Upregulation Of Microglial ZEB1 Ameliorates Brain Damage During Acute Ischemic Stroke

Objective: Inflammation-mediated damage occurs in the acute and chronic phases of ischemic stroke in humans and in the animal model,transient middle cerebral artery occlusion(MCAO).Microglia,as the brain's macrophage,is key immune-competent cell that can respond to environmental and physiologic changes during ischemic stroke but the consequence of activated microglia remains unclear.Therefore,understanding the specific mechanisms governing microglia during ischemic stroke is vital for reducing disease burden and intervene microglia response may shape the outcome of stroke.Methods: We first measured the expression of ZEB1 after stroke in the protein and RNA levels and then we developed a conditional transgenic mice system to investigate the mechanism of ZEB1.Multiple clinical tests and pathological changes were assessed in the transgenic and wild type mice after stroke.Results: We found ZEB1 highly expressed in the brain's ipsilateral hemisphere by and up-regulated mainly in microglia.Genetic upregulation of ZEB1 in microglia regulates the immune response in the central nervous system and alleviates the brain injury after ischemic stroke.Our data indicated that,the over-expression of ZEB1 mediates the microglia response during ischemic stroke and in turn,inhibit the production of CXCL1 from astrocyte through TGF-?1 dependent pathway.The reduced CXCL1 leads to the decline of neutrophil infiltration thereby reducing CNS inflammation.Interpretation: Based on our results demonstrating the importance of ZEB1 in microglia-orchestrated neuroinflammation,we present here at physiologic for future investigations of microglial function in the CNS as a potential means of reducing stroke-induced neurologic injury.