MFG-E8 Mediates Primary Phagocytosis of Viable Neurons during Neuroinflammation
Open accessAbstract
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.
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Endotoxin directly and indirectly activates microglia that damage neurons via nitric oxide, oxidants and cytokines, and by phagocytosis of synapses and neurons.
“Endotoxin directly and indirectly activates microglia that damage neurons via nitric oxide, oxidants and cytokines, and by phagocytosis of synapses and neurons.”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [60]
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- Authors
- Fricker, M., Neher, J. J., Zhao, J.-W., Théry, C., Tolkovsky, A. M., & Brown, G. C.
- Affiliations
- University of Cambridge (GB)
- Inserm (FR)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2012-02-22
- Volume
- 32
- Issue
- 8
- Pages
- 2657-2666
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC3312099
- OpenAlex
- W2138810799
- Cited by
- 218
- References
- 55
- Citations by year
- 2026: 12 · 2025: 12 · 2024: 17 · 2023: 12 · 2022: 17 · 2021: 32 · 2020: 13 · 2019: 16 · 2018: 17 · 2017: 11 · 2016: 8 · 2015: 15 · 2014: 13 · 2013: 15 · 2012: 7
- FWCI
- 8.04
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust (RG50995, 084645)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- MFG-E8, lactadherin, neuroinflammation, lipopolysaccharide, integrin αvβ3, phosphatidylserine, neuronal cell death, striatum, receptor antagonists
- MeSH terms
- Amino Acid Chloromethyl Ketones, Analysis of Variance, Animals, Animals, Newborn, Antigens, Surface, beta-Galactosidase, Cell Count, Cells, Cultured, Cerebellum, Corpus Striatum, Disease Models, Animal, Encephalitis, Enzyme Inhibitors, Enzyme-Linked Immunosorbent Assay, Etoposide, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Lipopolysaccharides, Male, Mice, Inbred C57BL, Milk Proteins, Mutation, Neuroglia, Neurons, Peptides, Cyclic, Phagocytosis, Phosphatidylserines, Phosphopyruvate Hydratase, Signal Transduction, Cytokines, Annexin A5, Mice, Knockout, Coculture Techniques, In Situ Nick-End Labeling, Lectins, Integrin alphaVbeta3, bcl-2-Associated X Protein, Mice, Rats
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