Defective sphingosine-1-phosphate receptor 1 (S1P(1)) phosphorylation exacerbates T(H)17-mediated autoimmune neuroinflammation

Sphingosine-1-phosphate (S1P) signaling regulates lymphocyte egress from lymphoid organs into systemic circulation. 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 a S1pr1 gene encoding phosphorylation-deficient receptors [S1P(1)(S5A)] developed severe experimental autoimmune encephalomyelitis (EAE) due to T helper (T(H)) 17-mediated autoimmunity in the peripheral immune and nervous system. S1P(1) directly activated Janus-like kinase–signal transducer and activator of transcription 3 (JAK-STAT3) pathway via interleukin 6 (IL-6). Impaired S1P(1) phosphorylation enhances T(H)17 polarization and exacerbates autoimmune neuroinflammation. These mechanisms may be pathogenic in MS.