Abstract 456: High Salt Induces Pathogenic Th17 Cells and Exacerbates Autoimmune Diseases
There has been a marked increase in the incidence of autoimmune diseases in the last half-century. While the underlying genetic basis of this class of diseases has recently been elucidated implicating predominantly immune response genes1, changes in environmental factors must ultimate be driving this increase. The recently identified population of interleukin (IL)-17 producing CD4+ helper T cells (Th17 cells) play 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 (MS) and genetic risk factors associated with MS are related to the IL23/Th17 pathway1, 2. However, little is known regarding the environmental factors that directly influence Th17 cells. Here we show that increased salt (sodium chloride; NaCl) concentrations found under physiological conditions in vivo dramatically boost the induction of murine and human Th17 cells. High salt conditions activates the p38/MAPK pathway involving the tonicity-responsive enhancer binding protein (TonEBP/NFAT5) and the serum- and glucocorticoid-inducible 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 display a highly pathogenic and stable phenotype as compared to cells differentiated under normal conditions characterized by the up-regulation of the pro-inflammatory cytokines GM-CSF, TNFα and IL-2. Moreover, mice fed with a high salt diet develop a very severe form of EAE in line with increased 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.
- © 2012 by American Heart Association, Inc.