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

• Published in: Nature (London) Vol. 496; no. 7446; pp. 518 - 522
• Main Authors: Kleinewietfeld, Markus, Manzel, Arndt, Titze, Jens, Kvakan, Heda, Yosef, Nir, Linker, Ralf A., Muller, Dominik N., Hafler, David A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25.04.2013
• Subjects: 631/250/38; Animals; Cells, Cultured; Encephalomyelitis, Autoimmune, Experimental - chemically induced; Encephalomyelitis, Autoimmune, Experimental - immunology; Encephalomyelitis, Autoimmune, Experimental - pathology; Gene Silencing; Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis; Humanities and Social Sciences; Humans; Immediate-Early Proteins - metabolism; Interleukin-2 - biosynthesis; letter; MAP Kinase Signaling System - drug effects; Mice; Mice, Inbred C57BL; multidisciplinary; p38 Mitogen-Activated Protein Kinases - deficiency; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; Phenotype; Protein-Serine-Threonine Kinases - metabolism; Science; Sodium Chloride, Dietary - pharmacology; Th17 Cells - drug effects; Th17 Cells - immunology; Th17 Cells - pathology; Transcription Factors - metabolism; Tumor Necrosis Factor-alpha - biosynthesis
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature11868

Increased salt concentrations are shown to induce murine and human T H 17 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 T H 17 cells. High-salt link to autoimmune diseases 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 (T H 17) 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 T H 17 differentiation in vitro and in vivo in mice. Markus Kleinewietfeld et al . find that salt induces murine and human T H 17 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 T H 17 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 T H 17 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 genes 1 , changes in environmental factors must ultimately be driving this increase. The newly identified population of interleukin (IL)-17-producing CD4 + helper T cells (T H 17 cells) has a pivotal role in autoimmune diseases 2 . Pathogenic IL-23-dependent T H 17 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–T H 17 pathway 1 , 2 . However, little is known about the environmental factors that directly influence T H 17 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 T H 17 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 T H 17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5 or SGK1 abrogates the high-salt-induced T H 17 cell development. The T H 17 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 T H 17 cells. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases through the induction of pathogenic T H 17 cells.