Letter | Published:

Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells

Nature volume 496, pages 518522 (25 April 2013) | Download Citation

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Abstract

There has been a marked increase in the incidence of autoimmune diseases in the past half-century. Although the underlying genetic basis of this class of diseases has recently been elucidated, implicating predominantly immune-response genes1, changes in environmental factors must ultimately be driving this increase. The newly identified population of interleukin (IL)-17-producing CD4+ helper T cells (TH17 cells) has a pivotal role in autoimmune diseases2. Pathogenic IL-23-dependent TH17 cells have been shown to be critical for the development of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, and genetic risk factors associated with multiple sclerosis are related to the IL-23–TH17 pathway1,2. However, little is known about the environmental factors that directly influence TH17 cells. Here we show that increased salt (sodium chloride, NaCl) concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human TH17 cells. High-salt conditions activate the p38/MAPK pathway involving nuclear factor of activated T cells 5 (NFAT5; also called TONEBP) and serum/glucocorticoid-regulated kinase 1 (SGK1) during cytokine-induced TH17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5 or SGK1 abrogates the high-salt-induced TH17 cell development. The TH17 cells generated under high-salt conditions display a highly pathogenic and stable phenotype characterized by the upregulation of the pro-inflammatory cytokines GM-CSF, TNF-α and IL-2. Moreover, mice fed with a high-salt diet develop a more severe form of EAE, in line with augmented central nervous system infiltrating and peripherally induced antigen-specific TH17 cells. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic TH17 cells.

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Gene Expression Omnibus

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The microarray data sets have been deposited in the Gene Expression Omnibus database under accession number GSE42569.

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Acknowledgements

The authors would like to thank S. Bhela, M. Zaidi, P. Quass, M. Mroz and S. Seubert for technical assistance and F. C. Luft for critical reading of the manuscript. We are grateful to J.-P. David and S. Teufel for providing Mx-Cre+ p38αfl/fl mice. This work was supported by a National MS Society Collaborative Research Center Award CA1061-A-18, National Institutes of Health Grants P01 AI045757, U19 AI046130, U19 AI070352, and P01 AI039671, and by a Jacob Javits Merit award (NS2427) from the National Institute of Neurological Disorders and Stroke, the Penates Foundation and the Nancy Taylor Foundation for Chronic Diseases, Inc. (to D.A.H.). R.A.L. was supported by the ELAN programme, University of Erlangen. D.N.M. was supported by the German Research Foundation (DFG) and the German Center for Cardiovascular Research (DZHK). J.T. was supported by the Interdisciplinary Center for Clinical Research at University of Erlangen and the German Research Foundation.

Author information

Author notes

    • Dominik N. Muller
    •  & David A. Hafler

    These authors contributed equally to this work.

Affiliations

  1. Departments of Neurology and Immunobiology, Yale School of Medicine, 15 York Street, New Haven, Connecticut 06520, USA

    • Markus Kleinewietfeld
    •  & David A. Hafler
  2. Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA

    • Markus Kleinewietfeld
    • , Nir Yosef
    •  & David A. Hafler
  3. Department of Neurology, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany

    • Arndt Manzel
    •  & Ralf A. Linker
  4. International Graduate School of Neuroscience, Ruhr-University Bochum, Universitätsstr. 150, 44801 Bochum, Germany

    • Arndt Manzel
  5. Division of Clinical Pharmacology, Vanderbilt University, 2213 Garland Avenue, Nashville, Tennessee 37232, USA

    • Jens Titze
  6. Interdisciplinary Center for Clinical Research and Department for Nephrology and Hypertension, University of Erlangen-Nuremberg, Glückstr. 6, 91054 Erlangen, Germany

    • Jens Titze
  7. Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max-Delbrück Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany

    • Heda Kvakan
    •  & Dominik N. Muller
  8. Helios Klinikum Berlin-Buch, Schwanebecker Chaussee 50, 13125 Berlin, Germany

    • Heda Kvakan
  9. Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen-Nuremberg, Glückstr. 6, 91054 Erlangen, Germany

    • Dominik N. Muller

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Contributions

M.K. designed the study, planned and performed experiments, analysed data and wrote the manuscript. A.M. planned and performed experiments, analysed data and wrote the manuscript. J.T. and H.K. interpreted data and supported the work with key suggestions and editing the manuscript. N.Y. analysed data. R.A.L. planned experiments, analysed data and wrote the manuscript. D.N.M. designed the study, planned experiments, analysed data and wrote the manuscript. D.A.H. designed the study, planned experiments, analysed data, and wrote the manuscript. M.K., D.N.M. and D.A.H. co-directed the project.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Markus Kleinewietfeld or David A. Hafler.

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DOI

https://doi.org/10.1038/nature11868

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