Abstract

High salt reduces the activation of IL-4- and IL-13-stimulated macrophages. Binger KJ, Gebhardt M, Heinig M, et al. J Clin Invest. 2015;2:125:4223–38. This article introduces the influence of increased osmolarity on activation, function, and recruitment of immune cells. Macrophages are highly heterogeneous immune cells with the potential to differentiate into M1- and M2-activated macrophages. M2 macrophage determination is linked to the production of IL-4– and IL-13–mediating Th2 immunity, wound healing, and the suppression of effector T-cell functions. A high intake of dietary salt (NaCl) has been linked to arterial hypertension, chronic inflammation, and autoimmune diseases. This article explores the impact of salt on (M2) macrophage determination. In several models, the authors explored the consequences of salt on M2 (IL-4+IL13) activation, induction and suppression. Bone marrow–derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages were used for the experiments. An increase in salt significantly reduced the activation of M2, IL-4, and IL-13 producing macrophages in vitro. Of note, effects of M2 macrophages had not been dependent on salt-responsive molecules including SGK1 and NFAT5, but had rather been mediated via perturbations in AKT/mTOR signalling. In vivo, mice fed with a high salt diet exhibited reduced M2 activation after chitin injection that delayed wound healing. Sodium ions appear critical in this context as hypertonicity by nonionic osmolytes, such as mannitol and urea in control groups, did not compromise M2 function and IL-4+IL-13 activation. The authors propose that high NaCl concentrations impact signalling pathways and cellular processes essential for macrophage activation. Unstimulated M(0) macrophages treated with high salt have shown increased cellular metabolism (glycolysis and OXPHOS) and a slightly decreased viability, indicating that NaCl also affects macrophage function. Collectively, this study provides evidence that high salt is linked to a compromise of anti-inflammatory M2 capacities, thus potentially leading to an overall imbalance in immune homeostasis. Sodium chloride inhibits the suppressive function of FOXP3+ regulatory T cells. Hernandez AL, Kitz A, Wu C, et al. J Clin Invest. 2015;2:125:4212–22. Regulatory T (Treg) cells display a central role for tolerance. In autoimmunity, the suppressive function of Treg cells is compromised and Treg cells will secrete proinflammatory cytokines including IFNγ and IL-17. Diet appears as an emerging environmental trigger. Here, physiologically elevated levels of sodium chloride have been shown to block the suppressive capacity of human and murine Foxp3+Treg cells in vitro and in vivo. In their article, the authors exposed CD4+CD25hiCD127loFoxp3+ Treg cells to 40 mM NaCl (high salt) or standard culture media. Of note, Treg cells preincubated under high-salt conditions lost their suppressor function in vitro. In a subsequent microarray analysis, Treg cells demonstrated Th1-type proinflammatory characteristics under high salt conditions and a luminex assay of Treg cell culture supernatants revealed a 6-fold increase of IFNγ secretion. The authors took their in vitro findings then in an in vivo model using immune-deficient mice that received either a high or a normal salt diet. Subsequently, mice received an adoptive transfer of CD25-depleted human peripheral blood mononuclear cells that resulted in graft versus host disease. Animals fed with a normal salt diet were symptom-free after a 40-day time course, whereas their high-salt diet counterparts developed significant disease. The IFNγ production had increased significantly under high salt conditions. Thus, high-salt diet induced in the secretion of IFNγ originating from Treg cells appears associated to a loss of suppressive functions. These data link a newly discovered environmental risk factor with a central immunologic dysfunction with relevance for clinical autoimmunity but potentially also for other alloimmune processes. The observation of an environmentally or dietary determined IFNγ signature in Treg cells in a genetically susceptible appears of broad clinical relevance.

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