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

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Identification of a factor that links apoptotic cells to phagocytes

Hanayama, Rikinari, Tanaka, Masato, Miwa, Keiko, Shinohara, Azusa, Iwamatsu, Akihiro, Nagata, Shigekazu·2002·Nature

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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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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: Hanayama, Rikinari
Tanaka, Masato
Nagata, Shigekazu
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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Identification of a factor that links apoptotic cells to phagocytes

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