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Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death
Open accessAbstract
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.
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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.”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [59]
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“However, treatment of glial-neuronal cultures with LPS alone results in little or no neuronal apoptosis or necrosis, but rather progressive loss of neurons over several days due to microglial phagocytosis of stressed-but-viable neurons and blocking the phagocytosis saves the neurons [59].”
From The endotoxin hypothesis of neurodegeneration (2019) · cites this paper as [59]
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Metadata
- Authors
- Neher, J. J., Neniskyte, U., Zhao, J.-W., Bal-Price, A., Tolkovsky, A. M., & Brown, G. C.
- Affiliations
- University of Cambridge (GB)
- Department of Biochemistry, University of Cambridge , Cambridge CB2 1QW ,
- Cambridge Centre for Brain Repair, University of Cambridge , Cambridge CB2 OPY ,
- In Vitro Toxicology Unit, European Centre for the Validation of Alternative Methods, Institute of Health and Consumer Protection, European Commission Joint Research Centre , 21027 Ispra ,
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-04
- Volume
- 186
- Issue
- 8
- Pages
- 4973-4983
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2120950413
- Cited by
- 373
- References
- 61
- Citations by year
- 2026: 8 · 2025: 20 · 2024: 27 · 2023: 30 · 2022: 30 · 2021: 36 · 2020: 30 · 2019: 24 · 2018: 25 · 2017: 21 · 2016: 30 · 2015: 21 · 2014: 18 · 2013: 30 · 2012: 16
- FWCI
- 12.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Joint Research Centre (European Commission) (submittedVersion)
- INFM-OAR (INFN Catania) (submittedVersion, other-oa)
- Funders
- Wellcome Trust (RG50995)
- Cambridge Trust
- Gates Cambridge Trust
- 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 › Cell Biology › Autophagy in Disease and Therapy
- Keywords
- microglial phagocytosis, neuronal cell death, phosphatidylserine exposure, milk fat globule epidermal growth factor 8, integrin αvβ3, peroxynitrite, lipoteichoic acid, lipopolysaccharide, TLR2, TLR4, microglial proliferation, neuroinflammation
- MeSH terms
- Animals, Antigens, Surface, Cells, Cultured, Cerebellum, Inflammation, Lipopolysaccharides, Milk Proteins, Neurons, Peptide Fragments, Phagocytosis, Phosphatidylserines, Teichoic Acids, Time Factors, Tumor Necrosis Factor-alpha, Amyloid beta-Peptides, Apoptosis, Microglia, Inflammation Mediators, Coculture Techniques, Toll-Like Receptor 2, Toll-Like Receptor 4, Rats, Interleukin-1beta
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