Microglial repopulation resolves inflammation and promotes brain recovery after injury
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Updated: Mar 6, 2026
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Rachel A Rice1, Jason Pham1, Rafael J Lee1
1Department of Neurobiology and Behavior, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, California, 92697.
Abstract:
Microglia mediate chronic neuroinflammation following central nervous system (CNS) disease or injury, and in doing so, damage the local brain environment by impairing recovery and contributing to disease processes. Microglia are critically dependent on signaling through the colony-stimulating factor 1 receptor (CSF1R) and can be eliminated via administration of CSF1R inhibitors. Resolving chronic neuroinflammation represents a universal goal for CNS disorders, but long-term microglial elimination may not be amenable to clinical use. Notably, withdrawal of CSF1R inhibitors stimulates new microglia to fully repopulate the CNS, affording an opportunity to renew this cellular compartment. To that end, we have explored the effects of acute microglial elimination, followed by microglial repopulation, in a mouse model of extensive neuronal loss. Neuronal loss leads to a prolonged neuroinflammatory response, characterized by the presence of swollen microglia expressing CD68 and CD45, as well as elevated levels of cytokines, chemokines, complement, and other inflammatory signals. These collective responses are largely resolved by microglial repopulation. Furthermore, microglial repopulation promotes functional recovery in mice, with elevated plus maze performance matching that of uninjured mice, despite the loss of 80% of hippocampal neurons. Analyses of synaptic surrogates revealed increases in PSD95 and synaptophysin puncta with microglial repopulation, suggesting that these cells sculpt and regulate the synaptic landscape. Thus, our results show that short-term microglial elimination followed by repopulation may represent a clinically feasible and novel approach to resolve neuroinflammatory events and promote brain recovery.
Insights
Short-term elimination of microglia, immune cells in the brain, followed by their regrowth, resolves neuroinflammation and aids brain recovery after injury. This approach offers a new therapeutic strategy for central nervous system disorders.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia play a key role in chronic neuroinflammation after central nervous system (CNS) injury.
- Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling and can be eliminated using CSF1R inhibitors.
- Long-term elimination of microglia may not be clinically viable, but repopulation after withdrawal offers a renewal opportunity.
Purpose of the Study:
- To investigate the effects of acute microglial elimination followed by repopulation in a mouse model of significant neuronal loss.
- To determine if microglial repopulation can resolve persistent neuroinflammation and promote functional recovery.
Main Methods:
- Utilized a mouse model with extensive neuronal loss to induce chronic neuroinflammation.
- Administered CSF1R inhibitors for acute microglial elimination, followed by drug withdrawal to allow repopulation.
- Assessed neuroinflammation markers (cytokines, chemokines, CD68, CD45) and functional recovery (elevated plus maze test).
- Analyzed synaptic markers (PSD95, synaptophysin) to evaluate synaptic landscape changes.
Main Results:
- Microglial repopulation effectively resolved prolonged neuroinflammation, reducing inflammatory signals and normalizing microglial morphology.
- Mice with microglial repopulation showed significant functional recovery, with performance on the elevated plus maze test comparable to uninjured controls, despite substantial neuronal loss.
- Synaptic markers PSD95 and synaptophysin increased with microglial repopulation, indicating a role in synaptic regulation and recovery.
Conclusions:
- Acute microglial elimination followed by repopulation is a promising strategy to resolve neuroinflammation.
- This approach promotes functional recovery and synaptic plasticity in the context of CNS injury.
- Short-term microglial modulation represents a potentially clinically feasible method for treating CNS disorders characterized by neuroinflammation.
