Depletion of microglia exacerbates postischemic inflammation and brain injury

J Cereb Blood Flow Metab. 2017 Jun;37(6):2224-2236. doi: 10.1177/0271678X17694185. Epub 2017 Jan 1.


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.

Keywords: Microglia; brain ischemia; colony-stimulating factor 1 receptor; neuroprotection.

MeSH terms

  • Aminopyridines / pharmacology
  • Animals
  • Brain Ischemia / diagnostic imaging
  • Brain Ischemia / immunology*
  • Brain Ischemia / pathology*
  • Cells, Cultured
  • Disease Models, Animal
  • Inflammation Mediators / metabolism*
  • Magnetic Resonance Imaging
  • Male
  • Mice, Inbred C57BL
  • Microglia / immunology*
  • Microglia / pathology*
  • Neurons / metabolism
  • Neurons / pathology
  • Primary Cell Culture
  • Proto-Oncogene Proteins c-kit / antagonists & inhibitors
  • Pyrroles / pharmacology
  • Reactive Oxygen Species / metabolism
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / antagonists & inhibitors


  • Aminopyridines
  • Csf1r protein, mouse
  • Inflammation Mediators
  • Pyrroles
  • Reactive Oxygen Species
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • pexidartinib
  • Proto-Oncogene Proteins c-kit