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

Autor:	Zhang S; Department of Pathology, Feinberg School of Medicine, Chicago, IL, USA; Feinberg Cardiovascular & Renal Research Institute, Feinberg School of Medicine, Chicago, IL, USA., Weinberg S; Department of Medicine, Feinberg School of Medicine, Chicago, IL, USA., DeBerge M; Department of Pathology, Feinberg School of Medicine, Chicago, IL, USA; Feinberg Cardiovascular & Renal Research Institute, Feinberg School of Medicine, Chicago, IL, USA., Gainullina A; ITMO University, Saint Petersburg, Russia; Washington University in St. Louis, St. Louis, MO, USA., Schipma M; Feinberg Cardiovascular & Renal Research Institute, Feinberg School of Medicine, Chicago, IL, USA., Kinchen JM; Metabolon Inc., Triangle Park, NC, USA., Ben-Sahra I; Department of Pharmacology, Feinberg School of Medicine, Chicago, IL, USA., Gius DR; Department of Radiation Oncology, Feinberg School of Medicine, Chicago, IL, USA., Yvan-Charvet L; Institut National de la Sante et de la Recherche Medicale (INSERM) U1065, Centre Mediterraneen de Medecine Moleculaire (C3M), Atip-Avenir, Nice, France., Chandel NS; Department of Medicine, Feinberg School of Medicine, Chicago, IL, USA., Schumacker PT; Department of Pediatrics, Feinberg School of Medicine, Chicago, IL, USA., Thorp EB; 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.
Jazyk:	angličtina
Zdroj:	Cell metabolism [Cell Metab] 2019 Feb 05; Vol. 29 (2), pp. 443-456.e5. Date of Electronic Publication: 2018 Dec 27.
DOI:	10.1016/j.cmet.2018.12.004
Abstrakt:	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. (Copyright © 2018 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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