Microglial elimination and repopulation ameliorates surgery-induced cognitive impairment in an ZEB1-dependent manner

Microglia, a key immune cell type, play a crucial role in surgery-induced cognitive impairment. This study aimed to investigate the effects of acute microglial elimination, followed by microglial repopulation, on surgery-induced cognitive impairment and the potential mechanism in a mice model of postoperative cognitive dysfunction (POCD). Methods: Partial hepatectomy was performed as a model of POCD. Aged male C57BL/6J mice were administered a CSF1R inhibitor, PLX5622, one week prior to surgery to remove activated microglia. In a subset of microglia-depleted mice, PLX5622 was discontinued for a week to facilitate microglial repopulation. Intraperitoneal injections of anti-Ly6G were given thrice weekly before surgery to investigate the role of surgery-induced neutrophil infiltration in postoperative cognitive impairment. To explore the underlying mechanism, ZEB1, CXCL1, TGF-β1, as well as Smad2 and NF-κB pathway were measured in microglia and astrocytes. Behavioral performance was evaluated by Morris water maze and Novel object recognition tests. Results: Microglial depletion alone failed to reverse surgery-induced spatial learning and memory impairment. Whereas microglial elimination and repopulation inhibited neutrophil infiltration and alleviated postoperative neurocognitive deficits. Furthermore, our data indicated that microglial elimination and repopulation-induced ZEB1 upregulation in microglia mediated immune responses in the central nervous system (CNS) and, in turn, inhibited the production of astrocytic CXCL1 through the TGF-β1 dependent pathway. This reduction in CXCL1 inhibited neutrophil infiltration into CNS, thereby alleviating surgery-induced cognitive impairment. Conclusions : Microglial elimination and subsequent repopulation effectively inhibits neutrophil infiltration and alleviates behavioral impairment following surgical challenge. The beneficial effects of these repopulated microglia are critically dependent on ZEB1 via TGF-β1 signaling in astrocytes. Targeting microglia may be a promising strategy for the prevention and treatment of POCD.