Clearance of apoptotic and necrotic cells and its immunological consequences
Abstract
The ultimate and most favorable fate of almost all dying cells is engulfment by neighboring or specialized cells. Efficient clearance of cells undergoing apoptotic death is crucial for normal tissue homeostasis and for the modulation of immune responses. Engulfment of apoptotic cells is finely regulated by a highly redundant system of receptors and bridging molecules on phagocytic cells that detect molecules specific for dying cells. Recognition of necrotic cells by phagocytes is less well understood than recognition of apoptotic cells, but an increasing number of recent studies, which are discussed here, are highlighting its importance. New observations indicate that the interaction of macrophages with dying cells initiates internalization of the apoptotic or necrotic targets, and that internalization can be preceded by "zipper"-like and macropinocytotic mechanisms, respectively. We emphasize that clearance of dying cells is an important fundamental process serving multiple functions in the regulation of normal tissue turnover and homeostasis, and is not just simple anti- or pro-inflammatory responses. Here we review recent findings on genetic pathways participating in apoptotic cell clearance, mechanisms of internalization, and molecules involved in engulfment of apoptotic versus necrotic cells, as well as their immunological consequences and relationships to disease pathogenesis.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Clearance of dying cells is a highly complex and orchestrated process involving multiple ligands, bridging molecules, and receptors with high redundancy.
“However, clearance of dying cells is a highly complex and orchestrated process involving interactions between multiple ligands on dying cells, bridging molecules, and receptors on phagocytes with a high degree of redundancy32.”
From Hepatocyte mitochondria-derived danger signals directly activate hepatic stellate cells and drive progression of liver fibrosis (2020) · cites this paper as [32]
Cites
Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3
Alexopoulou, L., Holt, A. C., Medzhitov, R., & Flavell, R. A. (2001) · Nature · doi:10.1038/35099560 · Cited by 6,129 · see citing works
Release of chromatin protein HMGB1 by necrotic cells triggers inflammation
Scaffidi, P., Misteli, T., & Bianchi, M. E. (2002) · Nature · doi:10.1038/nature00858 · Cited by 4,221 · see citing works
Fadok, V. A., Bratton, D. L., Konowal, A., Freed, P. W., Westcott, J. Y., & Henson, P. M. (1998) · Journal of Clinical Investigation · doi:10.1172/jci1112 · Cited by 3,166 · cited 3× · see citing works
“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].”
BackgroundIdentification of a factor that links apoptotic cells to phagocytes
Hanayama, R., Tanaka, M., Miwa, K., Shinohara, A., Iwamatsu, A., & Nagata, S. (2002) · Nature · doi:10.1038/417182a · Cited by 1,401 · see citing works
mRNA is an endogenous ligand for toll-like receptor 3
Karikó, K., Ni, H., Capodici, J., Lamphier, M., & Weissman, D. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m310175200 · Cited by 1,062 · see citing works
Autoimmune Disease and Impaired Uptake of Apoptotic Cells in MFG-E8-Deficient Mice
Hanayama, R., Tanaka, M., Miyasaka, K., Aozasa, K., Koike, M., Uchiyama, Y., & Nagata, S. (2004) · Science · doi:10.1126/science.1094359 · Cited by 992 · see citing works
Hodge, S., Hodge, G., Scicchitano, R., Reynolds, P. N., & Holmes, M. (2003) · Immunology & Cell Biology · doi:10.1046/j.1440-1711.2003.t01-1-01170.x · Cited by 440 · cited 1× · see citing works
“Defective or inefficient clearance of dying cells may contribute to persistence of inflammation and excessive tissue injury, as well as several different human pathologies, including systemic lupus erythematosus (SLE) [182–184], cystic fibrosis [185], chronic obstructive pulmonary disease [186] and diabetes [187].”
BackgroundApoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment
Brown, S., Heinisch, I., Ross, E., Shaw, K., Buckley, C. D., & Savill, J. (2002) · Nature · doi:10.1038/nature00811 · Cited by 390 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Immunogenic cell death and DAMPs in cancer therapy
Krysko, D. V., Garg, A. D., Kaczmarek, A., Krysko, O., Agostinis, P., & Vandenabeele, P. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3380 · Cited by 3,223 · see citing works
Self-citationAlveolar macrophages: plasticity in a tissue-specific context
Hussell, T., & Bell, T. J. (2014) · Nature Reviews Immunology · doi:10.1038/nri3600 · Cited by 1,377 · see citing works
Shaping cups into phagosomes and macropinosomes
Swanson, J. A. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2447 · Cited by 941 · see citing works
Consensus guidelines for the detection of immunogenic cell death
Kepp, O., Senovilla, L., Vitale, I., Vacchelli, E., Adjemian, S., Agostinis, P., Apetoh, L., Aranda, F., Barnaba, V., Bloy, N., et al. (2014) · OncoImmunology · doi:10.4161/21624011.2014.955691 · Cited by 832 · see citing works
Self-citationEmerging role of damage-associated molecular patterns derived from mitochondria in inflammation
Krysko, D. V., Agostinis, P., Krysko, O., Garg, A. D., Bachert, C., Lambrecht, B. N., & Vandenabeele, P. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.01.005 · Cited by 680 · see citing works
Self-citationClearance of apoptotic cells by phagocytes
Erwig, L.-P., & Henson, P. M. (2008) · Cell Death & Differentiation · doi:10.1038/sj.cdd.4402184 · Cited by 422 · see citing works
An, P., Wei, L.-L., Zhao, S., Sverdlov, D. Y., Vaid, K. A., Miyamoto, M., Kuramitsu, K., Lai, M., & Popov, Y. V. (2020) · Nature Communications · doi:10.1038/s41467-020-16092-0 · Cited by 319 · see citing works
Neutrophils in tuberculosis: friend or foe?
Lowe, D. M., Redford, P. S., Wilkinson, R. J., O’Garra, A., & Martineau, A. R. (2012) · Trends in Immunology · doi:10.1016/j.it.2011.10.003 · Cited by 312 · see citing works
Ecto‐calreticulin in immunogenic chemotherapy
Obeid, M., Tesniere, A., Panaretakis, T., Tufi, R., Joza, N., Van Endert, P., Ghiringhelli, F., Apetoh, L., Chaput, N., Flament, C., et al. (2007) · Immunological Reviews · doi:10.1111/j.1600-065x.2007.00567.x · Cited by 202 · see citing works
Pattern recognition receptors in the immune response against dying cells
Jeannin, P., Jaillon, S., & Delneste, Y. (2008) · Current Opinion in Immunology · doi:10.1016/j.coi.2008.04.013 · Cited by 165 · see citing works
Development and Functions of Alveolar Macrophages
Woo, Y. D., Jeong, D., & Chung, D. H. (2021) · Molecules and Cells · doi:10.14348/molcells.2021.0058 · Cited by 110 · see citing works
Li, H.-N., Barlow, P. G., Bylund, J., Mackellar, A., Björstad, Å., Conlon, J., Hiemstra, P. S., Haslett, C., Gray, M., Simpson, A. J., et al. (2009) · Journal of Leukocyte Biology · doi:10.1189/jlb.0209050 · Cited by 49 · see citing works
- Authors
- Krysko, D. V., D’Herde, K., & Vandenabeele, P.
- Affiliations
- Vlaams Instituut voor Biotechnologie (BE)
- Corresponding author
- Krysko, Dmitri V.
- Venue
- Apoptosis
- Published
- 2006-08-24
- Volume
- 11
- Issue
- 10
- Pages
- 1709-1726
- ISSN
- 1360-8185 (ISSN-L)
- 1573-675X
- OpenAlex
- W2009600776
- Cited by
- 316
- References
- 8
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 7 · 2023: 8 · 2022: 5 · 2021: 10 · 2020: 7 · 2019: 13 · 2018: 8 · 2017: 15 · 2016: 14 · 2015: 19 · 2014: 23 · 2013: 18 · 2012: 27
- FWCI
- 10.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- APOPTOSIS (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- 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
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- efferocytosis, necrotic cell clearance, phagocytosis, macrophages, tissue homeostasis, immunological effects, macropinocytosis, inflammation, pathogenesis
- MeSH terms
- Animals, Humans, Immunity, Innate, Macrophages, Models, Biological, Necrosis, Phagocytosis, Receptors, Cell Surface, Apoptosis, Evolution, Molecular
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
