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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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MethodSelf-citationPhagocytosis and the actin cytoskeleton
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BackgroundResultInfluentialMacrophage Dysfunction Impairs Resolution of Inflammation in the Wounds of Diabetic Mice
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BackgroundCD47-blocking antibodies restore phagocytosis and prevent atherosclerosis
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BackgroundInnate Immunity and the Failing Heart
Mann, D. L. (2015) · Circulation Research · doi:10.1161/circresaha.116.302317 · Cited by 690
Goerdt, S., & Orfanos, C. E. (1999) · Immunity · doi:10.1016/s1074-7613(00)80014-x · Cited by 678
Human CD14 mediates recognition and phagocytosis of apoptotic cells
Devitt, A., Moffatt, O., Raykundalia, C., Capra, J. D., Simmons, D. L., & Gregory, C. D. (1998) · Nature · doi:10.1038/33169 · Cited by 681
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“Tolerance is accomplished through several distinct mech- anisms, including suppression of inflammatory cytokine produc- tion and release of anti-inflammatory cytokines such as IL-10 and TGF-b (Fadok et al., 1998b; Li and Flavell, 2008; Voll et al., 1997).”
InfluentialResolution of Lung Inflammation by CD44
Teder, P., Vandivier, R. W., Jiang, D., Liang, J., Cohn, L. E., Puré, E., Henson, P. M., & Noble, P. W. (2002) · Science · doi:10.1126/science.1069659 · Cited by 676
Self-citationMartinez, J., Almendinger, J., Oberst, A., Ness, R., Dillon, C. P., Fitzgerald, P., Hengartner, M. O., & Green, D. R. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1113421108 · Cited by 655
RetractedPara-Inflammation in the Aging Retina
Xu, H., Chen, M., & Forrester, J. V. (2009) · Progress in Retinal and Eye Research · doi:10.1016/j.preteyeres.2009.06.001 · Cited by 659
“Uptake of apoptotic cells by phagocytes induces anti-inflammatory responses, including the production of transforming growth factor b (TGF-b) and interleukin-10 production (Fadok et al., 1998a,b; Voll et al., 1997).”
BackgroundStuart, L. M., & Ezekowitz, R. A. B. (2005) · Immunity · doi:10.1016/j.immuni.2005.05.002 · Cited by 667
Adiponectin Promotes Macrophage Polarization toward an Anti-inflammatory Phenotype
Ohashi, K., Parker, J. L., Ouchi, N., Higuchi, A., Vita, J. A., Gokce, N., Pedersen, A. A., Kalthoff, C., Tullin, S., Sams, A., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.088708 · Cited by 646
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“of regulatory pathways in phagocytes and release of anti-inflammatory cytokines (1, 2).”
BackgroundFadok, V., de Cathelineau, A., Daleke, D. L., Henson, P., & Bratton, D. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m003649200 · Cited by 689
Self-citationThe immune system and cardiac repair
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Resolution of Inflammation: What Controls Its Onset?
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“Early data from Kunkel’s group showed a suppressive effect of PGE2 on macrophage TNF-α and IL-1β production (242, 243), and this has been confirmed by other investigators (238).”
BackgroundResultEngulfment of apoptotic cells: signals for a good meal
Ravichandran, K. S., & Lorenz, U. M. (2007) · Nature reviews. Immunology · doi:10.1038/nri2214 · Cited by 663
Godson, C., Mitchell, S., Harvey, K., Petasis, N. A., Hogg, N., & Brady, H. R. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.4.1663 · Cited by 638
Role of innate and adaptive immune mechanisms in cardiac injury and repair
Epelman, S., Liu, P. P., & Mann, D. L. (2015) · Nature reviews. Immunology · doi:10.1038/nri3800 · Cited by 663
Kazama, H., Ricci, J.-E., Herndon, J. M., Hoppe, G., Green, D. R., & Ferguson, T. A. (2008) · Immunity · doi:10.1016/j.immuni.2008.05.013 · Cited by 627
“Although these mediators can stimulate immunity, apoptotic cells can inhibit inflammatory and immunological responses driven by macrophages and DCs (Fadok et al., 1998).”
BackgroundInfluentialScientific and Medical Aspects of Ozone Therapy. State of the Art
Bocci, V. A. (2006) · Archives of Medical Research · doi:10.1016/j.arcmed.2005.08.006 · Cited by 676
“As might be expected, two biological studies (40,41) have shown the possibility of controlling a chronic oxidative stress (33) and of activating regulatory T cells for downregulating a chronic inflammation.”
BackgroundTissue-specific macrophages: how they develop and choreograph tissue biology
Mass, E., Nimmerjahn, F., Kierdorf, K., & Schlitzer, A. (2023) · Nature Reviews Immunology · doi:10.1038/s41577-023-00848-y · Cited by 621
Ellis, S., Lin, E. J., & Tartar, D. (2018) · Current Dermatology Reports · doi:10.1007/s13671-018-0234-9 · Cited by 625
Macrophage activation by endogenous danger signals
Zhang, X., & Mosser, D. (2007) · The Journal of Pathology · doi:10.1002/path.2284 · Cited by 629
“GCs have been known to promote macrophage phagocytosis of apoptotic neutrophils [107], thereby inhibiting the release of pro-inflammatory cytokines [108].”
BackgroundFaria, A. M. C., & Weiner, H. L. (2005) · Immunological Reviews · doi:10.1111/j.0105-2896.2005.00280.x · Cited by 601
“Thus, two classes of apoptosis-related events in the gut mucosa may contribute to the generation of an immunosuppressive milieu: apoptosis of T cells (61) and clearance of apoptotic cells by macrophages (65) and DCs (64).”
BackgroundJanus-faced microglia: beneficial and detrimental consequences of microglial phagocytosis
Sierra, A., Abiega, O., Shahraz, A., & Neumann, H. (2013) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2013.00006 · Cited by 574
“Over the past 20 years, it has been made clear that the phagocytosis of apoptotic cells is largely anti-inflammatory (Stern et al., 1996; Voll et al., 1997; Fadok et al., 1998).”
BackgroundDiverse macrophage populations mediate acute lung inflammation and resolution
Aggarwal, N. R., King, L. S., & D’Alessio, F. R. (2014) · American Journal of Physiology-Lung Cellular and Molecular Physiology · doi:10.1152/ajplung.00341.2013 · Cited by 595
“AEC, alveolar epithelial cell; CCL2, chemokine (C-C motif) ligand 2; CCR2, chemokine (C-C motif) receptor 2; GM-CSF, granulocyte macrophage colony-stimulating factor; IFN-␥, interferon-␥; IL, interleukin; IL-1ra, interleukin 1 receptor antagonist; iNOS, inducible nitric oxide synthase; IRF, interferon regulator factor…”
InfluentialInhibition of apoptosis induced by ischemia-reperfusion prevents inflammation
Daemen, M. A. R. C., Veer, C. V. ′., Denecker, G., Heemskerk, V. H., Wolfs, T. G. A. M., Clauss, M. A., Vandenabeele, P., & Buurman, W. A. (1999) · Journal of Clinical Investigation · doi:10.1172/jci6974 · Cited by 565
“which states that apoptosis represents a physiological mode of cell deletion allowing disposal of superfluous cells with minimal tissue reaction, or even with active restraining of inflammation (5).”
BackgroundBeginnings of a Good Apoptotic Meal: The Find-Me and Eat-Me Signaling Pathways
Ravichandran, K. S. (2011) · Immunity · doi:10.1016/j.immuni.2011.09.004 · Cited by 559
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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