[PDF][PDF] Efferocytosis fuels requirements of fatty acid oxidation and the electron transport chain to polarize macrophages for tissue repair

S Zhang, S Weinberg, M DeBerge, A Gainullina… - Cell metabolism, 2019 - cell.com
S Zhang, S Weinberg, M DeBerge, A Gainullina, M Schipma, JM Kinchen, I Ben-Sahra
Cell metabolism, 2019cell.com
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 β-oxidation, the electron transport chain, and heightened …
Summary
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 β-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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