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Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.
Open accessAbstract
Apoptosis in vivo is followed almost inevitably by rapid uptake into adjacent phagocytic cells, a critical process in tissue remodeling, regulation of the immune response, or resolution of inflammation. Phagocytosis of apoptotic cells by macrophages has been suggested to be a quiet process that does not lead to production of inflammatory mediators. Here we show that phagocytosis of apoptotic neutrophils (in contrast to immunoglobulin G-opsonized apoptotic cells) actively inhibited the production of interleukin (IL)-1beta, IL-8, IL-10, granulocyte macrophage colony-stimulating factor, and tumor necrosis factor-alpha, as well as leukotriene C4 and thromboxane B2, by human monocyte-derived macrophages. In contrast, production of transforming growth factor (TGF)-beta1, prostaglandin E2, and platelet-activating factor (PAF) was increased. The latter appeared to be involved in the inhibition of proinflammatory cytokine production because addition of exogenous TGF-beta1, prostaglandin E2, or PAF resulted in inhibition of lipopolysaccharide-stimulated cytokine production. Furthermore, anti-TGF-beta antibody, indomethacin, or PAF receptor antagonists restored cytokine production in lipopolysaccharide-stimulated macrophages that had phagocytosed apoptotic cells. These results suggest that binding and/or phagocytosis of apoptotic cells induces active antiinflammatory or suppressive properties in human macrophages. Therefore, it is likely that resolution of inflammation depends not only on the removal of apoptotic cells but on active suppression of inflammatory mediator production. Disorders in either could result in chronic inflammatory diseases.
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“Some of the more common cytokines used in biomaterial‐based research involves the proinflammatory IFN‐γ or IL‐4, which are important effectors in steering the macrophage phenotypes.[ 103 , 232 , 233 , 234 ]”
From Unraveling and Harnessing the Immune Response at the Cell–Biomaterial Interface for Tissue Engineering Purposes (2024) · cites this paper as [234]
In the citing paper
“Interestingly, phagocytosis of neutrophils is also a central element to induce the phenotype switch of macrophages from pro-inflammatory M1 to a reparative M2 phenotype [73].”
From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [73]
In the citing paper
“2-AG increases the number of phagocytosing macrophages, which leads to increased production of anti-inflammatory cytokines, e.g., TGF-β1 and decreased output of pro-inflammatory cytokines, e.g., TNF-α by macrophages [73].”
From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [73]
In the citing paper
“Their apoptosis and engulfment by macrophages (efferocytosis) provides a key signal to the local immune milieu, including macrophages, to transition to an anti-inflammatory, pro-repair state”
From Immunology of Wound Healing (2018) · cites this paper as [47]
In the citing paper
“In physiologic wound repair, neutrophils undergo apoptosis after carrying out their various functions at the site of injury. Local macrophage uptake of apoptotic neutrophils then triggers a transition out of inflammatory phase [47–49].”
From Immunology of Wound Healing (2018) · cites this paper as [47]
In the citing paper
“Macrophages in the wound site are responsible for phagocytosis of apoptotic neutrophils, a process known as efferocytosis [73••]. This action itself induces macrophages to transition from a pro-inflammatory phenotype, to an anti-inflammatory phenotype”
From Immunology of Wound Healing (2018) · cites this paper as [47]
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“, transforming growth factor (TGF)- 1] (23, 42).”
Golpon, H. A., Fadok, V. A., Tarasevičienė-Stewart, L., Scerbavicius, R., Sauer, C., Welte, T., Henson, P. M., & Voelkel, N. F. (2004) · The FASEB Journal · doi:10.1096/fj.04-1853fje · Cited by 217
Self-citationMechanisms of inflammation in gout
Dalbeth, N., & Haskard, D. O. (2005) · Lara D. Veeken · doi:10.1093/rheumatology/keh640 · Cited by 211
“Phagocytosis of apoptotic neutrophils by macrophages also promotes the production of anti-inflammatory factors, including transforming growth factor (TGF)- [64].”
BackgroundErythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage
Chang, C.-F., Goods, B. A., Askenase, M. H., Hammond, M. D., Renfroe, S. C., Steinschneider, A. F., Landreneau, M. J., Ai, Y., Beatty, H. E., da Costa, L. H. A., et al. (2017) · Journal of Clinical Investigation · doi:10.1172/jci95612 · Cited by 217
“The culture was UV irradiated for 10 minutes to induce apoptosis as previously described (97).”
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Hoffmann, P. R., Kench, J. A., Vondracek, A., Kruk, E. R., Daleke, D. L., Jordan, M. B., Marrack, P., Henson, P. M., & Fadok, V. A. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.3.1393 · Cited by 210
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Apoptosis in rheumatoid arthritis
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Surfactant Protein A Enhances Alveolar Macrophage Phagocytosis of Apoptotic Neutrophils
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“For example, it has been shown that their phagocytosis inhibits pro-inlammatory cytokines production by macrophages, while increasing anti-inlammatory factors release [33].”
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“TGFbs have anti-inflammatory functions in the immune system (Crowe et al., 2000; Fadok et al., 1998) and are acutely neuroprotective at the time of stroke (Pang et al., 2001; Ruocco et al., 1999).”
BackgroundA Perspective on Mammalian Caspases as Positive and Negative Regulators of Inflammation
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Apoptosis and inflammation in renal reperfusion injury
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“” Under physiological conditions apoptotic bodies have been reported to be phagocytized without provoking an immune response, apoptotic cells can even actively suppress inflammation (30).”
BackgroundApoptotic Cells and Innate Immune Stimuli Combine to Regulate Macrophage Cytokine Secretion
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“It has recently been shown that ac death may play an important role in the resolution phase of inflammation, switching off production of proinflammatory mediators and stimulating production of anti-inflammatory cytokines such as TGF- from recruited macrophages that have internalized ac (5, 6).”
BackgroundRole of hepatic resident and infiltrating macrophages in liver repair after acute injury
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“Another important function of macrophages is to phagocytose dead cells and cellular debris [6] [7] [8].”
BackgroundTumor-Associated Macrophages in the Cutaneous SCC Microenvironment Are Heterogeneously Activated
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The macrophage in HIV-1 infection: From activation to deactivation?
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Surfactant Proteins A and D Suppress Alveolar Macrophage Phagocytosis via Interaction with SIRPα
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“Phagocytosis assays were performed after pairing: (1)”
Self-citationApoptotic cell recognition receptors and scavenger receptors
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“This signaling ultimately leads to anti-inflammatory cytokine production and secretion (4, 5, 22, 23).”
BackgroundThe role of the bone marrow in neutrophil clearance under homeostatic conditions in the mouse
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The role of apoptosis in acute lung injury
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“Phagocytosis of apoptotic neutrophils inhibits macrophage production of IL-1 , IL-8, IL-10, GM-CSF, and tumor necrosis factor- and increases the production of the anti-inflammatory mediators transforming growth factor (TGF)- 1 and prostaglandin E2 (13, 14).”
BackgroundMediators of the Resolution of the Inflammatory Response
Sugimoto, M. A., Vago, J. P., Perretti, M., & Teixeira, M. M. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.01.007 · Cited by 212
Apoptosis in rheumatoid arthritis
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Metadata
- Authors
- Fadok, V. A., Bratton, D. L., Konowal, A., Freed, P. W., Westcott, J. Y., & Henson, P. M.
- Affiliations
- National Jewish Health (US)
- ORCID
- Henson, P M
- Venue
- Journal of Clinical Investigation
- Published
- 1998-02-15
- Volume
- 101
- Issue
- 4
- Pages
- 890-898
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508637
- OpenAlex
- W2095537212
- Semantic Scholar
- 3e88d8a52759097d481b92ec0d06606afbadafab
- Cited by
- 3,166
- References
- 50
- Citations by year
- 2026: 60 · 2025: 74 · 2024: 91 · 2023: 82 · 2022: 91 · 2021: 129 · 2020: 114 · 2019: 125 · 2018: 106 · 2017: 113 · 2016: 117 · 2015: 109 · 2014: 116 · 2013: 130 · 2012: 133
- FWCI
- 29.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL34303, P01HL034303)
- National Institute of General Medical Sciences (GM48211, R01GM048211)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- phagocytosis of apoptotic cells, macrophages, inflammation resolution, anti-inflammatory macrophages, inflammatory cytokines, TGF-β1, prostaglandin E2, platelet-activating factor, autocrine and paracrine signaling, neutrophil apoptosis, monocyte-derived macrophages, indomethacin, PAF receptor antagonists
- MeSH terms
- Humans, Inflammation, Macrophages, Neutrophils, Phagocytosis, Platelet Activating Factor, Solubility, Thromboxane B2, Dinoprostone, Cytokines, Transforming Growth Factor beta, Apoptosis, Leukotriene C4, Jurkat Cells
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