title: Mitochondrial Dysfunction Prevents Repolarization of Inflammatory Macrophages.
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.
authors.affiliation: 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.
authors.forename: Jan
authors.initials: J
authors.lastname: Van den Bossche
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Baardman
authors.affiliation: 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.
authors.forename: Natasja A
authors.initials: NA
authors.lastname: Otto
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands.
authors.forename: Saskia
authors.initials: S
authors.lastname: van der Velden
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands.
authors.forename: Annette E
authors.initials: AE
authors.lastname: Neele
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands.
authors.forename: Susan M
authors.initials: SM
authors.lastname: van den Berg
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands.
authors.forename: Rosario
authors.initials: R
authors.lastname: Luque-Martin
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands.
authors.forename: Hung-Jen
authors.initials: HJ
authors.lastname: Chen
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands.
authors.forename: Marieke C S
authors.initials: MC
authors.lastname: Boshuizen
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ahmed
authors.affiliation: Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands.
authors.forename: Marten A
authors.initials: MA
authors.lastname: Hoeksema
authors.affiliation: 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.
authors.forename: Alex F
authors.initials: AF
authors.lastname: de Vos
authors.affiliation: 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.
authors.forename: Menno P J
authors.initials: MP
authors.lastname: de Winther
mesh_terms: D000818:Animals; D016764:Cell Polarity / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D007371:Interferon-gamma / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010641:Phenotype
chemical_list: D008070:Lipopolysaccharides; D015847:Interleukin-4; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D005947:Glucose
keywords: M1 M2 polarization; alternative macrophage activation; immunometabolism; inflammation; macrophage plasticity; macrophage polarization; macrophage repolarization; metabolism; mitochondrial dysfunction