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         headline:Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells
         description:Increased salt concentrations are shown to induce murine and human TH17 cells by a mechanism that depends on activation of p38/MAPK, NFAT5 and SGK1; mice kept on a high-salt diet develop a more severe experimental autoimmune encephalomyelitis due to increased induction of TH17 cells. Two independent groups have come to the same surprising conclusion: that increased salt concentrations promote autoimmune disease by stimulating the production of interleukin-17-producing helper T (TH17) cells from CD4+ T cells. Chuan Wu et al. show that increases in salt concentrations induce serum glucocorticoid kinase 1 (SGK1) in T cells and enhance TH17 differentiation in vitro and in vivo in mice. Markus Kleinewietfeld et al. find that salt induces murine and human TH17 cells by a mechanism dependent on activation of SGK1 and the p38 MAP kinase/NFAT5 pathway. Mice on a high-salt diet develop a more severe experimental autoimmune encephalomyelitis, a model for brain inflammation, owing to high numbers of infiltrating TH17 cells. These studies raise the possibility that high salt intake might trigger tissue inflammation and autoimmune disease in humans. A further paper from Nir Yosef et al. presents a global view of the gene networks regulating TH17 cell differentiation. 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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      headline:Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells
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            type:Organization
            name:University of Erlangen-Nuremberg, Glückstr. 6, 91054 Erlangen, Germany
            address:
               name:Interdisciplinary Center for Clinical Research and Department for Nephrology and Hypertension, University of Erlangen-Nuremberg, Glückstr. 6, 91054 Erlangen, Germany,
               type:PostalAddress
            type:Organization
      name:Heda Kvakan
      affiliation:
            name: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
            address:
               name: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,
               type:PostalAddress
            type:Organization
            name:Helios Klinikum Berlin-Buch, Schwanebecker Chaussee 50, 13125 Berlin, Germany
            address:
               name:Helios Klinikum Berlin-Buch, Schwanebecker Chaussee 50, 13125 Berlin, Germany,
               type:PostalAddress
            type:Organization
      name:Nir Yosef
      affiliation:
            name:Broad Institute of MIT and Harvard, 7 Cambridge Center
            address:
               name:Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Ralf A. Linker
      affiliation:
            name:University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany
            address:
               name:Department of Neurology, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany,
               type:PostalAddress
            type:Organization
      name:Dominik N. Muller
      affiliation:
            name: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
            address:
               name: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,
               type:PostalAddress
            type:Organization
            name:Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen-Nuremberg, Glückstr. 6, 91054 Erlangen, Germany
            address:
               name:Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen-Nuremberg, Glückstr. 6, 91054 Erlangen, Germany,
               type:PostalAddress
            type:Organization
      name:David A. Hafler
      affiliation:
            name:Yale School of Medicine, 15 York Street, New Haven, Connecticut 06520, USA
            address:
               name:Departments of Neurology and Immunobiology, Yale School of Medicine, 15 York Street, New Haven, Connecticut 06520, USA,
               type:PostalAddress
            type:Organization
            name:Broad Institute of MIT and Harvard, 7 Cambridge Center
            address:
               name:Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, USA
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Departments of Neurology and Immunobiology, Yale School of Medicine, 15 York Street, New Haven, Connecticut 06520, USA,
      name:Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, USA
      name:Department of Neurology, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany,
      name:International Graduate School of Neuroscience, Ruhr-University Bochum, Universitätsstr. 150, Bochum, Germany
      name:Division of Clinical Pharmacology, Vanderbilt University, 2213 Garland Avenue, Nashville, Tennessee 37232, USA,
      name:Interdisciplinary Center for Clinical Research and Department for Nephrology and Hypertension, University of Erlangen-Nuremberg, Glückstr. 6, 91054 Erlangen, Germany,
      name: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,
      name:Helios Klinikum Berlin-Buch, Schwanebecker Chaussee 50, 13125 Berlin, Germany,
      name:Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, USA
      name:Department of Neurology, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany,
      name: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,
      name:Nikolaus-Fiebiger-Center for Molecular Medicine, University of Erlangen-Nuremberg, Glückstr. 6, 91054 Erlangen, Germany,
      name:Departments of Neurology and Immunobiology, Yale School of Medicine, 15 York Street, New Haven, Connecticut 06520, USA,
      name:Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, USA
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