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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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Phagocytosis Triggers Macrophage Release of Fas Ligand and Induces Apoptosis of Bystander Leukocytes
Brown, S. B., & Savill, J. (1999) · The Journal of Immunology · doi:10.4049/jimmunol.162.1.480 · Cited by 276
“Indeed, our data support reports that Mf-ingesting apoptotic cells may generate antiinflammatory responses such as IL-10 release (33, 34), because M f-derived FasL might be expected to promote “antiinflammatory” elimination of other leukocytes, including eosinophils, monocytes, and activated T cells (8, 11, 13).”
Stuart, L. M., Lucas, M., Simpson, C., Lamb, J. R., Savill, J., & Lacy‐Hulbert, A. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.168.4.1627 · Cited by 275
LC3-Associated Phagocytosis and Inflammation
Heckmann, B. L., Boada-Romero, E., Cunha, L. D., Magne, J., & Green, D. R. (2017) · Journal of Molecular Biology · doi:10.1016/j.jmb.2017.08.012 · Cited by 276
Nair, M. G., Du, Y., Perrigoue, J., Zaph, C., Taylor, J. J., Goldschmidt, M. H., Swain, G. P., Yancopoulos, G. D., Valenzuela, D. M., Murphy, A. J., et al. (2009) · The Journal of Experimental Medicine · doi:10.1084/jem.20082048 · Cited by 278
Bird, T. G., Müller, M., Boulter, L., Vincent, D. F., Ridgway, R. A., Lopez-Guadamillas, E., Lu, W.-Y., Jamieson, T., Govaere, O., Campbell, A. D., et al. (2018) · Science Translational Medicine · doi:10.1126/scitranslmed.aan1230 · Cited by 261
“Macrophages are a known source of TGF ligands, particularly in the context of tissue injury (32).”
BackgroundMesenchymal stromal cell apoptosis is required for their therapeutic function
Pang, S. H. M., D’Rozario, J., Mendonca, S., Bhuvan, T., Payne, N. L., Zheng, D., Hisana, A., Wallis, G., Barugahare, A., Powell, D., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-26834-3 · Cited by 245
LC3-associated phagocytosis at a glance
Heckmann, B. L., & Green, D. R. (2019) · Journal of Cell Science · doi:10.1242/jcs.222984 · Cited by 280
“This homeostatic process does not normally elicit an immune response; it is therefore regarded as immunologically silent and is characterized by the inhibition of pro-inflammatory cytokines, including IL-6, IL-1β and CXCL-10 (Fadok et al., 1998; Kim et al., 2004; Martin et al., 2014; Mukundan et al., 2009; Xiao et al.…”
BackgroundLiver fibrosis: cellular mechanisms of progression and resolution
Henderson, N. C., & Iredale, J. P. (2007) · Clinical Science · doi:10.1042/cs20060242 · Cited by 270
Païdassi, H., Tacnet‐Delorme, P., Garlatti, V., Darnault, C., Ghebrehiwet, B., Gaboriaud, C., Arlaud, G. J., & Frachet, P. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.4.2329 · Cited by 283
Clearance of apoptotic and necrotic cells and its immunological consequences
Krysko, D. V., D’Herde, K., & Vandenabeele, P. (2006) · Apoptosis · doi:10.1007/s10495-006-9527-8 · Cited by 316
“Several groups proposed that phagocytosis of apoptotic cells induces an anti-inflammatory reaction by leading to production of transforming growth factor β (TGF-β), prostaglandin E2 and platelet activating factor (PAF) [103, 104].”
BackgroundPhotodynamic therapy: illuminating the road from cell death towards anti-tumour immunity
Garg, A. D., Nowis, D., Golab, J., & Agostinis, P. (2010) · Apoptosis · doi:10.1007/s10495-010-0479-7 · Cited by 297
Inflammation-associated cancer: NF-κB is the lynchpin
Li, Q., Withoff, S., & Verma, I. M. (2005) · Trends in Immunology · doi:10.1016/j.it.2005.04.003 · Cited by 270
Monocytes and Macrophages in COVID-19
Knoll, R., Schultze, J. L., & Schulte-Schrepping, J. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.720109 · Cited by 279
Concepts of tissue injury and cell death in inflammation: a historical perspective
Wallach, D., Kang, T., & Kovalenko, A. (2013) · Nature reviews. Immunology · doi:10.1038/nri3561 · Cited by 266
Pathogenesis and management issues for non-alcoholic fatty liver disease
Duvnjak, M. (2007) · World Journal of Gastroenterology · doi:10.3748/wjg.v13.i34.4539 · Cited by 266
Functional Role of Monocytes and Macrophages for the Inflammatory Response in Acute Liver Injury
Zimmermann, H. W., Trautwein, C., & Tacke, F. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00056 · Cited by 272
“Phagocytosis of apoptotic neutrophil remnants by macrophages also attenuates production of proinflammatory cytokines like IL-1β and IL-8 in a TGF-β1, PGE2, and platelet-activating-factor (PAF) dependent fashion (Fadok et al., 1998).”
BackgroundOral tolerance, food allergy, and immunotherapy: Implications for future treatment
Burks, A. W., Laubach, S. S., & Jones, S. M. (2008) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2008.02.037 · Cited by 261
Oral Tolerance: Therapeutic Implications for Autoimmune Diseases
Faria, A. M. C., & Weiner, H. L. (2006) · Journal of Immunology Research · doi:10.1080/17402520600876804 · Cited by 260
“Keywords: Oral tolerance, nasal tolerance, autoimmune diseases, bystander suppression”
BackgroundThe role of eosinophils and neutrophils in inflammation
Sampson, A. P. (2000) · Clinical & Experimental Allergy · doi:10.1046/j.1365-2222.2000.00092.x · Cited by 259
Kim, Y. S., Kim, S. S., Cho, J. J., Choi, D. H., Hwang, O., Shin, D. H., Chun, H. S., Beal, M. F., & Joh, T. H. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.4346-04.2005 · Cited by 256
“The engulfment of apoptotic cells elicit important consequences for immune responses , such as induction of anti-inflammatory mediators (Voll et al., 1997; Fadok et al., 1998; Huynh et al., 2002).”
BackgroundClancy, R. M., Kapur, R. P., Molad, Y., Askanase, A., & Buyon, J. P. (2004) · Arthritis & Rheumatism · doi:10.1002/art.11430 · Cited by 258
Kuang, D., Wu, Y., Chen, N., Chéng, J., Zhuang, S., & Zheng, L. (2007) · Blood · doi:10.1182/blood-2007-01-068031 · Cited by 262
Partial Epithelial-to-Mesenchymal Transition and Other New Mechanisms of Kidney Fibrosis
Lovisa, S., Zeisberg, M., & Kalluri, R. (2016) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2016.06.004 · Cited by 263
“Macrophage-secreted TGF-b is considered to be the major mediator of the pro-fibrotic effect [109], but a recent study has reported that this may not be the case because conditional deletion of TGF-b in macrophages does not affect the degree of kidney fibrosis in either ischemic or obstructive fibrosis models [110].”
BackgroundDeath-defying immunity: do apoptotic cells influence antigen processing and presentation?
Albert, M. L. (2004) · Nature reviews. Immunology · doi:10.1038/nri11308 · Cited by 267
The role of the purinergic P2X7 receptor in inflammation
Lister, M. F., Sharkey, J., Sawatzky, D. A., Hodgkiss, J. P., Davidson, D. J., Rossi, A. G., & Finlayson, K. (2007) · Journal of Inflammation · doi:10.1186/1476-9255-4-5 · Cited by 260
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Szondy, Z., Sarang, Z., Molnár, P., Németh, T., Piacentini, M., Mastroberardino, P. G., Falasca, L., Aeschlimann, D. P., Kovács, J., Kiss, I., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0832466100 · Cited by 251
Cues for apoptotic cell engulfment: eat-me, don't eat-me and come-get-me signals
Grimsley‐Myers, C. M. (2003) · Trends in Cell Biology · doi:10.1016/j.tcb.2003.10.004 · Cited by 248
Role of apoptosis in the pathogenesis of acute renal failure
Bonegio, R. G. B., & Lieberthal, W. (2002) · Current Opinion in Nephrology & Hypertension · doi:10.1097/00041552-200205000-00006 · Cited by 251
Human myeloperoxidase in innate and acquired immunity
Arnhold, J., & Flemmig, J. (2010) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2010.04.008 · Cited by 254
Definition of human autoimmunity — autoantibodies versus autoimmune disease
Lleò, A., Invernizzi, P., Gao, B., Podda, M., & Gershwin, M. E. (2009) · Autoimmunity Reviews · doi:10.1016/j.autrev.2009.12.002 · Cited by 249
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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