Hypercapnia induces IL-1β overproduction via activation of NLRP3 inflammasome: implication in cognitive impairment in hypoxemic adult rats.
Hypercapnia induces IL-1β overproduction via activation of NLRP3 inflammasome: implication in cognitive impairment in hypoxemic adult rats.
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高碳酸血症通过激活 NLRP3 炎性体诱导 IL-1 β 过量产生：对低氧成年大鼠认知障碍的影响
DOI：
10.1186/s12974-017-1051-y
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发表时间：
2018-01-05
影响因子：
9.3
通讯作者：
Zeng HK
中科院分区：
文献类型：
--
作者：
Ding HG;Deng YY;Yang RQ;Wang QS;Jiang WQ;Han YL;Huang LQ;Wen MY;Zhong WH;Li XS;Yang F;Zeng HK
认知障碍是急性呼吸窘迫综合征（ARDS）的常见并发症之一。越来越多的证据表明，白介素 1 β (IL-1β) 在诱导认知功能障碍中的神经元凋亡中发挥作用。用于降低 ARDS 患者肺部发病率的肺保护性通气策略几乎总是导致高碳酸血症。一些研究报告称，高碳酸血症会增加认知障碍和中枢神经系统 (CNS) 外 IL-1β 分泌的风险。然而，缺氧条件下高碳酸血症加重认知障碍的潜在机制仍不清楚。本研究旨在探讨高碳酸血症是否会通过激活缺氧中枢神经系统中的NLRP3（NLR家族，含有pyrin结构域3）炎症小体来增加IL-1β的分泌并加重认知障碍。采用高碳酸血症/低氧血症的SD大鼠，采用Western blotting或双免疫荧光法评估NLRP3、caspase-1、IL-1β、Bcl-2、Bax和caspase-3的表达，并使用该模型进行Morris水迷宫实验。此外，使用caspase-1抑制剂Z-YVAD-FMK处理BV-2小胶质细胞，通过Western blotting或双重免疫荧光确定高碳酸血症增强IL-1β表达的作用是否需要激活NLRP3炎性体。通过因子方差分析分析交互作用。当观察到相互作用时进行简单效应分析。高碳酸血症治疗和低氧治疗对认知障碍、海马神经元凋亡、NLRP3炎性体激活和IL-1β上调存在交互作用。高碳酸血症+缺氧治疗对大鼠学习记忆的损害较单独缺氧治疗更为严重。缺氧海马中高碳酸血症导致 Bcl-2 表达水平降低，而 Bax 和 caspase-3 表达水平升高。在体内和体外，高碳酸血症均显着增加缺氧激活的小胶质细胞中 NLRP3、caspase-1 和 IL-1β 的表达。药物抑制 NLRP3 炎性体激活和 IL-1β 释放可能会改善神经元凋亡。目前的结果表明，高碳酸血症通过缺氧激活的小胶质细胞激活 NLRP3 炎症小体诱导的 IL-1β 过量产生可能会加剧神经炎症，增加神经元细胞死亡，并导致认知障碍的发病机制。
Cognitive impairment is one of common complications of acute respiratory distress syndrome (ARDS). Increasing evidence suggests that interleukin-1 beta (IL-1β) plays a role in inducing neuronal apoptosis in cognitive dysfunction. The lung protective ventilatory strategies, which serve to reduce pulmonary morbidity for ARDS patients, almost always lead to hypercapnia. Some studies have reported that hypercapnia contributes to the risk of cognitive impairment and IL-1β secretion outside the central nervous system (CNS). However, the underlying mechanism of hypercapnia aggravating cognitive impairment under hypoxia has remained uncertain. This study was aimed to explore whether hypercapnia would partake in increasing IL-1β secretion via activating the NLRP3 (NLR family, pyrin domain-containing 3) inflammasome in the hypoxic CNS and in aggravating cognitive impairment. The Sprague-Dawley (SD) rats that underwent hypercapnia/hypoxemia were used for assessment of NLRP3, caspase-1, IL-1β, Bcl-2, Bax, and caspase-3 expression by Western blotting or double immunofluorescence, and the model was also used for Morris water maze test. In addition, Z-YVAD-FMK, a caspase-1 inhibitor, was used to treat BV-2 microglia to determine whether activation of NLRP3 inflammasome was required for the enhancing effect of hypercapnia on expressing IL-1β by Western blotting or double immunofluorescence. The interaction effects were analyzed by factorial ANOVA. Simple effects analyses were performed when an interaction was observed. There were interaction effects on cognitive impairment, apoptosis of hippocampal neurons, activation of NLRP3 inflammasome, and upregulation of IL-1β between hypercapnia treatment and hypoxia treatment. Hypercapnia + hypoxia treatment caused more serious damage to the learning and memory of rats than those subjected to hypoxia treatment alone. Expression levels of Bcl-2 were reduced, while that of Bax and caspase-3 were increased by hypercapnia in hypoxic hippocampus. Hypercapnia markedly increased the expression of NLRP3, caspase-1, and IL-1β in hypoxia-activated microglia both in vivo and in vitro. Pharmacological inhibition of NLRP3 inflammasome activation and release of IL-1β might ameliorate apoptosis of neurons. The present results suggest that hypercapnia-induced IL-1β overproduction via activating the NLRP3 inflammasome by hypoxia-activated microglia may augment neuroinflammation, increase neuronal cell death, and contribute to the pathogenesis of cognitive impairments.
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影响因子：
38.9
作者：
Dellinger RP;Levy MM;Rhodes A;Annane D;Gerlach H;Opal SM;Sevransky JE;Sprung CL;Douglas IS;Jaeschke R;Osborn TM;Nunnally ME;Townsend SR;Reinhart K;Kleinpell RM;Angus DC;Deutschman CS;Machado FR;Rubenfeld GD;Webb S;Beale RJ;Vincent JL;Moreno R;Surviving Sepsis Campaign Guidelines Committee including The Pediatric Subgroup
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影响因子：
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作者：
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影响因子：
3.6
作者：
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通讯作者：
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DOI：
10.1074/jbc.m109.067298
发表时间：
2010-04-02
期刊：
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影响因子：
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作者：
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通讯作者：
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影响因子：
6.7
作者：
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通讯作者：
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