Journal
NATURE IMMUNOLOGY
Volume 14, Issue 11, Pages 1166-U128Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.2730
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Funding
- Neurology Department Startup Funds
- Guthy-Jackson Charitable Foundation for Neuromyelitis Optica Research
- US National Institutes of Health [R37-HL67330, PO1-HL70694, RO1HL89934]
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Sphingosine 1-phosphate (S1P) signaling regulates lymphocyte egress from lymphoid organs into systemic circulation. The sphingosine phosphate receptor 1 (S1P(1)) agonist FTY-720 (Gilenya) arrests immune trafficking and prevents multiple sclerosis (MS) relapses. However, alternative mechanisms of S1P-S1P(1) signaling have been reported. Phosphoproteomic analysis of MS brain lesions revealed S1P(1) phosphorylation on S351, a residue crucial for receptor internalization. Mutant mice harboring an S1pr1 gene encoding phosphorylation-deficient receptors(S1P(1)(S5A)) developed severe experimental autoimmune encephalomyelitis (EAE) due to autoimmunity mediated by interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) in the peripheral immune and nervous system. S1P(1) directly activated the Jak-STAT3 signal-transduction pathway via IL-6. Impaired S1P(1) phosphorylation enhances T(H)17 polarization and exacerbates autoimmune neuroinflammation. These mechanisms may be pathogenic in MS.
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