Efferocytosis Fuels Requirements of Fatty Acid Oxidation and the Electron Transport Chain to Polarize Macrophages for Tissue Repair.
Cell Metab
; 29(2): 443-456.e5, 2019 02 05.
Article
em En
| MEDLINE
| ID: mdl-30595481
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 ß-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.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Interleucina-10
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Ácidos Graxos
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Macrófagos
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Mitocôndrias
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NAD
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article