The DOI matches its Crossref record; 70 of the 70 references it cites were found in a registry or an index.
Macrophage Metabolism of Apoptotic Cell-Derived Arginine Promotes Continual Efferocytosis and Resolution of Injury
Open accessAbstract
Continual efferocytic clearance of apoptotic cells (ACs) by macrophages prevents necrosis and promotes injury resolution. How continual efferocytosis is promoted is not clear. Here, we show that the process is optimized by linking the metabolism of engulfed cargo from initial efferocytic events to subsequent rounds. We found that continual efferocytosis is enhanced by the metabolism of AC-derived arginine and ornithine to putrescine by macrophage arginase 1 (Arg1) and ornithine decarboxylase (ODC). Putrescine augments HuR-mediated stabilization of the mRNA encoding the GTP-exchange factor Dbl, which activates actin-regulating Rac1 to facilitate subsequent rounds of AC internalization. Inhibition of any step along this pathway after first-AC uptake suppresses second-AC internalization, whereas putrescine addition rescues this defect. Mice lacking myeloid Arg1 or ODC have defects in efferocytosis in vivo and in atherosclerosis regression, while treatment with putrescine promotes atherosclerosis resolution. Thus, macrophage metabolism of AC-derived metabolites allows for optimal continual efferocytosis and resolution of injury.
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“Earlier studies identified a conserved metabolic circuit essential for the high efferocytic activity of reparative macrophages. This pathway involves the conversion of apoptotic cell-derived arginine and ornithine into putrescine via arginase 1 (Arg1) and ornithine decarboxylase (ODC).”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [51]
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“Thus, metabolic processing of one apoptotic cell augments the capacity to clear the next, providing a fundamental mechanism for injury resolution.”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [51]
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“Putrescine, in turn, fuels a self-reinforcing cycle that promotes continual efferocytosis—the sequential clearance of apoptotic corpses—by enhancing Rac1-dependent phagosome internalization (51).”
From Macrophage duality in liver diseases: heterogeneity, plasticity, and the quest for precision therapeutics (2026) · cites this paper as [51]
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Macrophages in Tissue Repair, Regeneration, and Fibrosis
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Alternative Activation of Macrophages: An Immunologic Functional Perspective
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Self-citationMetabolism via Arginase or Nitric Oxide Synthase: Two Competing Arginine Pathways in Macrophages
Rath, M., ller, I. M. ⁄., Kropf, P., Closs, E. I., & Munder, M. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00532 · Cited by 1,332
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Phagocytosis of apoptotic cells in homeostasis
Arandjelovic, S., & Ravichandran, K. S. (2015) · Nature Immunology · doi:10.1038/ni.3253 · Cited by 959
Arginase-1–Expressing Macrophages Suppress Th2 Cytokine–Driven Inflammation and Fibrosis
Pesce, J. T., Ramalingam, T. R., Mentink-Kane, M. M., Wilson, M. S., El Kasmi, K. C., Smith, A. M., Thompson, R. W., Cheever, A. W., Murray, P. J., & Wynn, T. A. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000371 · Cited by 816
A-González, N., Bensinger, S. J., Hong, C., Beceiro, S., Bradley, M. N., Zelcer, N., Deniz, J. M., Ramírez, C. M., Díaz, M., Gallardo, G., et al. (2009) · Immunity · doi:10.1016/j.immuni.2009.06.018 · Cited by 703
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Self-citationDrugging the efferocytosis process: concepts and opportunities
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Metadata
- Authors
- Yurdagul, A., Subramanian, M., Wang, X., Crown, S. B., Ilkayeva, O. R., Darville, L., Kolluru, G. K., Rymond, C. C., Gerlach, B. D., Zheng, Z., Kuriakose, G., Kevil, C. G., Koomen, J. M., Cleveland, J. L., Muoio, D. M., & Tabas, I.
- Affiliations
- Columbia University Irving Medical Center (US)
- Institute of Genomics and Integrative Biology (IN)
- Columbia University (US)
- Duke University (US)
- Moffitt Cancer Center (US)
- Louisiana State University Health Sciences Center Shreveport (US)
- Corresponding author
- Yurdagul, Arif
- Tabas, Ira
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2020-03
- Volume
- 31
- Issue
- 3
- Pages
- 518-533.e10
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC7173557
- OpenAlex
- W3004079464
- Cited by
- 525
- References
- 70
- Citations by year
- 2026: 112 · 2025: 101 · 2024: 97 · 2023: 76 · 2022: 61 · 2021: 57 · 2020: 21
- FWCI
- 18.48
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- 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 › Biochemistry, Genetics and Molecular Biology › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- efferocytosis, macrophage metabolism, arginine metabolism, ornithine, putrescine, arginase-1, ornithine decarboxylase, Rac1, actin cytoskeleton, atherosclerosis regression
- MeSH terms
- ELAV-Like Protein 1, Animals, Arginase, Arginine, Humans, Macrophages, Male, Mice, Inbred C57BL, Ornithine Decarboxylase, Phagocytosis, Putrescine, RNA, Messenger, Apoptosis, Gene Deletion, Jurkat Cells, Guanine Nucleotide Exchange Factors, rac1 GTP-Binding Protein, RNA Stability, Myeloid Cells
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