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Identification of a factor that links apoptotic cells to phagocytes

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 tissue1. 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 receptor2. Here, we report a factor that links apoptotic cells to phagocytes. We found that milk fat globule-EGF-factor 8 (MFG-E8)3,4, 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 αvβ3 integrin. The NIH3T3 cell transformants that expressed a high level of αvβ3 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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Figure 1: Establishment of monoclonal antibody that enhances the phagocytosis of apoptotic cells.
Figure 2: Identification of MFG-E8, and its expression.
Figure 3: Binding of MFG-E8 to aminophospholipids and integrin-expressing cells.
Figure 4: MFG-E8-L-dependent engulfment of apoptotic cells.

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Acknowledgements

We thank T. Kitamura for the retrovirus expression system, Y. Seto for maintaining the mice, and S. Aoyama for secretarial assistance. This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports and Culture in Japan.

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Correspondence to Shigekazu Nagata.

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Hanayama, R., Tanaka, M., Miwa, K. et al. Identification of a factor that links apoptotic cells to phagocytes. Nature 417, 182–187 (2002). https://doi.org/10.1038/417182a

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