1P1 directly activated the Jak-STAT3 signal-transduction pathway via IL-6. Impaired S1P1 phosphorylation enhances TH17 polarization and exacerbates autoimmune neuroinflammation. These mechanisms may be pathogenic in MS.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Autopsy
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Brain / immunology
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Brain / metabolism*
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Brain / pathology
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Encephalomyelitis, Autoimmune, Experimental / genetics
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / metabolism*
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Female
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Gene Expression Regulation
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Humans
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Inflammation
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Interleukin-17 / genetics
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Interleukin-17 / immunology
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Interleukin-17 / metabolism*
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Interleukin-6 / genetics
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Interleukin-6 / immunology
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Interleukin-6 / metabolism
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Janus Kinases / genetics
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Janus Kinases / immunology
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Janus Kinases / metabolism
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Lysophospholipids / immunology
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Lysophospholipids / metabolism*
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Mice
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Multiple Sclerosis / genetics
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Multiple Sclerosis / immunology
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Multiple Sclerosis / metabolism*
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Multiple Sclerosis / pathology
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Phosphorylation
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Receptors, Lysosphingolipid / genetics
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Receptors, Lysosphingolipid / immunology
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Receptors, Lysosphingolipid / metabolism*
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STAT3 Transcription Factor / genetics
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STAT3 Transcription Factor / immunology
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STAT3 Transcription Factor / metabolism
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Signal Transduction / immunology*
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Sphingosine / analogs & derivatives*
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Sphingosine / immunology
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Sphingosine / metabolism
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Th17 Cells
Substances
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Interleukin-17
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Interleukin-6
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Lysophospholipids
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Receptors, Lysosphingolipid
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STAT3 Transcription Factor
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Stat3 protein, mouse
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sphingosine 1-phosphate
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Janus Kinases
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Sphingosine