Sodium Chloride Drives Autoimmune Disease by the Induction of Pathogenic Th17 Cells

By Markus Kleinewietfeld, A. Manzel, J. Titze, H. Kvakan, Nir Yosef, R. Linker, D. Muller, David A. Hafler. Nature, 2013

1,347 citations recorded by the source corpus.

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.

Subfields: Immunology, Nutrition and Dietetics

View Paper: https://www.semanticscholar.org/paper/466e5a58ba9a992a60467b9108ea05170affb3de

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

In Nutrition and Dietetics

Citations in the corpus

Salt-responsive gut commensal modulates TH17 axis and disease (2017, positive): “However, in the actively-induced EAE and hypertension models used here and in humans, high salt enhanced T H 17 cells.”
Lactate Regulates Metabolic and Pro-inflammatory Circuits in Control of T Cell Migration and Effector Functions (2015, background): “In this context, it has recently been suggested that increased salt (sodium chloride, NaCl) concentrations found locally under physiological conditions in vivo markedly boost the induction of murine and human Th17 cells in autoimmune conditions [46].”
Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013, background): “salt (NaCl) (37, 38) and short-chain fatty acids (39) can influence TH17 and Treg homeostasis, respectively.”
The role of microbiome in central nervous system disorders (2013, positive): “Unhealthy diet patterns containing high levels of fat or salt could accelerate neuroinflammation during EAE (Kleinewietfeld et al., 2013; Piccio et al., 2008).”
Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine. (2015, positive): “The gut microbiome, along with various dietary habits such as high salt intake, has been recently established as an environmental contributor to the pathogenesis of multiple sclerosis (MS) (Berer et al., 2011; Kleinewietfeld et al., 2013), a T-cellmediated autoimmune disease of the central nervous s”