<scp>STING</scp> Driving Synaptic Phagocytosis of Hippocampal Microglia/Macrophages Contributes to Cognitive Impairment in Sepsis‐Associated Encephalopathy in Mice
Xin Lv, Min Jia, Feng Xiao, Jia‐xiong Jian, Jianjun Yang, Daqing Ma, Mu‐Huo Ji, Yu‐gang Diao, Jin-Chun Shen
Abstract
BACKGROUND: Sepsis-associated encephalopathy (SAE) is a serious neurologic complication in septic patients with poor prognoses. There is increasing evidence that stimulator of interferon genes (STING) plays a crucial role in neuroinflammation and cognitive impairment. However, whether sepsis associated with STING changes contributes to cognitive impairment is unknown. METHODS: Male adult mice received lipopolysaccharide (LPS) injection (a single dose of 4 mg/kg; i.p. injection) and 30 min later, they were injected with STING inhibitor C-176 (a single dose of 30 mg/kg, i.p. injection). Behavioral assessments, biochemical measurements, in vivo and ex vivo electrophysiology techniques were conducted to investigate the association between LPS-induced STING overexpression and cognitive function. RESULTS: Cognitive impairment was associated with STING overexpression and activation of microglia/macrophages. Phagocytosis of microglia/macrophages as well as complement C1q release were increased after LPS injection, leading to abnormal pruning synapses, synaptic transmission reduction, long-term potentiation (LTP) impairment, as well as abnormal theta oscillation in the hippocampus. Notably, STING inhibitor C-176 significantly reversed these changes. CONCLUSIONS: Sepsis-induced STING overexpression in microglia/macrophages may lead to synaptic loss, abnormal theta oscillation and LTP impairment through microglia/macrophages activation and complement C1q modulation, ultimately resulting in cognitive impairment.