title: Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells.
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 genes, 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 diseases. 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 pathway. 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.
authors: Departments of Neurology and Immunobiology, Yale School of Medicine, 15 York Street, New Haven, Connecticut 06520, USA. markus.kleinewietfeld@yale.edu
authors: Markus
authors: M
authors: Kleinewietfeld
authors: Arndt
authors: A
authors: Manzel
authors: Jens
authors: J
authors: Titze
authors: Heda
authors: H
authors: Kvakan
authors: Nir
authors: N
authors: Yosef
authors: Ralf A
authors: RA
authors: Linker
authors: Dominik N
authors: DN
authors: Muller
authors: David A
authors: DA
authors: Hafler
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced* / Q000276:immunology* / Q000473:pathology; D020868:Gene Silencing; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D007376:Interleukin-2 / Q000096:biosynthesis; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017673:Sodium Chloride, Dietary / Q000494:pharmacology*; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D017874:Immediate-Early Proteins; D007376:Interleukin-2; D017346:Protein Serine-Threonine Kinases; D017673:Sodium Chloride, Dietary; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases; C118125:NFAT5 protein, human; C492200:Nfat5 protein, mouse