Mitochondrial Dysfunction Prevents Repolarization of Inflammatory Macrophages
Jan Van den Bossche,
Jeroen Baardman,
Natasja A. Otto,
Saskia van der Velden,
Annette E. Neele,
Susan M. van den Berg,
Rosario Luque-Martin,
Hung-Jen Chen,
Marieke C.S. Boshuizen,
Mohamed Ahmed,
Marten A. Hoeksema,
Alex F. de Vos,
Menno P.J. de Winther
Affiliations
Jan Van den Bossche
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands
Jeroen Baardman
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands
Natasja A. Otto
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands
Saskia van der Velden
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands
Annette E. Neele
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands
Susan M. van den Berg
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands
Rosario Luque-Martin
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands
Hung-Jen Chen
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands
Marieke C.S. Boshuizen
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands
Mohamed Ahmed
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands
Marten A. Hoeksema
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands
Alex F. de Vos
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands
Menno P.J. de Winther
Department of Medical Biochemistry, Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam 1105, the Netherlands
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.
