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

Nature Immunology volume 14, pages 1166–1172 (2013)Cite this article

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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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Figure 1: S1P1 phosphorylation in active MS brain lesions.
Figure 2: S1P1(S5A) mice developed severe EAE.
Figure 3: Enhanced STAT3-mediated TH17 polarization in S1P1(S5A) EAE mice.
Figure 4: S1P-S1P1 signaling activates STAT3 phosphorylation.
Figure 5: IL-6 is crucial for S1P1-mediated STAT3 activation.

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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.).

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Author notes

  1. Christopher S Garris and Linfeng Wu: These authors contributed equally to this work.

Authors and 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. Division of Medical Sciences, Graduate Program in Immunology, 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. Department of Pathology and Laboratory Medicine, Center for Vascular Biology, 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. Department of Cell Biology, Center for Vascular 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.

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Correspondence to May H Han.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–8 and Supplementary Tables 2 and 3 (PDF 14246 kb)

Supplementary Table 1

Dataset from phosphoproteomic analysis of MS brain lesions. (XLSX 1188 kb)

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Garris, C., Wu, L., Acharya, S. et al. Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation. Nat Immunol 14, 1166–1172 (2013). https://doi.org/10.1038/ni.2730

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