Cited by 486Phagocytosis and Immune RegulationSirtuins and Resveratrol in MedicineImmune cells in cancer

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

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Zhang, Shuang, Weinberg, Samuel, DeBerge, Matthew, Gainullina, Anastasiia, Schipma, Matthew, Kinchen, Jason M., Ben-Sahra, Issam, Gius, David R. +4 more·2019·Cell Metabolism

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.

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Authors
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.
Affiliations
  • Northwestern University (US)
  • ITMO University (RU)
  • Metabolon (United States) (US)
Corresponding author
Thorp, Edward B.
Venue
Cell Metabolism
Publisher
Elsevier BV
Published
2019-02
Volume
29
Issue
2
Pages
443-456.e5
ISSN
1550-4131 (ISSN-L)
OpenAlex
W2907223756
Cited by
485
References
65
Citations by year
2026: 82 · 2025: 90 · 2024: 84 · 2023: 71 · 2022: 45 · 2021: 62 · 2020: 31 · 2019: 20
FWCI
12.06
Type
journal article
Language
en
Open access
Locations
  • Cell Metabolism (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • NHLBI (F32HL127958, HL122309, HL139812)
  • Chicago Biomedical Consortium
  • Sidney Bess Memorial Fund (2R01CA152601-A1, 1R01CA152799-01A1, 1R01CA168292-01A1, 1R01CA214025-01)
  • Avon Foundation
  • Lynn Sage Cancer Research Foundation
  • Chicago Community Trust
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
  • Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
efferocytosis, macrophage polarization, IL-10, mitochondrial beta-oxidation, electron transport chain, NAD+, SIRT1, PBX1, mitochondrial complex III, wound healing, myocardial injury, cardiac rupture, anti-inflammatory macrophages, tissue repair
MeSH terms
Animals, Electron Transport, Fatty Acids, Humans, Inflammation, Macrophages, Mice, Inbred C57BL, Mitochondria, NAD, Oxidation-Reduction, Wound Healing, Interleukin-10, Jurkat Cells, Mice, Cytophagocytosis

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