Sodium Chloride Drives the Induction of Pathogenic Th17 Cells (S11.004)

OBJECTIVE: To identify new environmental factors that may lead to risk of developing multiple sclerosis. BACKGROUND: MS is an inflammatory CNS disease and genetic risk is primarily associated with immunologic genes common among the autoimmune diseases. It is thought that MS occurs in genetically susceptible individuals in response to altered environmental influences. We recently observed that increases in inflammatory Th17 cells were observed in individuals with increased fast food intake associated with high salt and fat diets. DESIGN/METHODS: Naive human CD4+ T cells were differentiated in vitro into Th17 cells in the presence or absence of high salt conditions, mimicking concentrations observed in vivo. To dissect the mechanism we applied global gene expression analysis and knockdown approaches by lentiviral transduction of shRNA. RESULTS: Human Th17 differentiation is dramatically boosted under high salt conditions. Furthermore Th17 cells induced under high salt conditions display a highly pathogenic and stable phenotype. Gene array analysis revealed that high salt 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. CONCLUSIONS: High salt conditions boost the induction of pathogenic Th17 cells in humans. This process is highly specific and dependent on the ancient stress related pathway of p38/MAPK, NFAT5 and SGK1. Thus, increased dietary salt intake might represent an environmental risk factor for the development of autoimmune diseases like MS through the induction of pathogenic Th17 cells. Disclosure: Dr. Kleinewietfeld has received royalty payments from Stemcell-Technologies. Dr. Manzel has nothing to disclose. Dr. Titze has nothing to disclose. Dr. Kvakan has nothing to disclose. Dr. Linker has received personal compensation for activities with BayerVital, Biogen Idec, NovartisPharma, Merck Serono, and TEVA Pharma. Dr. Linker has received research support from BayerVital, Biogen Idec, NovartisPharma, Merck Serono, and TEVA Pharma. Dr. Muller has nothing to disclose. Dr. Hafler has received personal compensation for activities with Wyeth, Beckman Coulter, and Novartis.