Rapid clearance of cellular debris by microglia limits secondary neuronal cell death after brain injury in vivo
Open accessAbstract
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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Microglia are present and highly activated in lesions of demyelination where they have both harmful and beneficial roles.
“Microglia are present and highly activated in lesions of demyelination where they have been described to have both harmful roles, such as production of cytotoxic cytokines, contribution to oxidative damage, and promotion of pathogenic T cell responses, as well as beneficial roles, including promotion of oligodendrocyte differentiation and clearance of myelin and cellular debris (14, 17–19).”
From Microglia depletion exacerbates demyelination and impairs remyelination in a neurotropic coronavirus infection (2020) · cites this paper as [14]
The Introduction (page not specified) describes microglial migration to brain-injury lesions, beneficial debris clearance, and potentially harmful oxidative damage. The paper studies brain injury, not demyelinating lesions; the cited passages do not support the claims about oligodendrocyte differentiation, cytotoxic cytokines, or pathogenic T-cell responses. (LLM, conf=0.87)
Experimental — accuracy not yet measuredMicroglia are capable of mediating an oxidative/respiratory burst in response to pathogen- and damage-AMPs, including aggregated protein and cellular debris.
“As phagocytes, microglia are capable of mediating an “oxidative/respiratory burst” in response to pathogen- and damage-AMPs, including aggregated protein and cellular debris [40,41].”
From ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease (2020) · cites this paper as [41]
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References 87 · Cited by 106
- Authors
- Herzog, C., Pons Garcia, L., Keatinge, M., Greenald, D., Moritz, C., Peri, F., & Herrgen, L.
- Affiliations
- University of Edinburgh (GB)
- Centre for Discovery Brain Sciences, The University of Edinburgh 1 , 49 Little France Crescent, Edinburgh EH16 4SB , UK
- European Molecular Biology Laboratory (DE)
- University of Zurich (CH)
- Corresponding author
- Herrgen, Leah
- Venue
- Development
- Publisher
- The Company of Biologists
- Published
- 2019-05-01
- Volume
- 146
- Issue
- 9
- ISSN
- 0950-1991 (ISSN-L)
- 1477-9129
- PMC
- PMC6526721
- OpenAlex
- W2943951895
- Cited by
- 106
- References
- 87
- Citations by year
- 2026: 10 · 2025: 11 · 2024: 15 · 2023: 16 · 2022: 18 · 2021: 17 · 2020: 14 · 2019: 5
- FWCI
- 5.95
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Development (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Edinburgh Research Explorer (University of Edinburgh) (acceptedVersion, other-oa)
- HighWire Press Open Archive (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Biogen
- University of Edinburgh
- Wellcome Trust (207701/Z/17/Z)
- Carnegie Trust for the Universities of Scotland (70457)
- Rosetrees Trust (M602)
- Stoneygate Trust (M602)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Keywords
- traumatic brain injury, microglia, phagocytosis, excitotoxicity, neuroprotection, zebrafish larvae, microglial migration, respiratory burst
- MeSH terms
- Animals, Brain, Brain Injuries, Larva, Macrophages, Neurons, Phagocytosis, Zebrafish, Cell Death, Microglia
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