Abstract Details

Title Sodium Chloride Drives the Induction of Pathogenic Th17 Cells

Topic MS and Related Diseases

Presentation(s) S11 - (-)

Poster/Presentation
Number 004

Objective

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.

Authors/Disclosures
PRESENTER	No disclosure on file
	No disclosure on file
	No disclosure on file
Marius Ringelstein	Marius Ringelstein has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Marius Ringelstein has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion.
	No disclosure on file
Ralf Linker (Uniklinik Erlangen)	Dr. Linker has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Linker has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Springer. The institution of Dr. Linker has received research support from Novartis. The institution of Dr. Linker has received research support from Biogen.
	No disclosure on file
David A. Hafler, MD, FAAN (Yale University School of Medicine, Dept of Neurology)	Dr. Hafler has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Hafler has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genetech. Dr. Hafler has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Roche. Dr. Hafler has received personal compensation in the range of $0-$499 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Joint Commission International.
Teri Schreiner, MD, MPH, FAAN (University of Colorado/ Children's Hospital of Colorado)	The institution of Dr. Schreiner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for CDC. Dr. Schreiner has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. The institution of Dr. Schreiner has received research support from Roche Genentech.

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