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Updated: Oct 16, 2025
Intravital Imaging of Axonal Interactions with Microglia and Macrophages in a Mouse Dorsal Column Crush Injury
Published on: November 23, 2014
Functional role of brain-engrafted macrophages against brain injuries
Xi Feng1,2, Elma S Frias1,2, Maria S Paladini1,2
1Brain and Spinal Injury Center, University of California San Francisco, San Francisco, USA.
Background:
Brain-resident microglia have a distinct origin compared to macrophages in other organs. Under physiological conditions, microglia are maintained by self-renewal from the local pool, independent of hematopoietic progenitors. Pharmacological depletion of microglia during whole-brain radiotherapy prevents synaptic loss and long-term recognition memory deficits. However, the origin or repopulated cells and the mechanisms behind these protective effects are unknown.
Methods:
CD45low/int/CD11b+ cells from naïve brains, irradiated brains, PLX5622-treated brains and PLX5622 + whole-brain radiotherapy-treated brains were FACS sorted and sequenced for transcriptomic comparisons. Bone marrow chimeras were used to trace the origin and long-term morphology of repopulated cells after PLX5622 and whole-brain radiotherapy. FACS analyses of intrinsic and exotic synaptic compartments were used to measure phagocytic activities of microglia and repopulated cells. In addition, concussive brain injuries were given to PLX5622 and brain-irradiated mice to study the potential protective functions of repopulated cells after PLX5622 + whole-brain radiotherapy.
Results:
After a combination of whole-brain radiotherapy and microglia depletion, repopulated cells are brain-engrafted macrophages that originate from circulating monocytes. Comparisons of transcriptomes reveal that brain-engrafted macrophages have an intermediate phenotype that resembles both monocytes and embryonic microglia. In addition, brain-engrafted macrophages display reduced phagocytic activity for synaptic compartments compared to microglia from normal brains in response to a secondary concussive brain injury. Importantly, replacement of microglia by brain-engrafted macrophages spare mice from whole-brain radiotherapy-induced long-term cognitive deficits, and prevent concussive injury-induced memory loss.
Conclusions:
Brain-engrafted macrophages prevent radiation- and concussion-induced brain injuries and cognitive deficits.
Insights
Repopulated brain macrophages, originating from monocytes, protect against radiation and concussion injuries. These cells prevent cognitive deficits after whole-brain radiotherapy and brain injury.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia, the brain's immune cells, are distinct from other macrophages and self-renew locally.
- Pharmacological depletion of microglia before radiotherapy prevents cognitive deficits, but cell origin and protective mechanisms remain unclear.
Purpose of the Study:
- To investigate the origin and function of cells repopulating the brain after microglia depletion and radiotherapy.
- To determine if these repopulated cells offer protection against brain injury and cognitive decline.
Main Methods:
- Transcriptomic analysis of cells from treated and untreated brains.
- Bone marrow chimeras to trace cell origin and morphology.
- Flow cytometry to assess phagocytic activity and synaptic compartment interactions.
- Induction of concussive brain injuries to evaluate protective functions.
Main Results:
- Repopulated cells are brain-engrafted macrophages derived from circulating monocytes.
- These macrophages exhibit an intermediate phenotype between monocytes and microglia.
- Brain-engrafted macrophages show reduced phagocytic activity and protect against radiation- and concussion-induced cognitive deficits.
Conclusions:
- Monocyte-derived macrophages can replace microglia after depletion and radiotherapy.
- These engrafted macrophages provide neuroprotection, preventing long-term cognitive impairments.
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