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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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Chen, W., & Konkel, J. E. (2009) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjp004 · Cited by 154
The exercise IL-6 enigma in cancer
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Cytochrome P450 4F subfamily: At the crossroads of eicosanoid and drug metabolism
Kalsotra, A., & Strobel, H. W. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2006.03.008 · Cited by 145
Intravenous apoptotic spleen cell infusion induces a TGF-β-dependent regulatory T-cell expansion
Kleinclauss, F., Perruche, S., Masson, E., Bittencourt, M. D. C., Biichlé, S., Remy-Martin, J.-P., Ferrand, C., Martin, M., Bittard, H., Chalopin, J. M., et al. (2005) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4401699 · Cited by 146
“Macrophages were thus sufficient to uptake apoptotic cells and possibly released TGF-b after phagocytosis.(19,26) Macrophages were more efficient than immature DC to uptake apoptotic cells(43) and were found in higher numbers than DC in the spleen.”
BackgroundPPARγ‐dependent regulation of human macrophages in phagocytosis of apoptotic cells
Majai, G. E., Sarang, Z., Csomós, K., Zahuczky, G., & Fésüs, L. (2007) · European Journal of Immunology · doi:10.1002/eji.200636398 · Cited by 151
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“Efferocytosis also upregulates prostaglandin E2 (PGE2) and impairs FcRmediated phagocytosis [54, 56], and intratracheal instillation of apoptotic cells enhances the resolution of LPSinduced acute pulmonary inflammation [57].”
BackgroundSadowska, J. M., & Ginebra, M.-P. (2020) · Journal of Materials Chemistry B · doi:10.1039/d0tb01379j · Cited by 144
Lindhorst, A., Raulien, N., Wieghofer, P., Eilers, J., Rossi, F. M. V., Bechmann, I., & Gericke, M. T. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03872-9 · Cited by 163
Apoptosis in cancer—implications for therapy
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Macrophage and Retinal Pigment Epithelium Phagocytosis
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Monocyte and Macrophage Abnormalities in Systemic Lupus Erythematosus
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“…receptor is well documented and deficiency of some of these components is associated with the development of autoimmune manifestations in mice (A-Gonzalez et al. 2009; Devitt et al. 1998; Fadok et al. 1992, 1998b; Scott et al. 2001), although their role on human SLE is less clear at this time.”
BackgroundInfluentialPreclinical murine tumor models: A structural and functional perspective
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“Of note, the secretion of TGFb by macrophages increases after ingestion of dying cells (Fadok et al., 1998).”
BackgroundC1q and MBL, components of the innate immune system, influence monocyte cytokine expression
Fraser, D. A., Bohlson, S. S., Jasinskiene, N., Rawal, N., Palmarini, G., Ruiz, S., Rochford, R. A., & Tenner, A. J. (2006) · Journal of Leukocyte Biology · doi:10.1189/jlb.1105683 · Cited by 143
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“We did not observe manifestations of antiphospholipid syndrome similar to those reported for anticardiolipin antibodies with reactivity against h2-glycoprotein I (47, 49, 50).”
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“These apoptotic neutrophils are removed by M2 macrophages via phagocytosis, resulting in the restoration and maintenance of anti-inflammatory and immune-tolerogenic milieu.(29) On the contrary, under pathological states when there is a wider extent of injury/ wound and PMN infiltration, which together with a prolonged…”
BackgroundRegulation of Innate and Adaptive Immunity by TGFβ
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Macrophage metabolism in atherosclerosis
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“ROS and aldehydes, a secondary product of the oxidation reaction, can activate HSCs, which shift into myofibroblasts in terms of phenotype with collagen-producing properties, subsequently leading to liver fibrosis via producing extracellular matrix proteins such as collagen I (COL I), COL III, COL IV, fibronectin, and…”
BackgroundMagnus, T., Chan, A., Grauer, O. M., Toyka, K. V., & Gold, R. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.167.9.5004 · Cited by 141
“A significant decrease was also observed for IL-12 production (Fig.”
BackgroundInfluentialPathophysiology of neuropathic lysosomal storage disorders
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“disagreement with the normal response of macrophages in the clearance of apoptotic cells, which is anti-inflammatory in nature (Fadok et al. 1998).”
BackgroundResultNeutrophils, IL-1β, and gout: is there a link?
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“Ingestion of apoptotic neutrophils results in the release of the anti-inflammatory cytokine TGF-β by these cells [102].”
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“These effects collectively promote inflammatory (M1) to wound healing/profibrotic (M2) macrophage phenotype transition and initiate the resolution of inflammation [86-91].”
BackgroundMultiple facets of macrophages in renal injury
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“As these studies show a large number of receptors can potentially be involved in apoptotic cell uptake but the recently identified phosphatidylserine receptor (PSR) plays a significant role in development of the anti-inflammatory phenotype [55].”
BackgroundEtiopathogenesis of systemic lupus erythematosus
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“Expression of IL-10 message and TGF 1 synthesis by macrophages correlates with the amount of PS molecules on the parasite surface: TGF 1 secretion defines NO production PS recognition triggers IL-10 message and TGF 1 production by macrophages (6, 13) and dendritic cells (14), leading to an antiinflammatory response.”
BackgroundThe consequences of apoptosis in autoimmunity
Lleò, A., Selmi, C. F., Invernizzi, P., Podda, M., & Gershwin, M. E. (2008) · Journal of Autoimmunity · doi:10.1016/j.jaut.2008.04.009 · Cited by 140
“Indeed, the most significant difference between phagocytosis of pathogens and the uptake of apoptotic cells has been traditionally considered the immune response: a pro-inflammatory reaction is often induced after phagocytosis whereas the secretion of antiinflammatory cytokines follows the engulfment of apoptotic cell…”
BackgroundHeras, K. L., García-Orue, I., Rancan, F., Igartúa, M., Santos‐Vizcaíno, E., & Hernández, R. M. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2024.115342 · Cited by 143
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“Moreover, while undergoing apoptosis, PMNs express on their surface a unique repertoire of markers, including phosphatidylserine, which enhances their phagocytosis (12, 13) and prevents the release of proinflammatory mediators from macrophages in favor of antiinflammatory cytokines such as transforming growth factor-β…”
Background
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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