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Cell Rep. 2016 Oct 11;17(3):684-696. doi: 10.1016/j.celrep.2016.09.008.

Mitochondrial Dysfunction Prevents Repolarization of Inflammatory Macrophages.

Author information

1
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands. Electronic address: j.vandenbossche@amc.uva.nl.
2
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands.
3
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands; Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands; Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands.
4
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands; Center for Infection and Immunity, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands.
5
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands; Institute for Cardiovascular Prevention (IPEK), Ludwig Maximillian's University, Pettenkoferstrasse 9, Munich 80336, Germany.

Abstract

Macrophages are innate immune cells that adopt diverse activation states in response to their microenvironment. Editing macrophage activation to dampen inflammatory diseases by promoting the repolarization of inflammatory (M1) macrophages to anti-inflammatory (M2) macrophages is of high interest. Here, we find that mouse and human M1 macrophages fail to convert into M2 cells upon IL-4 exposure in vitro and in vivo. In sharp contrast, M2 macrophages are more plastic and readily repolarized into an inflammatory M1 state. We identify M1-associated inhibition of mitochondrial oxidative phosphorylation as the factor responsible for preventing M1→M2 repolarization. Inhibiting nitric oxide production, a key effector molecule in M1 cells, dampens the decline in mitochondrial function to improve metabolic and phenotypic reprogramming to M2 macrophages. Thus, inflammatory macrophage activation blunts oxidative phosphorylation, thereby preventing repolarization. Therapeutically restoring mitochondrial function might be useful to improve the reprogramming of inflammatory macrophages into anti-inflammatory cells to control disease.

KEYWORDS:

M1 M2 polarization; alternative macrophage activation; immunometabolism; inflammation; macrophage plasticity; macrophage polarization; macrophage repolarization; metabolism; mitochondrial dysfunction

PMID:
27732846
DOI:
10.1016/j.celrep.2016.09.008
[Indexed for MEDLINE]
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