Review articleSodium chloride triggers Th17 mediated autoimmunity
Introduction
A vast number of animal and human studies revealed a role for CD4+ T helper 17 (Th17) cells and their downstream pathways as important drivers of autoimmune diseases. Indeed, Th17 cells were already implicated in the development of inflammatory bowel disease (Gálvez, 2014), rheumatoid arthritis (Annunziato et al., 2009; Azizi et al., 2013), psoriasis (Annunziato et al., 2009) and also multiple sclerosis (MS). First studies using the murine experimental autoimmune encephalomyelitis (EAE) model revealed that interleukin (IL) 23 deficient mice are protected from the disease (Cua et al., 2003). Thus, IL-23 directly acts on T cells, promoting the induction of Th17 cells (Aggarwal et al., 2003). In accordance, the transfer of myelin antigen-specific Th17 cells was very potent in inducing EAE in naive recipient mice (Jäger et al., 2009; Langrish et al., 2005). Strikingly, Th17 cells most frequently occur in the intestine, where they help to protect against extracellular pathogens and maintain the barrier function of the gut (Conti et al., 2009). Yet, depending on the modulating factors they are exposed to, Th17 cells can also have pro-inflammatory properties, characterized by the up-regulation of IL-23 receptor (IL-23R) and an increased secretion of IL-17A, granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNF) α and IL-2 (Ghoreschi et al., 2010). Dietary components might represent such modulating factors, implicating the diet as a potential risk factor in autoimmune diseases. The excess consumption of salt (sodium chloride) has repeatedly been associated with an increased risk of developing high blood pressure (Mozaffarian et al., 2014), disturbances in normal kidney function (Fellner et al., 2014), cancer (D'Elia et al., 2014) and chronic inflammation (Sundström et al., 2015). Moreover, there is growing evidence that excess salt affects the immune system, and first studies assume that high salt enhances MS disease activity (Farez et al., 2015). It is thus not surprising that salt restriction is widely viewed as an essential part of a healthy life style. The latest World Health Organization guidelines recommend adults to consume less than 5 g salt or 2 g sodium per day (Guideline: Sodium Intake for Adults and Children, 2012). However, the estimated average salt intake is about two to three times higher as the recommended maximum level (Brown et al., 2009), rendering it a potential risk factor in various diseases, including MS.
Section snippets
High-salt effects on immune cells
Several immune cell subtypes are potentially important in mediating the detrimental effects of excess sodium chloride. First studies investigated a possible effect of high salt concentrations on the innate immune system. While dendritic cells do not respond to excess sodium chloride in vitro and in vivo (Jörg et al., 2016), monocytes acquire a highly pro-inflammatory state (Shapiro and Dinarello, 1995). RNA analyses revealed the induction of a set of pro-inflammatory genes, including
High-salt affects the gut microbiome
In vitro studies investigating the effect of high-salt on various immune cells used comparable sodium chloride concentrations to those measured in the intestinal lumen after ingesting a high-salt diet. Moreover, before being absorbed and distributed to tissues, sodium chloride passes the gastrointestinal tract (Jose et al., 2016). Indeed, studies in models of inflammatory bowel disease imply the gut as relevant organ mediating effects of salt on the immune system (Monteleone et al., 2017; Wei
Linking excess salt to human disease
Recently published studies investigating high dietary salt intake as a potential risk factor in MS yielded controversial results. In an observational study of two independent cohorts of 70 MS patients, high dietary salt intake resulted in higher relapse rates as well as increased numbers of new MRI lesions compared to patients with moderate dietary salt intake (Farez et al., 2015). Accordingly, high salt has been implicated to influence human immune responses in general. Long-time salt intake
Conclusion
A major challenge for all studies addressing the effect of dietary habits in MS is that it is not possible to account for all potential confounders: sodium intake may be linked to healthy or unhealthy food that may exaggerate the effect of sodium intake. In fact, processed foods or fast foods are one of the main sources of salt, containing up to 100-times more sodium than homemade meals (Brown et al., 2009). Besides salt, fast food contains high amounts of fat, and it was recently shown that
Disclosures and acknowledgments
MK was supported by the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (640116), by a SALK-grant from the government of Flanders, Belgium and by an Odysseus-grant of the Research Foundation Flanders (FWO) (G0G1216FWO), Belgium.
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