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Efferocytosis induces macrophage proliferation to help resolve tissue injury
Open accessAbstract
Apoptotic cell clearance by macrophages (efferocytosis) promotes resolution signaling pathways, which can be triggered by molecules derived from the phagolysosomal degradation of apoptotic cells. We show here that nucleotides derived from the hydrolysis of apoptotic cell DNA by phagolysosomal DNase2a activate a DNA-PKcs-mTORC2/Rictor pathway that increases Myc to promote non-inflammatory macrophage proliferation. Efferocytosis-induced proliferation expands the pool of resolving macrophages in vitro and in mice, including zymosan-induced peritonitis, dexamethasone-induced thymocyte apoptosis, and atherosclerosis regression. In the dexamethasone-thymus model, hematopoietic Rictor deletion blocked efferocytosing macrophage proliferation, apoptotic cell clearance, and tissue resolution. In atherosclerosis regression, silencing macrophage Rictor or DNase2a blocked efferocyte proliferation, apoptotic cell clearance, and plaque stabilization. In view of previous work showing that other types of apoptotic cell cargo can promote resolution in individual efferocytosing macrophages, the findings here suggest that signaling-triggered apoptotic cell-derived nucleotides can amplify this benefit by increasing the number of these macrophages.
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“This expands the pool of reparative macrophages, enhancing their capacity for continual apoptotic cell clearance and tissue resolution, and may underlie the sustained reparative capacity exhibited by MerTK+ macrophages (46).”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [46]
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“Mechanistically, this approach can harness pathways such as EIMP, which stabilizes a reparative phenotype via the DNase2a-DNA-PKcs-mTORC2-Myc axis (46).”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [46]
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“This aligns with previous research suggesting a role for lipid metabolism in TAM-mediated efferocytosis.”
From Macrophage efferocytosis mediated by the TP63-RAC2 pathway promotes immunosuppressive remodeling in esophageal cancer (2026) · cites this paper as [16]
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“Complementing this rapid functional rewiring, efferocytosis itself can trigger macrophage proliferation through a defined DNase2a–DNA-PKcs–mTORC2–Myc pathway — a process termed efferocytosis-induced macrophage proliferation (EIMP).”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [46]
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Metadata
- Authors
- Gerlach, B. D., Ampomah, P. B., Yurdagul, A., Liu, C., Lauring, M. C., Wang, X., Kasikara, C., Kong, N., Shi, J., Tao, W., & Tabas, I.
- Affiliations
- Columbia University Irving Medical Center (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Tabas, Ira
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2021-12
- Volume
- 33
- Issue
- 12
- Pages
- 2445-2463.e8
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC8665147
- OpenAlex
- W3212263362
- Cited by
- 360
- References
- 71
- Citations by year
- 2026: 79 · 2025: 105 · 2024: 91 · 2023: 53 · 2022: 31 · 2021: 1
- FWCI
- 16.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 371 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R35 HL145228, K99 HL145131, P20 GM121307, P30CA013696, R01 HL087123, R01 HL127464, S10OD020056, S10RR025686, S10RR027050, T32 5T32HL007343-42)
- American Heart Association (20POST35210962)
- Harvard Medical School (122829)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- efferocytosis, macrophage proliferation, DNA-PKcs, mTORC2, Rictor, c-Myc, atherosclerosis regression, plaque stabilization, peritonitis, thymocyte apoptosis, phagolysosomes
- MeSH terms
- Animals, Macrophages, Mice, Inbred C57BL, Phagocytosis, Apoptosis, Cell Proliferation, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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