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

Shuang Zhang, Samuel Weinberg, Matthew DeBerge, Anastasiia Gainullina, Matthew Schipma, Jason M. Kinchen, Issam Ben-Sahra, David R. Gius, Laurent Yvan-Charvet, Navdeep S. Chandel, Paul T. Schumacker, Edward B. Thorp*

*Corresponding author for this work

Research output: Contribution to journalArticle

28 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)443-456.e5
JournalCell Metabolism
Volume29
Issue number2
DOIs
StatePublished - Feb 5 2019

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Keywords

  • efferocytosis
  • immunometabolism
  • macrophage
  • wound healing

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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