title: 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 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.
authors: Department of Genetics, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.
authors: Rikinari
authors: R
authors: Hanayama
authors: Masato
authors: M
authors: Tanaka
authors: Keiko
authors: K
authors: Miwa
authors: Azusa
authors: A
authors: Shinohara
authors: Akihiro
authors: A
authors: Iwamatsu
authors: Shigekazu
authors: S
authors: Nagata
mesh_terms: D016475:3T3 Cells; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000954:Antigens, Surface; D017209:Apoptosis; D002448:Cell Adhesion; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004705:Endocytosis / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008894:Milk Proteins; D009842:Oligopeptides / Q000378:metabolism; D010586:Phagocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010718:Phosphatidylserines / Q000378:metabolism; D019030:Receptors, Vitronectin / Q000378:metabolism; D013864:Thioglycolates / Q000494:pharmacology; D013950:Thymus Gland / Q000166:cytology / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D008562:Membrane Glycoproteins; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D009842:Oligopeptides; D010718:Phosphatidylserines; D019030:Receptors, Vitronectin; D013864:Thioglycolates; C047981:arginyl-glycyl-aspartic acid