Garris, ChristopherWu, LinfengAcharya, SwatiArac, AhmetBlaho, Victoria A.Huang, YingxiangMoon, Byoung SanAxtell, Robert C.Ho, Peggy P.Steinberg, Gary K.Lewis, David B.Sobel, Raymond A.Han, David K.Steinman, LawrenceSnyder, Michael P.Hla, TimothyHan, May H.2014-07-072014Garris, C. S., L. Wu, S. Acharya, A. Arac, V. A. Blaho, Y. Huang, B. S. Moon, et al. 2014. “Defective sphingosine-1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation.” Nature immunology 14 (11): 1166-1172. doi:10.1038/ni.2730. http://dx.doi.org/10.1038/ni.2730.1529-2908http://nrs.harvard.edu/urn-3:HUL.InstRepos:12406821Sphingosine-1-phosphate (S1P) signaling regulates lymphocyte egress from lymphoid organs into systemic circulation. 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 a S1pr1 gene encoding phosphorylation-deficient receptors [S1P1(S5A)] developed severe experimental autoimmune encephalomyelitis (EAE) due to T helper (TH) 17-mediated autoimmunity in the peripheral immune and nervous system. S1P1 directly activated Janus-like kinase–signal transducer and activator of transcription 3 (JAK-STAT3) pathway via interleukin 6 (IL-6). Impaired S1P1 phosphorylation enhances TH17 polarization and exacerbates autoimmune neuroinflammation. These mechanisms may be pathogenic in MS.en-USJournal Article2014-07-0710.1038/ni.2730