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Characterization and Isolation of Mouse Primary Microglia by Density Gradient Centrifugation
Published on: February 16, 2018
Depletion of microglia exacerbates postischemic inflammation and brain injury
Wei-Na Jin1,2, Samuel Xiang-Yu Shi2,3, Zhiguo Li1,2
11 Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.
Abstract:
Brain ischemia elicits microglial activation and microglia survival depend on signaling through colony-stimulating factor 1 receptor (CSF1R). Although depletion of microglia has been linked to worse stroke outcomes, it remains unclear to what extent and by what mechanisms activated microglia influence ischemia-induced inflammation and injury in the brain. Using a mouse model of transient focal cerebral ischemia and reperfusion, we demonstrated that depletion of microglia via administration of the dual CSF1R/c-Kit inhibitor PLX3397 exacerbates neurodeficits and brain infarction. Depletion of microglia augmented the production of inflammatory mediators, leukocyte infiltration, and cell death during brain ischemia. Of note, microglial depletion-induced exacerbation of stroke severity did not solely depend on lymphocytes and monocytes. Importantly, depletion of microglia dramatically augmented the production of inflammatory mediators by astrocytes after brain ischemia . In vitro studies reveal that microglia restricted ischemia-induced astrocyte response and provided neuroprotective effects. Our findings suggest that neuroprotective effects of microglia may result, in part, from its inhibitory action on astrocyte response after ischemia.
Insights
Microglia depletion worsens stroke outcomes by increasing inflammation and brain damage. Microglia protect the brain by inhibiting harmful astrocyte responses during ischemia.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Microglial activation is crucial after brain ischemia, with survival depending on colony-stimulating factor 1 receptor (CSF1R) signaling.
- The precise role and mechanisms of activated microglia in modulating ischemia-induced brain inflammation and injury remain incompletely understood.
Purpose of the Study:
- To investigate the extent and mechanisms by which activated microglia influence brain inflammation and injury following cerebral ischemia.
- To elucidate the neuroprotective role of microglia in the context of ischemic stroke.
Main Methods:
- Utilized a mouse model of transient focal cerebral ischemia and reperfusion.
- Administered a dual CSF1R/c-Kit inhibitor (PLX3397) to deplete microglia.
- Assessed neurodeficits, brain infarction, inflammatory mediator production, leukocyte infiltration, and cell death.
- Conducted in vitro studies to examine microglial-astrocyte interactions.
Main Results:
- Microglial depletion exacerbated neurodeficits and brain infarction following ischemia.
- Depletion led to increased inflammatory mediators, leukocyte infiltration, and cell death.
- The exacerbation of stroke severity was not solely dependent on lymphocytes and monocytes.
- Microglial depletion significantly augmented inflammatory mediator production by astrocytes.
- In vitro studies showed microglia restricted ischemia-induced astrocyte responses and conferred neuroprotection.
Conclusions:
- Microglia play a critical neuroprotective role in ischemic stroke.
- This neuroprotection is partly mediated by the inhibition of detrimental astrocyte responses.
- Targeting CSF1R to deplete microglia may worsen stroke outcomes by removing these protective functions.
