High salt reduces the activation of IL-4– and IL-13–stimulated macrophages
Katrina J. Binger, … , Jens Titze, Dominik N. Müller
Katrina J. Binger, … , Jens Titze, Dominik N. Müller
Published November 2, 2015; First published October 20, 2015
Citation Information: J Clin Invest. 2015;125(11):4223-4238. https://doi.org/10.1172/JCI80919.
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Categories: Research Article Cardiology Immunology Nephrology Vascular biology

High salt reduces the activation of IL-4– and IL-13–stimulated macrophages

Abstract

A high intake of dietary salt (NaCl) has been implicated in the development of hypertension, chronic inflammation, and autoimmune diseases. We have recently shown that salt has a proinflammatory effect and boosts the activation of Th17 cells and the activation of classical, LPS-induced macrophages (M1). Here, we examined how the activation of alternative (M2) macrophages is affected by salt. In stark contrast to Th17 cells and M1 macrophages, high salt blunted the alternative activation of BM-derived mouse macrophages stimulated with IL-4 and IL-13, M(IL-4+IL-13) macrophages. Salt-induced reduction of M(IL-4+IL-13) activation was not associated with increased polarization toward a proinflammatory M1 phenotype. In vitro, high salt decreased the ability of M(IL-4+IL-13) macrophages to suppress effector T cell proliferation. Moreover, mice fed a high salt diet exhibited reduced M2 activation following chitin injection and delayed wound healing compared with control animals. We further identified a high salt–induced reduction in glycolysis and mitochondrial metabolic output, coupled with blunted AKT and mTOR signaling, which indicates a mechanism by which NaCl inhibits full M2 macrophage activation. Collectively, this study provides evidence that high salt reduces noninflammatory innate immune cell activation and may thus lead to an overall imbalance in immune homeostasis.

Authors

Katrina J. Binger, Matthias Gebhardt, Matthias Heinig, Carola Rintisch, Agnes Schroeder, Wolfgang Neuhofer, Karl Hilgers, Arndt Manzel, Christian Schwartz, Markus Kleinewietfeld, Jakob Voelkl, Valentin Schatz, Ralf A. Linker, Florian Lang, David Voehringer, Mark D. Wright, Norbert Hubner, Ralf Dechend, Jonathan Jantsch, Jens Titze, Dominik N. Müller

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Figure 6

HSD leads to impaired wound healing in vivo.

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HSD leads to impaired wound healing in vivo. (A) Two cutaneous wounds we...
(A) Two cutaneous wounds were applied to the back of mice, which were then fed an NSD or HSD for 14 days. The closure of the wounds was monitored at the desired times in this 14-day period, at the end of which skin samples from the wounded area were subjected to qPCR analysis. (B) Representative images of wounds from mice on an NSD and HSD during 14 days after wounding. (C) The percent change in wound area is plotted over time. The experiment was repeated twice independently, at which point the values from 7 individual mice were pooled (n = 13 wounds per group). *P < 0.05 and **P < 0.01 by 2-way ANOVA. (D) The number of wounds completely healed (gray) vs. incompletely healed (white) at the end of the experiment (14 days). (E) Real-time qPCR analysis of M2 signature genes at wound sites from mice on an NSD and HSD. The P value shown for the effect of HSD was calculated by 2-way ANOVA. **P < 0.01. n = 5 (biological).