Efferocytosis Fuels Requirements of Fatty Acid Oxidation and the Electron Transport Chain to Polarize Macrophages for Tissue Repair

Zhang, S.; Weinberg, S.; DeBerge, M.; Gainullina, A.; Schipma, M.; Kinchen, J. M.; Ben-Sahra, I.; Gius, D. R.; Charvet, L. Y.; Chandel, N. S.; Schumacker, P. T.; Thorp, E. B.

Cell Metab. 2019 Jan 1

Abstract

During wound injury, efferocytosis fills the macrophage with a metabolite load nearly equal to the phagocyte itself. A timely question pertains to how metabolic phagocytic signaling regulates the signature anti-inflammatory macrophage response. Here we report the metabolome of activated macrophages during efferocytosis to reveal an interleukin-10 (IL-10) cytokine escalation that was independent of glycolysis yet bolstered by apoptotic cell fatty acids and mitochondrial beta-oxidation, the electron transport chain, and heightened coenzyme NAD(+). Loss of IL-10 due to mitochondrial complex III defects was remarkably rescued by adding NAD(+) precursors. This activated a SIRTUIN1 signaling cascade, largely independent of ATP, that culminated in activation of IL-10 transcription factor PBX1. Il-10 activation by the respiratory chain was also important in vivo, as efferocyte mitochondrial dysfunction led to cardiac rupture after myocardial injury. These findings highlight a new paradigm whereby macrophages leverage efferocytic metabolites and electron transport for anti-inflammatory reprogramming that culminates in organ repair.

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