Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation

CS Garris, L Wu, S Acharya, A Arac, VA Blaho… - Nature …, 2013 - nature.com
CS Garris, L Wu, S Acharya, A Arac, VA Blaho, Y Huang, BS Moon, RC Axtell, PP Ho…
Nature immunology, 2013nature.com
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 …
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.
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