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

Nature Immunology 14, 1166–1172 (2013) | Download Citation

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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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Acknowledgements

We thank J. Saba (Children's Hospital Oakland Research Institute) for providing THI. Supported by Neurology Department Startup Funds, Guthy-Jackson Charitable Foundation for Neuromyelitis Optica Research (M.H.H.), and US National Institutes of Health grants R37-HL67330, PO1-HL70694 and RO1HL89934 (T.H.).

Author information

    • Christopher S Garris
    •  & Linfeng Wu

    These authors contributed equally to this work.

Affiliations

  1. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA.

    • Christopher S Garris
    • , Yingxiang Huang
    • , Byoung San Moon
    • , Robert C Axtell
    • , Peggy P Ho
    • , Lawrence Steinman
    •  & May H Han

  2. Graduate Program in Immunology, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.

    • Christopher S Garris

  3. Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.

    • Linfeng Wu
    •  & Michael P Snyder

  4. Department of Pediatrics, Division of Allergy, Immunology and Rheumatology, Stanford, California, USA.

    • Swati Acharya
    •  & David B Lewis

  5. Department of Neurosurgery, Stanford University School of Medicine, Stanford, California, USA.

    • Ahmet Arac
    •  & Gary K Steinberg

  6. Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York, New York, USA.

    • Victoria A Blaho
    •  & Timothy Hla

  7. Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.

    • Raymond A Sobel

  8. Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, Connecticut, USA.

    • David K Han

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Contributions

C.S.G. and M.H.H. formulated the hypothesis and designed all experiments. L.W., M.P.S. and D.K.H. contributed to the phosphoproteomic analysis. V.A.B. performed the in vitro experiment with S1P1-deficient T cells, and T.H. contributed to experiments related to S1P signaling. S.A. and D.B.L. assisted with siRNA experiments, R.A.S. with the histopathological studies, and A.A. and G.K.S. with intracellular cytokine staining and flow cytometry. R.C.A., P.P.H. and L.S. contributed to the EAE-related experiments. Y.H. and B.S.M. performed immunoblots and in vitro assays.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to May H Han.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–8 and Supplementary Tables 2 and 3

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    Supplementary Table 1

    Dataset from phosphoproteomic analysis of MS brain lesions.

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https://doi.org/10.1038/ni.2730

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