Zhang Xinyue, Cui Xiaotong, Sun Naihui, Wu Xinyi, Pan Xue, Wang Renyi, Chen Zitong, Li Yilong, Hu Yue, Liu Fang, Cao Xuezhao
Department of Anesthesiology, The First Hospital of China Medical University, Shenyang, Liaoning, China.
Department of Neurology, The First Hospital of China Medical University, Shenyang, Liaoning, China.
FASEB J. 2025 Mar 15;39(5):e70440. doi: 10.1096/fj.202402492R.
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.
小胶质细胞在术后认知功能障碍（POCD）中起关键作用。本研究调查了小胶质细胞耗竭及随后的再填充对POCD的影响及其潜在机制。通过部分肝切除术建立老年POCD小鼠模型，并给予集落刺激因子1受体（CSF1R）抑制剂PLX5622以促进小胶质细胞耗竭和再填充。用抗Ly6G抗体评估中性粒细胞的参与情况，而在BV2小胶质细胞系中通过短发夹RNA（shRNA）敲低和慢病毒过表达来调控锌指E盒结合蛋白1（ZEB1）。使用转化生长因子-β1（TGF-β1）中和抗体来阐明ZEB1与其下游通路之间的关系。结果表明，单纯的小胶质细胞耗竭并不能逆转认知障碍。然而，小胶质细胞再填充显著减少了中性粒细胞浸润，并改善了术后的认知功能。这种改善与小胶质细胞中ZEB1的上调相关，ZEB1通过TGF-β1信号传导减少星形胶质细胞的CXCL1产生，从而减少中性粒细胞向海马体的迁移。这些发现表明，依赖于ZEB1和TGF-β1信号传导的小胶质细胞再填充有效地减轻了神经炎症，减少了中性粒细胞浸润，并增强了认知功能，突出了小胶质细胞作为预防和治疗POCD的有前景的靶点。
