STING Driving Synaptic Phagocytosis of Hippocampal Microglia/Macrophages Contributes to Cognitive Impairment in Sepsis-Associated Encephalopathy in Mice

IF 4.8 1区 医学 Q1 NEUROSCIENCES
Xin Lv, Min Jia, Xiao Feng, Jia-xiong Jian, Jian-jun Yang, Da-qing Ma, Mu-huo Ji, Yu-gang Diao, Jin-chun Shen
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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.

Abstract Image

STING驱动海马小胶质细胞/巨噬细胞突触吞噬与脓毒症相关脑病小鼠认知障碍有关
背景:脓毒症相关脑病(SAE)是脓毒症患者预后不良的严重神经系统并发症。越来越多的证据表明,干扰素基因刺激因子(STING)在神经炎症和认知障碍中起着至关重要的作用。然而,与STING变化相关的脓毒症是否会导致认知障碍尚不清楚。方法:雄性成年小鼠注射脂多糖(LPS)(单次剂量4 mg/kg;30 min后注射STING抑制剂C-176(单次剂量30 mg/kg,腹腔注射)。通过行为评估、生化测量、体内和离体电生理技术来研究lps诱导的STING过表达与认知功能之间的关系。结果:认知障碍与小胶质细胞/巨噬细胞的STING过表达和活化有关。注射LPS后,小胶质细胞/巨噬细胞吞噬增加,补体C1q释放增加,导致突触剪枝异常,突触传递减少,长期增强(LTP)功能受损,海马theta振荡异常。值得注意的是,STING抑制剂C-176显著逆转了这些变化。结论:败血症诱导的STING在小胶质细胞/巨噬细胞中过表达,可能通过小胶质细胞/巨噬细胞活化和补体C1q调节导致突触丢失、θ振荡异常和LTP损伤,最终导致认知功能障碍。
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来源期刊
CNS Neuroscience & Therapeutics
CNS Neuroscience & Therapeutics 医学-神经科学
CiteScore
7.30
自引率
12.70%
发文量
240
审稿时长
2 months
期刊介绍: CNS Neuroscience & Therapeutics provides a medium for rapid publication of original clinical, experimental, and translational research papers, timely reviews and reports of novel findings of therapeutic relevance to the central nervous system, as well as papers related to clinical pharmacology, drug development and novel methodologies for drug evaluation. The journal focuses on neurological and psychiatric diseases such as stroke, Parkinson’s disease, Alzheimer’s disease, depression, schizophrenia, epilepsy, and drug abuse.
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