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 John Schipma, Jason M. Kinchen, Issam Ben-Sahra, David R Gius, Laurent Yvan-Charvet, Navdeep Chandel, Paul T Schumacker, Edward Benjamin Thorp*

*Corresponding author for this work

Research output: Contribution to journalArticle

6 Citations (Scopus)

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

Fingerprint

Electron Transport
Fatty Acids
Macrophages
Interleukin-10
NAD
Anti-Inflammatory Agents
Heart Rupture
Metabolome
Electron Transport Complex III
Coenzymes
Wounds and Injuries
Glycolysis
Phagocytes
Transcription Factors
Adenosine Triphosphate
Cytokines

Keywords

  • efferocytosis
  • immunometabolism
  • macrophage
  • wound healing

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

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title = "Efferocytosis Fuels Requirements of Fatty Acid Oxidation and the Electron Transport Chain to Polarize Macrophages for Tissue Repair",
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.",
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Efferocytosis Fuels Requirements of Fatty Acid Oxidation and the Electron Transport Chain to Polarize Macrophages for Tissue Repair. / Zhang, Shuang; Weinberg, Samuel; DeBerge, Matthew; Gainullina, Anastasiia; Schipma, Matthew John; Kinchen, Jason M.; Ben-Sahra, Issam; Gius, David R; Yvan-Charvet, Laurent; Chandel, Navdeep; Schumacker, Paul T; Thorp, Edward Benjamin.

In: Cell Metabolism, Vol. 29, No. 2, 05.02.2019, p. 443-456.e5.

Research output: Contribution to journalArticle

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AU - Zhang, Shuang

AU - Weinberg, Samuel

AU - DeBerge, Matthew

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AU - Schipma, Matthew John

AU - Kinchen, Jason M.

AU - Ben-Sahra, Issam

AU - Gius, David R

AU - Yvan-Charvet, Laurent

AU - Chandel, Navdeep

AU - Schumacker, Paul T

AU - Thorp, Edward Benjamin

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