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 Schipma; Jason M. Kinchen; Issam Ben-Sahra; David R. Gius; Laurent Yvan-Charvet; Navdeep S. Chandel; Paul T. Schumacker; Edward B. Thorp

doi:10.1016/j.cmet.2018.12.004

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

289 Scopus citations

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	https://doi.org/10.1016/j.cmet.2018.12.004
State	Published - Feb 5 2019

Funding

Funding support from NHLBI F32HL127958 (M.D.) and HL122309 and HL139812 (E.B.T.), Chicago Biomedical Consortium , AHA predoctoral fellowship to S.Z., NU presidential fellowship to S.Z., and Sidney Bess Memorial Fund . Special thanks to Lennell Reynolds, Jr. at the NU imaging facility. D.R.G. is supported by 2R01CA152601-A1 , 1R01CA152799-01A1 , 1R01CA168292-01A1 , 1R01CA214025-01 , the Avon Foundation for Breast Cancer Research, the Lynn Sage Cancer Research Foundation , the Zell Family Foundation, and the Chicago Biomedical Consortium as well the Searle Funds at The Chicago Community Trust .

Keywords

efferocytosis
immunometabolism
macrophage
wound healing

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2018.12.004

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Zhang, S., Weinberg, S., DeBerge, M., Gainullina, A., Schipma, M., Kinchen, J. M., Ben-Sahra, I., Gius, D. R., Yvan-Charvet, L., Chandel, N. S., Schumacker, P. T., & Thorp, E. B. (2019). Efferocytosis Fuels Requirements of Fatty Acid Oxidation and the Electron Transport Chain to Polarize Macrophages for Tissue Repair. Cell Metabolism, 29(2), 443-456.e5. https://doi.org/10.1016/j.cmet.2018.12.004

@article{8c4491e58da941d3a28e7f4480557a88,

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.",

keywords = "efferocytosis, immunometabolism, macrophage, wound healing",

author = "Shuang Zhang and Samuel Weinberg and Matthew DeBerge and Anastasiia Gainullina and Matthew Schipma and Kinchen, {Jason M.} and Issam Ben-Sahra and Gius, {David R.} and Laurent Yvan-Charvet and Chandel, {Navdeep S.} and Schumacker, {Paul T.} and Thorp, {Edward B.}",

note = "Funding Information: Funding support from NHLBI F32HL127958 (M.D.) and HL122309 and HL139812 (E.B.T.), Chicago Biomedical Consortium, AHA predoctoral fellowship to S.Z., NU presidential fellowship to S.Z., and Sidney Bess Memorial Fund. Special thanks to Lennell Reynolds, Jr. at the NU imaging facility. D.R.G. is supported by 2R01CA152601-A1, 1R01CA152799-01A1, 1R01CA168292-01A1, 1R01CA214025-01, the Avon Foundation for Breast Cancer Research, the Lynn Sage Cancer Research Foundation, the Zell Family Foundation, and the Chicago Biomedical Consortium as well the Searle Funds at The Chicago Community Trust. Funding Information: Funding support from NHLBI F32HL127958 (M.D.) and HL122309 and HL139812 (E.B.T.), Chicago Biomedical Consortium , AHA predoctoral fellowship to S.Z., NU presidential fellowship to S.Z., and Sidney Bess Memorial Fund . Special thanks to Lennell Reynolds, Jr. at the NU imaging facility. D.R.G. is supported by 2R01CA152601-A1 , 1R01CA152799-01A1 , 1R01CA168292-01A1 , 1R01CA214025-01 , the Avon Foundation for Breast Cancer Research, the Lynn Sage Cancer Research Foundation , the Zell Family Foundation, and the Chicago Biomedical Consortium as well the Searle Funds at The Chicago Community Trust . Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",

year = "2019",

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doi = "10.1016/j.cmet.2018.12.004",

language = "English (US)",

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Zhang, S, Weinberg, S, DeBerge, M, Gainullina, A, Schipma, M, Kinchen, JM, Ben-Sahra, I, Gius, DR, Yvan-Charvet, L, Chandel, NS , Schumacker, PT & Thorp, EB 2019, 'Efferocytosis Fuels Requirements of Fatty Acid Oxidation and the Electron Transport Chain to Polarize Macrophages for Tissue Repair', Cell Metabolism, vol. 29, no. 2, pp. 443-456.e5. https://doi.org/10.1016/j.cmet.2018.12.004

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

AU - Kinchen, Jason M.

AU - Ben-Sahra, Issam

AU - Gius, David R.

AU - Yvan-Charvet, Laurent

AU - Chandel, Navdeep S.

AU - Schumacker, Paul T.

AU - Thorp, Edward B.

N1 - Funding Information: Funding support from NHLBI F32HL127958 (M.D.) and HL122309 and HL139812 (E.B.T.), Chicago Biomedical Consortium, AHA predoctoral fellowship to S.Z., NU presidential fellowship to S.Z., and Sidney Bess Memorial Fund. Special thanks to Lennell Reynolds, Jr. at the NU imaging facility. D.R.G. is supported by 2R01CA152601-A1, 1R01CA152799-01A1, 1R01CA168292-01A1, 1R01CA214025-01, the Avon Foundation for Breast Cancer Research, the Lynn Sage Cancer Research Foundation, the Zell Family Foundation, and the Chicago Biomedical Consortium as well the Searle Funds at The Chicago Community Trust. Funding Information: Funding support from NHLBI F32HL127958 (M.D.) and HL122309 and HL139812 (E.B.T.), Chicago Biomedical Consortium , AHA predoctoral fellowship to S.Z., NU presidential fellowship to S.Z., and Sidney Bess Memorial Fund . Special thanks to Lennell Reynolds, Jr. at the NU imaging facility. D.R.G. is supported by 2R01CA152601-A1 , 1R01CA152799-01A1 , 1R01CA168292-01A1 , 1R01CA214025-01 , the Avon Foundation for Breast Cancer Research, the Lynn Sage Cancer Research Foundation , the Zell Family Foundation, and the Chicago Biomedical Consortium as well the Searle Funds at The Chicago Community Trust . Publisher Copyright: © 2018 Elsevier Inc.

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

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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

C2 - 30595481

AN - SCOPUS:85060353127

SN - 1550-4131

VL - 29

SP - 443-456.e5

JO - Cell Metabolism

JF - Cell Metabolism

IS - 2

ER -

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

Abstract

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