Microglial repopulation alleviates surgery-induced neuroinflammation and cognitive impairment in a ZEB1-dependent manner.

Microglia play a crucial role in postoperative cognitive dysfunction (POCD). This study investigated the effects of microglial depletion and subsequent repopulation on POCD and its underlying mechanisms. An aged mouse model of POCD was induced by partial hepatectomy, and the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 was administered to facilitate microglial depletion and repopulation. Neutrophil involvement was assessed with anti-Ly6G antibodies, while ZEB1 was manipulated through shRNA knockdown and lentiviral overexpression in the BV2 microglial cell line. A TGF-β1 neutralizing antibody was employed to elucidate the relationship between ZEB1 and its downstream pathways. The results indicated that microglial depletion alone did not reverse cognitive impairments. However, microglial repopulation significantly reduced neutrophil infiltration and improved cognitive function post-surgery. This improvement correlated with ZEB1 upregulation in microglia, which decreased CXCL1 production by astrocytes via TGF-β1 signaling, thereby reducing neutrophil migration to the hippocampus. These findings suggest that microglial repopulation, dependent on ZEB1 and TGF-β1 signaling, effectively alleviates neuroinflammation, reduces neutrophil infiltration, and enhances cognitive function, highlighting microglia as a promising target for the prevention and treatment of POCD.