Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells

Abstract

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 ultimately be driving this increase. The newly identified population of interleukin (IL)-17 producing CD4+ helper T cells (Th17 cells) plays 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 locally under physiological conditions in vivo dramatically boost the induction of murine and human Th17 cells. High-salt conditions activate the p38/MAPK pathway involving the tonicity-responsive enhancer binding protein (TonEBP/NFAT5) and the 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 display a highly pathogenic and stable phenotype 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 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.

Western lifestyle and immunopathology of multiple sclerosis

“…In agreement with these findings, T H 17 cells generated under salt‐enriched conditions show a highly pathogenic phenotype in vitro 74, 75. This increase in T H 17 responses under high salt conditions was shown to be mediated by p38 mitogen‐activated protein kinase (MAPK), nuclear factor of activated T cells (NFAT5), and serum glucocorticoid kinase‐1 (SGK1) 74, 75. Consistently, a T cell–specific knockout of Sgk1 in mice ameliorated EAE disease severity that was seen on a high salt diet 75.…”

“…A possible explanation of these divergent results is the different treatments and baseline characteristics of the MS patients included in the studies, as well as the divergent approaches to assess sodium intake in these retrospective analyses. Several studies have shown that high sodium diets could exacerbate EAE 74, 75, 77, 79. When analyzing CD4 + T cells, this effect was accompanied by increased numbers of T H 17 cells and a higher infiltration of T H 17 cells into the CNS 74, 75.…”

“…When analyzing CD4 + T cells, this effect was accompanied by increased numbers of T H 17 cells and a higher infiltration of T H 17 cells into the CNS 74, 75. In agreement with these findings, T H 17 cells generated under salt‐enriched conditions show a highly pathogenic phenotype in vitro 74, 75. This increase in T H 17 responses under high salt conditions was shown to be mediated by p38 mitogen‐activated protein kinase (MAPK), nuclear factor of activated T cells (NFAT5), and serum glucocorticoid kinase‐1 (SGK1) 74, 75.…”

“…The salt consumption varies considerably among countries, ranging from 1.5 g of sodium per day in East African countries to 3.9 g of sodium per day in high‐income countries 73. Recently, many studies have demonstrated that a high intake of sodium chloride can be an important factor potentially influencing autoimmunity in both humans and rodents 74, 75, 76, 77, 78, 79, 80, 81, 82. In patients with RRMS in Argentina, increased sodium intake was associated with enhanced disease exacerbation and new lesion development 76.…”

Hypertension as an autoimmune and inflammatory disease

“…48 A diet rich in salt is implicated as a possible cause of increased inflammation and the autoimmune response. 49 This may be partially due to the induction of pathogenic TH17 cells. 50 IL-17-producing CD4 (+) helper T cells are a newly described sub-population of T cells, and these cells have a pivotal role in autoimmune diseases.…”