Cited by 373Neuroinflammation and Neurodegeneration MechanismsPhagocytosis and Immune RegulationAutophagy in Disease and Therapy

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Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death

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Neher, Jonas J, Neniskyte, Urte, Zhao, Jing-Wei, Bal-Price, Anna, Tolkovsky, Aviva M, Brown, Guy C·2011·The Journal of Immunology

DOI 10.4049/jimmunol.1003600

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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.

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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 ,
ORCID: Neher, Jonas J
Tolkovsky, Aviva M
Brown, Guy C
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
DOI: 10.4049/jimmunol.1003600
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
Licence: academic.oup.com/pages/standard-publication-reuse-rights (vor)
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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Inhibition of Microglial Phagocytosis Is Sufficient To Prevent Inflammatory Neuronal Death

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