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 October 20, 2015
Citation Information: J Clin Invest. 2015;125(11):4223-4238. https://doi.org/10.1172/JCI80919.
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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 5

HSD reduces M2 activation in vivo.

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HSD reduces M2 activation in vivo. (A) Mice were fed an NSD or an HSD fo...
(A) Mice were fed an NSD or an HSD for 14 days, at which point chitin was injected i.p. After 2 days, PECs were collected from the i.p. space by lavage and the desired immune populations were sorted by FACS and analyzed by qPCR. (B) Representative flow cytometry plots showing staining for macrophages (CD11b+F4/80+) of PECs from mice on NSD and HSD. (C) Quantification from B of the proportion and actual number of macrophages in PECs from mice on each respective diet. n = 4 (biological). (D) Gating strategy for the isolation of the desired immune populations by FACS. Following the gating of macrophages (Mac; CD11b+F4/80+) cells were then gated on CD11b–F4/80– and subsequently sorted as B220+ (B cells), CD3+ (T cells), or B220–CD3– (Neg). The final purity of each sorted population is shown below, where macrophages were >85% and all other populations were >90%. (E) The expression of M2 signature genes in immune cell populations sorted from PECs as described in D. (n = 4 NSD vs. n = 4 HSD biological replicates). *P < 0.05, #P < 0.01, and †P < 0.0001 by 2-way ANOVA.