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 language | English (US) |
|---|---|
| Pages (from-to) | 443-456.e5 |
| Journal | Cell Metabolism |
| Volume | 29 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 5 2019 |
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Keywords
- efferocytosis
- immunometabolism
- macrophage
- wound healing
ASJC Scopus subject areas
- Physiology
- Molecular Biology
- Cell Biology
Cite this
}
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 journal › Article
TY - JOUR
T1 - Efferocytosis Fuels Requirements of Fatty Acid Oxidation and the Electron Transport Chain to Polarize Macrophages for Tissue Repair
AU - Zhang, Shuang
AU - Weinberg, Samuel
AU - DeBerge, Matthew
AU - Gainullina, Anastasiia
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
PY - 2019/2/5
Y1 - 2019/2/5
N2 - 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.
AB - 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.
KW - efferocytosis
KW - immunometabolism
KW - macrophage
KW - wound healing
UR - http://www.scopus.com/inward/record.url?scp=85060353127&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85060353127&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2018.12.004
DO - 10.1016/j.cmet.2018.12.004
M3 - Article
VL - 29
SP - 443-456.e5
JO - Cell Metabolism
JF - Cell Metabolism
SN - 1550-4131
IS - 2
ER -