title: Depletion of microglia exacerbates postischemic inflammation and brain injury.
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.
authors.affiliation: 1 Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.|2 Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Wei-Na
authors.initials: WN
authors.lastname: Jin
authors.affiliation: 2 Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.|3 Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ, USA.
authors.forename: Samuel Xiang-Yu
authors.initials: SX
authors.lastname: Shi
authors.affiliation: 1 Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.|2 Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Li
authors.affiliation: 1 Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.|2 Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Minshu
authors.initials: M
authors.lastname: Li
authors.affiliation: 2 Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Kristofer
authors.initials: K
authors.lastname: Wood
authors.affiliation: 3 Department of Basic Medical Sciences, University of Arizona College of Medicine, Phoenix, AZ, USA.
authors.forename: Rayna J
authors.initials: RJ
authors.lastname: Gonzales
authors.affiliation: 1 Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China.|2 Department of Neurology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Liu
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D002545:Brain Ischemia / Q000000981:diagnostic imaging / Q000276:immunology* / Q000473:pathology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism*; D008279:Magnetic Resonance Imaging; D008297:Male; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D061251:Primary Cell Culture; D019009:Proto-Oncogene Proteins c-kit / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors
chemical_list: D000631:Aminopyridines; C000604004:Csf1r protein, mouse; D018836:Inflammation Mediators; D011758:Pyrroles; D017382:Reactive Oxygen Species; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; C000600259:pexidartinib; D019009:Proto-Oncogene Proteins c-kit
keywords: Microglia; brain ischemia; colony-stimulating factor 1 receptor; neuroprotection