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Rapid clearance of cellular debris by microglia limits secondary neuronal cell death after brain injury in vivo


Herzog, Chiara; Pons Garcia, Laura; Keatinge, Marcus; Greenald, David; Moritz, Christian; Peri, Francesca; Herrgen, Leah (2019). Rapid clearance of cellular debris by microglia limits secondary neuronal cell death after brain injury in vivo. Development, 146(9):dev174698.

Abstract

Moderate or severe traumatic brain injury (TBI) causes widespread neuronal cell death. Microglia, the resident macrophages of the brain, react to injury by migrating to the lesion site, where they phagocytose cellular debris. Microglial phagocytosis can have both beneficial (e.g. debris clearance) and detrimental (e.g. respiratory burst, phagoptosis) consequences. Hence, whether the overall effect of microglial phagocytosis after brain injury in vivo is neuroprotective or neurotoxic is not known. Here, we establish a system with which to carry out dynamic real-time analyses of the mechanisms regulating cell death after brain injury in vivo. We show that mechanical injury to the larval zebrafish brain induces distinct phases of primary and secondary cell death. Excitotoxicity contributes to secondary cell death in zebrafish, reflecting findings from mammals. Microglia arrive at the lesion site within minutes of injury, where they rapidly engulf dead cells. Importantly, the rate of secondary cell death is increased when the rapid removal of cellular debris by microglia is reduced pharmacologically or genetically. In summary, our results provide evidence that microglial debris clearance is neuroprotective after brain injury in vivo.

Abstract

Moderate or severe traumatic brain injury (TBI) causes widespread neuronal cell death. Microglia, the resident macrophages of the brain, react to injury by migrating to the lesion site, where they phagocytose cellular debris. Microglial phagocytosis can have both beneficial (e.g. debris clearance) and detrimental (e.g. respiratory burst, phagoptosis) consequences. Hence, whether the overall effect of microglial phagocytosis after brain injury in vivo is neuroprotective or neurotoxic is not known. Here, we establish a system with which to carry out dynamic real-time analyses of the mechanisms regulating cell death after brain injury in vivo. We show that mechanical injury to the larval zebrafish brain induces distinct phases of primary and secondary cell death. Excitotoxicity contributes to secondary cell death in zebrafish, reflecting findings from mammals. Microglia arrive at the lesion site within minutes of injury, where they rapidly engulf dead cells. Importantly, the rate of secondary cell death is increased when the rapid removal of cellular debris by microglia is reduced pharmacologically or genetically. In summary, our results provide evidence that microglial debris clearance is neuroprotective after brain injury in vivo.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
Scopus Subject Areas:Life Sciences > Molecular Biology
Life Sciences > Developmental Biology
Uncontrolled Keywords:Developmental Biology, Molecular Biology
Language:English
Date:1 May 2019
Deposited On:07 Feb 2020 15:20
Last Modified:29 Jul 2020 14:01
Publisher:Company of Biologists
ISSN:0950-1991
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1242/dev.174698

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