title: MFG-E8 mediates primary phagocytosis of viable neurons during neuroinflammation.
abstract: Milk-fat globule EGF factor-8 (MFG-E8, SED1, lactadherin) is known to mediate the phagocytic removal of apoptotic cells by bridging phosphatidylserine (PS)-exposing cells and the vitronectin receptor (VR) on phagocytes. However, we show here that MFG-E8 can mediate phagocytosis of viable neurons during neuroinflammation induced by lipopolysaccharide (LPS), thereby causing neuronal death. In vitro, inflammatory neuronal loss is independent of apoptotic pathways, and is inhibited by blocking the PS/MFG-E8/VR pathway (by adding PS blocking antibodies, annexin V, mutant MFG-E8 unable to bind VR, or VR antagonist). Neuronal loss is absent in Mfge8 knock-out cultures, but restored by adding recombinant MFG-E8, without affecting inflammation. In vivo, LPS-induced neuronal loss is reduced in the striatum of Mfge8 knock-out mice or by coinjection of an MFG-E8 receptor (VR) inhibitor into the rat striatum. Our data show that blocking MFG-E8-dependent phagocytosis preserves live neurons, implying that phagocytosis actively contributes to neuronal death during brain inflammation.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Fricker
authors.forename: Jonas J
authors.initials: JJ
authors.lastname: Neher
authors.forename: Jing-Wei
authors.initials: JW
authors.lastname: Zhao
authors.forename: Clotilde
authors.initials: C
authors.lastname: Théry
authors.forename: Aviva M
authors.initials: AM
authors.lastname: Tolkovsky
authors.forename: Guy C
authors.initials: GC
authors.lastname: Brown
mesh_terms: D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017304:Annexin A5 / Q000378:metabolism; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism*; D002452:Cell Count; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D018920:Coculture Techniques; D003342:Corpus Striatum / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004660:Encephalitis / Q000139:chemically induced / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005047:Etoposide / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D037102:Lectins / Q000378:metabolism; D008070:Lipopolysaccharides; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D010718:Phosphatidylserines / Q000494:pharmacology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000172:deficiency; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D017304:Annexin A5; D000954:Antigens, Surface; C494827:Bax protein, mouse; D016207:Cytokines; D004791:Enzyme Inhibitors; D005904:Glial Fibrillary Acidic Protein; D039302:Integrin alphaVbeta3; D037102:Lectins; D008070:Lipopolysaccharides; C490919:Mfge8 protein, mouse; D008894:Milk Proteins; D010456:Peptides, Cyclic; D010718:Phosphatidylserines; D051028:bcl-2-Associated X Protein; C103192:butyloxycarbonyl-O-methyl-aspartyl-fluoromethyl ketone; C092113:cyclo(arginyl-glycyl-aspartyl-phenylalanyl-valyl); D005047:Etoposide; D001616:beta-Galactosidase; D010751:Phosphopyruvate Hydratase