Mitochondria-targeted drugs enhance Nlrp3 inflammasome-dependent IL-1β secretion in association with alterations in cellular redox and energy status.
Mitochondria-targeted drugs enhance Nlrp3 inflammasome-dependent IL-1β secretion in association with alterations in cellular redox and energy status.
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DOI：
10.1016/j.freeradbiomed.2013.01.025
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发表时间：
2013-07
影响因子：
7.4
通讯作者：
Ckless, Karina
中科院分区：
文献类型：
--
作者：
Jabaut, Joshua;Ather, Jennifer L.;Taracanova, Alexandra;Poynter, Matthew E.;Ckless, Karina
关键词：
Nlrp3 炎症小体响应一系列环境和内源性分子而被激活，导致骨髓细胞进行 caspase-1 依赖性 IL-1β 加工和分泌。几种已鉴定的 Nlrp3 炎性体激活剂也会触发活性氧 (ROS) 的产生。然而，NADPH 氧化酶是炎性体激活过程中 ROS 产生的主要来源的最初概念越来越不被接受。因此，最近人们探讨了线粒体衍生的 ROS 的重要性。在本研究中，我们探讨了线粒体功能障碍和 ROS 产生对原代小鼠腹腔巨噬细胞中血清淀粉样蛋白 A (SAA) 诱导的 Nlrp3 炎性体刺激和 IL-1β 分泌的影响。为了诱导线粒体功能障碍，我们使用了抗霉素 A（可阻断复合物 III 的电子流）和羰基氰化物-对三氟甲氧基苯腙 (FCCP)（一种线粒体氧化磷酸化解偶联剂）。我们还利用了一种针对线粒体的超氧化物歧化酶 (SOD) 模拟物 MnTBAP，以及广谱抗氧化剂 DPI（二亚苯基氯化铵）和依布硒啉。我们的研究结果表明，SAA 单独以时间依赖性方式诱导线粒体 ROS。我们观察到，仅在刺激前添加时，MnTBAP 和依布硒啉才能阻断 SAA 引起的 IL-1β 分泌，而 DPI 则可增强 IL-1β 分泌。令人惊讶的是，这些影响与细胞内或线粒体 ROS 水平没有直接关系。我们还发现，线粒体靶向药物无论对线粒体功能和 ROS 水平有何影响，都会增加 IL-1β 分泌，这表明线粒体 ROS 依赖和独立机制在 SAA 刺激的细胞中的 Nlrp3 炎性体 - IL-1β 分泌轴中发挥作用。最后，我们发现 FCCP 显着维持了 Nlrp3 炎性体复合物的关联，这可以解释所测试的药物中在增强 SAA 处理的细胞中 IL-1β 分泌方面的最强效果。总体而言，我们的数据表明，Nlrp3 炎性体 - IL-1β 分泌轴是一种高度调控的炎症途径，不仅容易受到线粒体或细胞内 ROS 变化的影响，而且还容易受到线粒体整体功能变化的影响。
The Nlrp3 inflammasome is activated in response to an array of environmental and endogenous molecules leading to caspase-1-dependent IL-1β processing and secretion by myeloid cells. Several identified Nlrp3 inflammasome activators also trigger reactive oxygen species (ROS) production. However, the initial concept that NADPH oxidases are the primary source of ROS production during inflammasome activation is becoming less accepted. Therefore, the importance of mitochondrial-derived ROS has been recently explored. In this study, we explore the impact of mitochondria dysfunction and ROS production on Nlrp3 inflammasome stimulation and IL-1β secretion induced by serum amyloid A (SAA) in primary mouse peritoneal macrophages. To induce mitochondrial dysfunction, we utilized antimycin A, which blocks electron flow at complex III, and carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), a mitochondrial oxidative phosphorylation uncoupler. We also utilized a superoxide dismutase (SOD) mimetic, MnTBAP, which targets the mitochondria, as well as the broad spectrum antioxidants DPI (diphenyleneiodonium chloride) and ebselen. Our findings demonstrate that SAA alone induces mitochondrial ROS in a time-dependent manner. We observed that MnTBAP and ebselen blocked IL-1β secretion caused by SAA only when added prior to stimulation, and DPI augmented IL-1β secretion. Surprisingly, these effects were not directly related to intracellular or mitochondrial ROS levels. We also found that mitochondrial-targeted drugs increased IL-1β secretion regardless of their impact on mitochondrial function and ROS levels, suggesting that mitochondrial ROS-dependent and -independent mechanisms play a role in the Nlrp3 inflammasome - IL-1β secretion axis in SAA-stimulated cells. Finally, we found that FCCP significantly sustained the association of the Nlrp3 inflammasome complex, which could explain the most robust effect among the drugs tested in enhancing IL-1β secretion in SAA-treated cells. Overall, our data suggest that the Nlrp3 inflammasome - IL-1β secretion axis is a very highly-regulated inflammatory pathway that is not only susceptible to changes in mitochondrial or intracellular ROS, but also to changes in overall mitochondrial function.
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