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

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.