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Cited by 1,401Phagocytosis and Immune RegulationCell death mechanisms and regulationCellular transport and secretion

The DOI matches its Crossref record; 32 of the 32 references it cites were found in a registry or an index.

Identification of a factor that links apoptotic cells to phagocytes

Hanayama, Rikinari, Tanaka, Masato, Miwa, Keiko, Shinohara, Azusa, Iwamatsu, Akihiro, Nagata, Shigekazu·2002·Nature
DOI 10.1038/417182a
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Abstract

Apoptotic cells are rapidly engulfed by phagocytes to prevent the release of potentially noxious or immunogenic intracellular materials from the dying cells, thereby preserving the integrity and function of the surrounding tissue. Phagocytes engulf apoptotic but not healthy cells, indicating that the apoptotic cells present a signal to the phagocytes, and the phagocytes recognize the signal using a specific receptor. Here, we report a factor that links apoptotic cells to phagocytes. We found that milk fat globule-EGF-factor 8 (MFG-E8), a secreted glycoprotein, was produced by thioglycollate-elicited macrophages. MFG-E8 specifically bound to apoptotic cells by recognizing aminophospholipids such as phosphatidylserine. MFG-E8, when engaged by phospholipids, bound to cells via its RGD (arginine-glycine-aspartate) motif--it bound particularly strongly to cells expressing alpha(v)beta(3) integrin. The NIH3T3 cell transformants that expressed a high level of alpha(v)beta(3) integrin were found to engulf apoptotic cells when MFG-E8 was added. MFG-E8 carrying a point mutation in the RGD motif behaved as a dominant-negative form, and inhibited the phagocytosis of apoptotic cells by peritoneal macrophages in vitro and in vivo. These results indicate that MFG-E8 secreted from activated macrophages binds to apoptotic cells, and brings them to phagocytes for engulfment.

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Metadata

Authors
Hanayama, R., Tanaka, M., Miwa, K., Shinohara, A., Iwamatsu, A., & Nagata, S.
Affiliations
  • The University of Osaka (JP)
  • Japan Science and Technology Agency (JP)
  • Kirin (Japan) (JP)
Corresponding author
Nagata, Shigekazu
ORCID
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2002-05
Volume
417
Issue
6885
Pages
182-187
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/417182a
OpenAlex
W2001567020
Cited by
1,401
References
31
Citations by year
2026: 37 · 2025: 40 · 2024: 64 · 2023: 56 · 2022: 46 · 2021: 82 · 2020: 61 · 2019: 58 · 2018: 56 · 2017: 71 · 2016: 59 · 2015: 72 · 2014: 76 · 2013: 73 · 2012: 63
FWCI
16.79
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature (publishedVersion)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Styrelsen för Internationellt Utvecklingssamarbete
  • Sidaction
  • Solar Energy Technologies Office
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
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
MFG-E8, efferocytosis, phagocytosis, phosphatidylserine, aminophospholipids, RGD motif, alpha v beta 3 integrin, macrophages, secreted glycoprotein, dominant-negative mutant, peritoneal macrophages
MeSH terms
Animals, Antibodies, Monoclonal, Antigens, Surface, Cell Adhesion, Cell Line, Cricetulus, Endocytosis, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Cricetinae, Membrane Glycoproteins, Milk Proteins, Oligopeptides, Phagocytes, Phosphatidylserines, Thioglycolates, Thymus Gland, 3T3 Cells, Apoptosis, Macrophages, Peritoneal, Receptors, Vitronectin, Mice

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