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Cell Metab. 2019 Feb 5;29(2):443-456.e5. doi: 10.1016/j.cmet.2018.12.004. Epub 2018 Dec 27.

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

Author information

1
Department of Pathology, Feinberg School of Medicine, Chicago, IL, USA; Feinberg Cardiovascular & Renal Research Institute, Feinberg School of Medicine, Chicago, IL, USA.
2
Department of Medicine, Feinberg School of Medicine, Chicago, IL, USA.
3
ITMO University, Saint Petersburg, Russia; Washington University in St. Louis, St. Louis, MO, USA.
4
Feinberg Cardiovascular & Renal Research Institute, Feinberg School of Medicine, Chicago, IL, USA.
5
Metabolon Inc., Triangle Park, NC, USA.
6
Department of Pharmacology, Feinberg School of Medicine, Chicago, IL, USA.
7
Department of Radiation Oncology, Feinberg School of Medicine, Chicago, IL, USA.
8
Institut National de la Sante et de la Recherche Medicale (INSERM) U1065, Centre Mediterraneen de Medecine Moleculaire (C3M), Atip-Avenir, Nice, France.
9
Department of Pediatrics, Feinberg School of Medicine, Chicago, IL, USA.
10
Department of Pathology, Feinberg School of Medicine, Chicago, IL, USA; Feinberg Cardiovascular & Renal Research Institute, Feinberg School of Medicine, Chicago, IL, USA. Electronic address: ebthorp@northwestern.edu.

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.

KEYWORDS:

efferocytosis; immunometabolism; macrophage; wound healing

PMID:
30595481
PMCID:
PMC6471613
[Available on 2020-02-05]
DOI:
10.1016/j.cmet.2018.12.004

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