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

IF 4.4 2区生物学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

The FASEB Journal Pub Date : 2025-03-07 DOI:10.1096/fj.202402492R

Xinyue Zhang, Xiaotong Cui, Naihui Sun, Xinyi Wu, Xue Pan, Renyi Wang, Zitong Chen, Yilong Li, Yue Hu, Fang Liu, Xuezhao Cao

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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.

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来源期刊

The FASEB Journal 生物-生化与分子生物学

CiteScore

9.20

自引率

2.10%

发文量

6243

审稿时长

3 months

期刊介绍： The FASEB Journal publishes international, transdisciplinary research covering all fields of biology at every level of organization: atomic, molecular, cell, tissue, organ, organismic and population. While the journal strives to include research that cuts across the biological sciences, it also considers submissions that lie within one field, but may have implications for other fields as well. The journal seeks to publish basic and translational research, but also welcomes reports of pre-clinical and early clinical research. In addition to research, review, and hypothesis submissions, The FASEB Journal also seeks perspectives, commentaries, book reviews, and similar content related to the life sciences in its Up Front section.