Critical role of NLRP3-caspase-1 pathway in age-dependent isoflurane-induced microglial inflammatory response and cognitive impairment.
Critical role of NLRP3-caspase-1 pathway in age-dependent isoflurane-induced microglial inflammatory response and cognitive impairment.
复制标题
NLRP3-caspase-1 通路在年龄依赖性异氟烷诱导的小胶质细胞炎症反应和认知障碍中的关键作用
DOI：
10.1186/s12974-018-1137-1
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发表时间：
2018-04-17
影响因子：
9.3
通讯作者：
Peng S
中科院分区：
文献类型：
--
作者：
Wang Z;Meng S;Cao L;Chen Y;Zuo Z;Peng S
老年患者在手术和麻醉后更容易发生术后认知功能障碍（POCD）。除了器官功能下降，POCD在老年患者中的具体发病机制尚不清楚。本研究旨在探讨NOD样受体蛋白3（NLRP 3）-caspase-1通路在异氟醚诱导的认知功能障碍中的重要作用。部分小鼠在异氟烷暴露前30 min腹腔注射Ac-YVAD-cmk（8 mg/kg），一种特异性caspase-1抑制剂。异氟醚麻醉后1周进行Morris水迷宫实验。异氟醚麻醉后24小时采集脑组织。Western blotting检测海马NLRP 3、白细胞介素（IL）-1β、IL-18的表达。小鼠小胶质细胞系BV-2和原代小胶质细胞培养物在暴露于异氟烷之前通过脂多糖引发30分钟。NLRP3是下调的RNA interference.ResultsCompared to the young mice，aged mice had an increased expression of NLRP3 in the hippocampus.异氟烷诱导老年小鼠认知功能障碍和海马炎症，但在年轻小鼠中没有。Ac-YVAD-cmk预处理可减弱上述作用（P< 0.05）。异氟醚激活NLRP 3-caspase-1通路，增加脂多糖预处理的细胞IL-18和IL-1β的分泌，而未预处理的细胞则无此作用。结论老年小鼠脑内NLRP 3启动状态可能参与了异氟醚诱导的海马炎症反应和认知功能障碍。
BackgroundElderly patients are more likely to suffer from postoperative cognitive dysfunction (POCD) after surgery and anesthesia. Except for declined organ function, the particular pathogenesis of POCD in elderly patients remains unknown. This study is carried out to determine the critical role of the NOD-like receptor protein 3 (NLRP3)-caspase-1 pathway in isoflurane-induced cognitive impairment.MethodsYoung (6–8 months old) and aged (14 months old) healthy male C57BL/6 mice were exposed to 1.5% isoflurane for 2 h. Some mice received intraperitoneal injection of Ac-YVAD-cmk (8 mg/kg), a specific inhibitor of caspase-1, 30 min before the isoflurane exposure. Morris water maze test was carried out 1 week after the isoflurane anesthesia. Brain tissues were harvested 24 h after the isoflurane anesthesia. Western blotting was carried out to detect the expression of NLRP3, interleukin (IL)-1β, and IL-18 in the hippocampus. Mouse microglial cell line BV-2 and primary microglial cultures were primed by lipopolysaccharide for 30 min before being exposed to isoflurane. NLRP3 was downregulated by RNA interference.ResultsCompared to young mice, aged mice had an increased expression of NLRP3 in the hippocampus. Isoflurane induced cognitive impairment and hippocampal inflammation in aged mice but not in young mice. These effects were attenuated by Ac-YVAD-cmk pretreatment (P< 0.05). Isoflurane activated NLRP3-caspase-1 pathway and increased the secretion of IL-18 and IL-1β in cells pretreated with lipopolysaccharide but not in cells without pretreatment. Downregulation of NLRP3 attenuated the activation of NLRP3 inflammasome by isoflurane.ConclusionsNLRP3 priming status in aged mouse brain may be involved in isoflurane-induced hippocampal inflammation and cognitive impairment.
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影响因子：
2.7
作者：
Lin, Daowei;Cao, Lin;Wang, Zhi;Li, Jiejie;Washington, Jacqueline M.;Zuo, Zhiyi
通讯作者：
Zuo, Zhiyi
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5
作者：
Norden DM;Godbout JP
通讯作者：
Godbout JP
影响因子：
13.5
作者：
Harry, G. Jean
通讯作者：
Harry, G. Jean
白介素-1β在术后认知功能障碍中的作用。
影响因子：
11.2
作者：
Cibelli M;Fidalgo AR;Terrando N;Ma D;Monaco C;Feldmann M;Takata M;Lever IJ;Nanchahal J;Fanselow MS;Maze M
通讯作者：
Maze M