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Polychlorinated Biphenyl Quinone Induces Caspase 1-Mediated Pyroptosis through Induction of Pro-inflammatory HMGB1-TLR4-NLRP3-GSDMD Signal Axis.
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2019-04-23 , DOI: 10.1021/acs.chemrestox.8b00376 Wenjing Dong 1 , Qiushuang Zhu 1 , Bingwei Yang 1 , Qi Qin 1 , Yawen Wang 1 , Xiaomin Xia 1 , Xiaokang Zhu 1 , Zixuan Liu 1 , Erqun Song 1 , Yang Song 1
Chemical Research in Toxicology ( IF 3.7 ) Pub Date : 2019-04-23 , DOI: 10.1021/acs.chemrestox.8b00376 Wenjing Dong 1 , Qiushuang Zhu 1 , Bingwei Yang 1 , Qi Qin 1 , Yawen Wang 1 , Xiaomin Xia 1 , Xiaokang Zhu 1 , Zixuan Liu 1 , Erqun Song 1 , Yang Song 1
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Polychlorinated biphenyls (PCBs) are one of the most refractory environmental pollutants. Because of their ubiquitous existence in the biological systems (including human body), it is important to investigate their toxic behavior. Our previous findings demonstrated that a high reactive metabolite of PCB, namely PCB29-pQ, causes several programmed cell death (PCD) such as intrinsic/extrinsic apoptosis and autophagic cell death. The mechanistic study suggested the toxic actions of PCB29-pQ is largely related to its reactive oxygen species (ROS)-generation ability. Pyroptosis is a caspase 1-mediated pro-inflammatory PCD, which was discovered recently. The aim of this study is to seek the linkage between pyroptosis and PCB29-pQ exposures. We first confirmed that PCB29-pQ stimulates Hela cells to produce excess amounts of ROS. Then we found PCB29-pQ activates NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome that mediates caspase 1 activation. The activated caspase 1 (cleaved caspase 1) promotes gasdermin D (GSDMD) cleavage and translocation, which facilitates the release of intracellular inflammatory substances by forming membrane hole, ultimately leading cells to pyroptosis. PCB29-pQ-induced high-mobility group box 1 (HMGB1) release and subsequent binding to its receptors [toll-like receptor 2 (TLR2), TLR4, TLR9, and receptor for advanced glycation end products (RAGE)] are essential for the activation of NLRP3 inflammasome. The current study revealed pyroptosis as a new death mode induced by PCB29-pQ, which enriched the understanding of PCBs-induced toxicity and helped to prevent the toxic effects of residual PCBs in the environment.
中文翻译：
多氯联苯醌通过诱导促炎性HMGB1-TLR4-NLRP3-GSDMD信号轴诱导Caspase 1介导的细胞凋亡。
多氯联苯（PCB）是最难处理的环境污染物之一。由于它们普遍存在于生物系统（包括人体）中，因此研究其毒性行为很重要。我们以前的发现表明，PCB的高反应性代谢产物PCB29-pQ会导致多种程序性细胞死亡（PCD），例如内在/外在凋亡和自噬细胞死亡。机理研究表明，PCB29-pQ的毒性作用与其活性氧（ROS）生成能力在很大程度上相关。细胞凋亡是一种由caspase 1介导的促炎性PCD，最近被发现。这项研究的目的是寻求热解与PCB29-pQ暴露之间的联系。我们首先证实PCB29-pQ刺激Hela细胞产生过量的ROS。然后，我们发现PCB29-pQ激活了介导caspase 1激活的NOD样受体含3个pyrin域的炎症小体。活化的半胱天冬酶1（裂解的半胱天冬酶1）促进加德敏D（GSDMD）的切割和转运，通过形成膜孔促进细胞内炎性物质的释放，最终导致细胞凋亡。PCB29-pQ诱导的高迁移率族盒1（HMGB1）释放并随后与其受体[toll样受体2（TLR2），TLR4，TLR9和晚期糖基化终产物（RAGE）的受体]结合是必需的。激活NLRP3炎性小体。当前的研究揭示了光解是由PCB29-pQ引起的一种新的死亡模式，这丰富了对PCBs诱导的毒性的理解，并有助于防止环境中残留PCBs的毒性作用。
更新日期：2019-04-12
中文翻译：
多氯联苯醌通过诱导促炎性HMGB1-TLR4-NLRP3-GSDMD信号轴诱导Caspase 1介导的细胞凋亡。
多氯联苯（PCB）是最难处理的环境污染物之一。由于它们普遍存在于生物系统（包括人体）中，因此研究其毒性行为很重要。我们以前的发现表明，PCB的高反应性代谢产物PCB29-pQ会导致多种程序性细胞死亡（PCD），例如内在/外在凋亡和自噬细胞死亡。机理研究表明，PCB29-pQ的毒性作用与其活性氧（ROS）生成能力在很大程度上相关。细胞凋亡是一种由caspase 1介导的促炎性PCD，最近被发现。这项研究的目的是寻求热解与PCB29-pQ暴露之间的联系。我们首先证实PCB29-pQ刺激Hela细胞产生过量的ROS。然后，我们发现PCB29-pQ激活了介导caspase 1激活的NOD样受体含3个pyrin域的炎症小体。活化的半胱天冬酶1（裂解的半胱天冬酶1）促进加德敏D（GSDMD）的切割和转运，通过形成膜孔促进细胞内炎性物质的释放，最终导致细胞凋亡。PCB29-pQ诱导的高迁移率族盒1（HMGB1）释放并随后与其受体[toll样受体2（TLR2），TLR4，TLR9和晚期糖基化终产物（RAGE）的受体]结合是必需的。激活NLRP3炎性小体。当前的研究揭示了光解是由PCB29-pQ引起的一种新的死亡模式，这丰富了对PCBs诱导的毒性的理解，并有助于防止环境中残留PCBs的毒性作用。
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