Ubiquitin-Specific Protease 8 Regulates Cognitive Dysfunction of Mice with Sepsis-Associated Encephalopathy Through SIRT1 Deubiquitination

Background: Sepsis-associated encephalopathy (SAE) is the most severe complication of sepsis. Ubiquitin-specific protease 8 (USP8) could improve cognitive and motor disorders in SAE. Objective: This study explored the mechanism of USP8 in SAE mice to provide new therapeutic targets for SAE. Methods: C57BL/6 mice were selected to establish SAE models by caecal ligation and puncture (CLP) and injected with lentivirus overexpressing USP8 one week before SAE modeling. Mouse weight changes were monitored, cognitive and learning abilities were tested by the Morris water maze test, behaviors were evaluated by open-field tests, and pathological changes in brain tissue were analyzed by H&E staining. Levels of USP8, TNF-α, IL-1β, IL-6, and IL-10, and SOD, GSH-Px activities, and MDA levels were detected by Western blot, ELISA, and kits. Co-immunoprecipitation assay verified the interaction between USP8 and SIRT1 and SIRT1 ubiquitination level. Results: In CLP mice, the body weight, cognitive function, and learning ability were decreased, along with motor disorder, abnormal morphological structure of neurons, and obvious inflammatory infiltration. USP8 protein in brain tissue was decreased, the levels of TNF-α, IL-1β, and IL-6 were increased, IL-10 was decreased, SOD and GSH-Px activities were decreased, and MDA level was increased. USP8 treatment improved cognitive dysfunction and inhibited inflammation and oxidative stress in CLP mice. USP8 promoted SIRT1 expression by direct deubiquitination. SIRT1 knockdown partially reversed the regulation of USP8 on SAE mice. Conclusion: USP8 can directly deubiquitinate SIRT1 and inhibit inflammatory reactions and oxidative stress, thus improving cognitive dysfunction in SAE mice.