GENETIC DELETION OF TRANSLOCATOR PROTEIN EXACERBATES POST-SEPSIS SYNDROME WITH ACTIVATION OF THE C1Q PATHWAY IN SEPTIC MOUSE MODEL
GENETIC DELETION OF TRANSLOCATOR PROTEIN EXACERBATES POST-SEPSIS SYNDROME WITH ACTIVATION OF THE C1Q PATHWAY IN SEPTIC MOUSE MODEL
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DOI：
10.1097/shk.0000000000002030
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发表时间：
2023-01-01
期刊：
影响因子：
3.1
通讯作者：
Aizawa，Hidenori
中科院分区：
文献类型：
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作者：
Kikutani，Kazuya;Hosokawa，Koji;Aizawa，Hidenori
大量脓毒症患者的生存表现出精神和认知障碍，称为脓毒症后综合征。了解潜在的病理生理学对于开发有效的疗法至关重要。转运蛋白18 kDa（TSPO）是一种涉及中枢神经系统炎症、氧化应激和类固醇生成的多方面线粒体蛋白。尽管有越来越多的证据表明TSPO是精神和神经退行性疾病的生物标志物，但这种蛋白质在脓毒症后综合征中的作用仍然难以捉摸。本研究的目的是研究TSPO在盲肠结扎和穿刺（CLP）手术诱导的脓毒症后与精神和认知障碍相关的小鼠行为长期损害中的作用。将动物分成三组：（i）野生型（WT）+假手术，（ii）WT+ CLP，和（iii）TSP 0敲除+ CLP。术后17天评估生存率和体重变化。通过高架十字迷宫、悬尾试验、Y型迷宫、旷场试验和握力试验，分别评估存活小鼠的焦虑样行为、抑郁样行为、认知功能、自主活动和前肢肌力。TSPO基因的缺失导致高死亡率和长期的体重减轻，并在CLP手术后17天（而不是手术前）加重焦虑样和抑郁样行为伴认知障碍。海马的RNA-seq分析显示，C1 q补体途径中基因（C1 qb、C1 qc和Tyrobp）的上调与CLP手术后很长时间出现的焦虑样行为显著相关。这些基因的表达预测了其他行为特征，包括尾部悬吊试验中的抑郁样行为和握力障碍，支持了C1 q通路在脓毒症后综合征中的作用。由于C1 q通路最近作为病理性突触消除的标签引起了人们的兴趣，因此目前的研究表明C1 q通路参与了脓毒症后综合征中观察到的精神和认知障碍。
Significant numbers of patients who survive sepsis exhibit psychiatric and cognitive impairments, termed post-sepsis syndrome. Understanding the underlying pathophysiology is essential to develop effective therapies. Translocator protein 18 kDa (TSPO) is a multifaceted mitochondrial protein implicated in inflammation, oxidative stress, and steroidogenesis in the central nervous system. Despite accumulated evidence demonstrating TSPO is a biomarker in psychiatric and neurodegenerative disorders, the role of this protein in post-sepsis syndrome remains elusive. The aim of this study was to investigate the role of TSPO in the long-term impairment of mouse behavior associated with psychiatric and cognitive impairments following sepsis induced by cecal ligation and puncture (CLP) surgery. Animals were divided into three groups:(i) wild type (WT)+ sham,(ii) WT+ CLP, and (iii) TSPO knock out+ CLP. Survival rate and body weight change were assessed up to 17 days after surgeries. Then, we also assessed anxiety-like behavior, depression-like behavior, cognitive function, locomotor activity, and forelimb muscle strength in surviving mice by elevated plus maze, tail suspension test, y-maze, open field test, and grip strength test, respectively. Deletion of the TSPO gene led to high mortality and prolonged weight loss and exacerbated anxiety-like and depressive-like behavior with cognitive impairment 17 days after, but not before, CLP surgery. RNA-seq analysis of the hippocampus revealed the upregulation of genes (C1qb, C1qc, and Tyrobp) in C1q complement pathways correlated significantly with anxiety-like behavior that appeared long after CLP surgery. The expressions of these genes predicted other behavioral traits, including depressive-like behavior in the tail suspension test and grip power impairment, supporting the role of the C1q pathway in post-sepsis syndrome. Because the C1q pathway has recently attracted interest as a tag for pathological synaptic elimination, the current study suggests the C1q pathway is involved in the psychiatric and cognitive impairments observed in post-sepsis syndrome.