Pharmacological and Genetic Inhibition of Translocator Protein 18 kDa Ameliorated Neuroinflammation in Murine Endotoxemia Model
Pharmacological and Genetic Inhibition of Translocator Protein 18 kDa Ameliorated Neuroinflammation in Murine Endotoxemia Model
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DOI：
10.1097/shk.0000000000001703
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发表时间：
2021-07-01
期刊：
影响因子：
3.1
通讯作者：
Aizawa, Hidenori
中科院分区：
文献类型：
--
作者：
Giga, Hiroshi;Ji, Bin;Aizawa, Hidenori
脓毒症相关脑病（SAE）是一种与脓毒症相关的弥漫性脑功能障碍。制定有效的早期诊断和治疗干预策略对于预防SAE预后不良至关重要。转运蛋白18kda （TSPO）是一种涉及类固醇生成和炎症反应的线粒体蛋白。尽管越来越多的证据表明TSPO参与中枢神经系统的神经炎症反应，但TSPO在SAE中的可能作用仍不清楚。本研究的目的是在小鼠全身注射LPS 24小时后，研究TSPO在神经炎症中的作用，结果一致显示小胶质细胞激活和行为抑制。定量聚合酶链反应分析显示，全身注射LPS诱导海马TSPO表达，与促炎细胞因子如肿瘤坏死因子- α和白细胞介素-1 β的增加有关。有趣的是，TSPO拮抗剂ONO-2952预处理或种系删除TSPO基因显示出抗炎作用，显著抑制lps诱导的这些细胞因子的产生。ONO-2952基因敲除或TSPO基因敲除所证明的这些效应与行为抑制的显著恢复有关，正如在开阔场分析中运动活动的改善所显示的那样。组织学分析表明，ONO-2952预处理可抑制lps诱导的小鼠海马表达tspo的小胶质细胞的活化。总之，这些结果表明TSPO在SAE小鼠模型中起着关键作用。基于这一发现，监测TSPO活性，以及动物模型中内毒素血症及其后遗症的进展，将加深我们对SAE潜在分子机制的理解。
Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction associated with sepsis. The development of an effective strategy for early diagnosis and therapeutic intervention is essential for the prevention of poor prognosis of SAE. Translocator protein 18 kDa (TSPO) is a mitochondrial protein implicated in steroidogenesis and inflammatory responses. Despite accumulating evidence that implicates TSPO in the neuroinflammatory response of the central nervous system, the possible role of TSPO in SAE remains unclear. The aim of this study is to address a role of TSPO in neuroinflammation using mice 24 h after systemic injection of LPS, which consistently demonstrated microglial activation and behavioral inhibition. Quantitative polymerase chain reaction analysis revealed that hippocampal TSPO expression was induced following the systemic LPS injection, associated with an increase in pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1 beta. Interestingly, pretreatment with the TSPO antagonist, ONO-2952, or germ-line deletion of the TSPO gene exhibited an anti-inflammatory effect with significant suppression of LPS-induced production of those cytokines. These effects demonstrated by the ONO-2952 or TSPO knockout were associated with significant recovery from behavioral inhibition, as shown by improved locomotor activity in the open field analysis. Histological analysis revealed that ONO-2952 pretreatment suppressed the LPS-induced activation of TSPO-expressing microglia in the hippocampus of mice. Collectively, these results suggest that TSPO plays a critical role in the SAE mouse model. Based on this finding, monitoring TSPO activity, as well as the progress of endotoxemia and its sequelae in the animal model, would deepen our understanding of the underlying molecular mechanism of SAE.