title: Inhibition of microglial phagocytosis is sufficient to prevent inflammatory neuronal death.
abstract: It is well-known that dead and dying neurons are quickly removed through phagocytosis by the brain's macrophages, the microglia. Therefore, neuronal loss during brain inflammation has always been assumed to be due to phagocytosis of neurons subsequent to their apoptotic or necrotic death. However, we report in this article that under inflammatory conditions in primary rat cultures of neurons and glia, phagocytosis actively induces neuronal death. Specifically, two inflammatory bacterial ligands, lipoteichoic acid or LPS (agonists of glial TLR2 and TLR4, respectively), stimulated microglial proliferation, phagocytic activity, and engulfment of ∼30% of neurons within 3 d. Phagocytosis of neurons was dependent on the microglial release of soluble mediators (and peroxynitrite in particular), which induced neuronal exposure of the eat-me signal phosphatidylserine (PS). Surprisingly, however, eat-me signaling was reversible, so that blocking any step in a phagocytic pathway consisting of PS exposure, the PS-binding protein milk fat globule epidermal growth factor-8, and its microglial vitronectin receptor was sufficient to rescue up to 90% of neurons without reducing inflammation. Hence, our data indicate a novel form of inflammatory neurodegeneration, where inflammation can cause eat-me signal exposure by otherwise viable neurons, leading to their death through phagocytosis. Thus, blocking phagocytosis may prevent some forms of inflammatory neurodegeneration, and therefore might be beneficial during brain infection, trauma, ischemia, neurodegeneration, and aging.
authors.affiliation: Department of Biochemistry, University of Cambridge, Cambridge CB2 1QW, United Kingdom. jjn24@cam.ac.uk
authors.forename: Jonas J
authors.initials: JJ
authors.lastname: Neher
authors.forename: Urte
authors.initials: U
authors.lastname: Neniskyte
authors.forename: Jing-Wei
authors.initials: JW
authors.lastname: Zhao
authors.forename: Anna
authors.initials: A
authors.lastname: Bal-Price
authors.forename: Aviva M
authors.initials: AM
authors.lastname: Tolkovsky
authors.forename: Guy C
authors.initials: GC
authors.lastname: Brown
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D000954:Antigens, Surface; D017209:Apoptosis / Q000276:immunology*; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology; D018920:Coculture Techniques; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D017628:Microglia / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008894:Milk Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology*; D010718:Phosphatidylserines / Q000494:pharmacology; D051381:Rats; D013682:Teichoic Acids / Q000494:pharmacology; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000954:Antigens, Surface; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C499941:MFGE8 protein, rat; D008894:Milk Proteins; D010446:Peptide Fragments; D010718:Phosphatidylserines; D013682:Teichoic Acids; C495343:Tlr2 protein, rat; C495347:Tlr4 protein, rat; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha; C074636:amyloid beta-protein (25-35); C009900:lipoteichoic acid