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Updated: May 23, 2025
A Mouse Model of Orthopedic Surgery to Study Postoperative Cognitive Dysfunction and Tissue Regeneration
Published on: February 27, 2018
Microglial repopulation alleviates surgery-induced neuroinflammation and cognitive impairment in a ZEB1-dependent
Xinyue Zhang1, Xiaotong Cui1, Naihui Sun1
1Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, Liaoning, China.
Abstract:
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.
Insights
Microglial repopulation, not depletion, improved cognitive function after surgery. This process involves ZEB1 and TGF-β1 signaling, reducing neuroinflammation and neutrophil infiltration in the brain.
Area of Science:
- Neuroscience
- Immunology
- Gerontology
Background:
- Postoperative cognitive dysfunction (POCD) is a significant concern, particularly in aged individuals.
- Microglia, the brain's resident immune cells, are implicated in the pathogenesis of POCD.
Purpose of the Study:
- To investigate the impact of microglial depletion and subsequent repopulation on POCD in aged mice.
- To elucidate the underlying molecular mechanisms, focusing on ZEB1 and TGF-β1 signaling pathways.
Main Methods:
- POCD was induced in aged mice via partial hepatectomy.
- Microglial depletion and repopulation were achieved using the CSF1R inhibitor PLX5622.
- ZEB1 manipulation in BV2 microglial cells and TGF-β1 signaling were assessed.
Main Results:
- Microglial depletion alone did not ameliorate cognitive deficits.
- Microglial repopulation significantly improved cognitive function and reduced neutrophil infiltration.
- ZEB1 upregulation in repopulated microglia decreased astrocyte-derived CXCL1 via TGF-β1, inhibiting neutrophil migration.
Conclusions:
- Microglial repopulation, mediated by ZEB1 and TGF-β1 signaling, effectively reverses POCD.
- Targeting microglial repopulation offers a potential therapeutic strategy for preventing and treating POCD.
