Increased Dietary Salt Causes Autoimmune Diseases by Stimulating Formation of Proinflammatory TH17 Cells

Three recent papers linked elevated dietary salt to the development of autoimmune diseases such as multiple sclerosis and type I diabetes by demonstrating the relationship between salt levels and the generation of T helper 17 (TH17) cells.

TH17 cells (interleukin-17 (IL-17)-producing helper T cells) are highly pro-inflammatory cells that are critical for clearing extracellular pathogens and for inducing multiple autoimmune diseases. To study the effect of salt concentration on TH17 cell metabolism investigators at Harvard Medical School (Boston, MA, USA) and Yale School of Medicine (New Haven, CT, USA) worked with cell cultures and with mouse populations where it was easy to adjust the level of dietary salt.

Details of the research and results were published in three papers that appeared in the March 6, 2013, online edition of the journal Nature. Among other factors, the investigators identified the protein serum glucocorticoid kinase 1 (SGK1), which is known to regulate salt levels in other types of cells, as a TH17-signal. The researchers found that mouse cells cultured in high-salt conditions had higher SGK1 expression and produced more TH17 cells than those grown in normal conditions. A modest increase in salt concentration induced SGK1 expression, promoted interleukin-23R expression, and enhanced TH17 cell differentiation in vitro and in vivo, accelerating the development of autoimmunity.

High-salt conditions activated the p38/MAPK pathway involving nuclear factor of activated T cells 5 (NFAT5; also called TONEBP) and SGK1 during cytokine-induced TH17 polarization. Gene silencing or chemical inhibition of p38/MAPK, NFAT5, or SGK1 abolished the high-salt-induced TH17 cell development. TH17 cells generated under high-salt conditions displayed a highly pathogenic and stable phenotype characterized by the upregulation of the proinflammatory cytokines.

"Humans were genetically selected for conditions in sub-Saharan Africa, where there was no salt," said senior author Dr. David Hafler, professor of neurology and immunobiology at Yale School of Medicine. "Today, Western diets all have high salt content and that has led to increase in hypertension and perhaps autoimmune disease as well. These are not diseases of bad genes alone or diseases caused by the environment, but diseases of a bad interaction between genes and the environment."

"Test-tube cell biology is performed based on the salt levels found in blood and not in the tissues where immune cells ultimately travel to fight infections," said Dr. Hafler. "That may have been a reason salt's role in autoimmunity has gone undetected. We may have been using the wrong concentrations of salt in our experiments for the past half-century. Nature did not want immune cells to become turned on in the pipeline, so perhaps blood salt levels are inhibitory."

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Harvard Medical School
Yale School of Medicine