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Updated: Jun 9, 2025
Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Microglia ameliorate delirium-like phenotypes in a murine model of acute ventilator-induced lung injury
Landon Scott1, Kevin D Winzey1, Debbie Moreira1
1Department of Neurology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
Background:
Delirium affects 50-85% of patients on mechanical ventilation and is associated with increased mortality, prolonged hospitalization, and a three-fold higher risk of dementia. Microglia, the resident immune cells of the brain, exhibit both neuroprotective and neurotoxic functions; however, their effects in mechanical ventilation-induced acute lung injury (VILI) are unknown. We hypothesize that in a model of short-term VILI, microglia play a neuroprotective role to ameliorate delirium-like phenotypes.
Methods:
Microglia depletion (n = 18) was accomplished using an orally administered colony stimulating factor 1 receptor inhibitor, while controls received a vehicle diet (n = 18). We then compared extent of neuronal injury in the frontal cortex and hippocampus using cleaved caspase-3 (CC3) and multiple delirium-like behaviors in microglia depleted and non-microglia depleted male mice (C57BL/6 J aged 4-9 months) following VILI. Delirium-like behaviors were evaluated using the Open Field, Elevated Plus Maze, and Y-maze assays. We subsequently evaluated whether repopulation of microglia (n = 14 repopulation, 14 vehicle) restored the phenotypes.
Results:
Frontal/hippocampal neuronal CC3 levels were significantly higher in microglia depleted VILI mice compared to vehicle-treated VILI controls (p < 0.01, p < 0.01, respectively). These structural changes were accompanied by worse delirium-like behaviors in microglia depleted VILI mice compared to vehicle controls. Specifically, microglia depleted VILI mice demonstrated: (1) significantly increased time in the periphery of the Open Field (p = 0.01), (2) significantly increased coefficient of variation (p = 0.02), (3) trend towards reduced time in the open arms of the Elevated Plus Maze (p = 0.09), and (4) significantly decreased spontaneous alternations on Y-maze (p < 0.01). There was a significant inverse correlation between frontal CC3 and percent spontaneous alternations (R2 = 0.51, p < 0.01). Microglia repopulation showed a near-complete return to vehicle levels of delirium like-behaviors.
Conclusions:
This study demonstrates that microglia depletion exacerbates structural and functional delirium-like phenotypes after VILI, while subsequent repopulation of microglia restores these phenotypes. These findings suggest a neuroprotective role for microglia in ameliorating neuronal and functional delirium-like phenotypes and call for consideration of interventions that leverage endogenous microglia physiology to mitigate delirium.
Insights
Microglia depletion worsens brain injury and delirium symptoms in a mechanical ventilation model. Restoring microglia improves these outcomes, suggesting a protective role for these immune cells in preventing delirium.
Area of Science:
- Neuroscience
- Immunology
- Critical Care Medicine
Background:
- Delirium is common in mechanically ventilated patients, increasing mortality and dementia risk.
- Microglia, the brain's immune cells, have unknown roles in mechanical ventilation-induced acute lung injury (VILI).
- This study investigates microglia's neuroprotective potential in VILI-associated delirium.
Purpose of the Study:
- To determine the role of microglia in VILI-induced delirium-like phenotypes.
- To assess if microglia depletion exacerbates neuronal injury and behavioral deficits.
- To evaluate if microglia repopulation can restore normal function.
Main Methods:
- Used a mouse model of VILI with and without microglia depletion via a CSF1R inhibitor.
- Assessed neuronal injury using cleaved caspase-3 (CC3) in the cortex and hippocampus.
- Evaluated delirium-like behaviors using Open Field, Elevated Plus Maze, and Y-maze tests.
Main Results:
- Microglia depletion significantly increased neuronal CC3 levels and worsened delirium-like behaviors in VILI mice.
- Depleted mice showed increased anxiety-like behavior and impaired cognitive function.
- Microglia repopulation reversed these detrimental structural and functional changes.
Conclusions:
- Microglia play a neuroprotective role in mitigating VILI-induced neuronal injury and delirium-like phenotypes.
- Targeting microglia may offer a therapeutic strategy for preventing or treating delirium in critical illness.
- These findings highlight the importance of endogenous microglia in brain health during mechanical ventilation.
