The DOI matches its Crossref record; 65 of the 65 references it cites were found in a registry or an index.
Efferocytosis Fuels Requirements of Fatty Acid Oxidation and the Electron Transport Chain to Polarize Macrophages for Tissue Repair
Open accessAbstract
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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“Efferocytosis leads to IL-10 induction in macrophages through signaling pathways activated by apoptotic cell cargo, including fatty acids and tryptophan (30, 40).”
From Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction–associated steatohepatitis (2025) · cites this paper as [40]
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“Among the proresolving molecules known to be induced by efferocytosis is interleukin-10 (IL-10) (30, 40)”
From Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction–associated steatohepatitis (2025) · cites this paper as [40]
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Cites
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“This approach confirmed that apoptotic cells (Annexin V+, PI−) specifically and reproducibly induced macrophages to produce the canonical antiinflammatory cytokine IL-10 (Fadok et al., 1998) (Figures 1D and 1E).”
BackgroundMethodResolution of inflammation: the beginning programs the end
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Oxidative metabolism and PGC-1β attenuate macrophage-mediated inflammation
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“In skeletal cells, SIRT1 controls the transcription of peroxisome proliferator-activated receptor-gamma co-acti-vator-1α (PGC-1α) (Amat et al., 2009), which separately has been linked to IL-10 induction (Morari et al., 2010) and oxidative metabolism in macrophages (Vats et al., 2006).”
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Saraiva, M., Vieira, P., & O’Garra, A. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20190418 · Cited by 1,157
Efferocytosis in health and disease
Doran, A. C., Yurdagul, A., & Tabas, I. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-019-0240-6 · Cited by 1,066
The role of macrophages in the resolution of inflammation
Watanabe, S., Alexander, M., Misharin, A. V., & Budinger, G. R. S. (2019) · Journal of Clinical Investigation · doi:10.1172/jci124615 · Cited by 925
The clearance of dead cells by efferocytosis
Boada-Romero, E., Martinez, J., Heckmann, B. L., & Green, D. R. (2020) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-0232-1 · Cited by 924
Obesity, Hypertension, and Cardiac Dysfunction
Mouton, A. J., Li, X., Hall, M. E., & Hall, J. E. (2020) · Circulation Research · doi:10.1161/circresaha.119.312321 · Cited by 561
Metadata
- 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.
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2019-02
- Volume
- 29
- Issue
- 2
- Pages
- 443-456.e5
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC6471613
- 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
- bronze
- doi.org
- Licence
- 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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