Nuclear Factor E2-Related Factor-2 Negatively Regulates NLRP3 Inflammasome Activity by Inhibiting Reactive Oxygen Species-Induced NLRP3 Priming
Nuclear Factor E2-Related Factor-2 Negatively Regulates NLRP3 Inflammasome Activity by Inhibiting Reactive Oxygen Species-Induced NLRP3 Priming
复制标题
核因子 E2 相关因子 2 通过抑制活性氧诱导的 NLRP3 启动负向调节 NLRP3 炎症小体活性
DOI：
10.1089/ars.2015.6615
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发表时间：
2017-01-01
影响因子：
6.6
通讯作者：
Hu, Rong
中科院分区：
文献类型：
--
作者：
Liu, Xiuting;Zhang, Xin;Hu, Rong
目的：NLRP3炎性小体是一种多蛋白复合物，可保护宿主免受多种病原体的侵害。然而，调节NLRP3炎性体激活的分子机制，特别是在启动阶段，仍然知之甚少。本研究旨在阐明核因子e2相关因子-2 （Nrf2）对NLRP3炎性小体激活的负调控作用。结果：我们报道了Nrf2激活抑制NLRP3表达、caspase-1切割和随后的IL-1 β生成。与正常细胞相比，nrf2缺陷细胞的cleaved - caspase-1表达上调，这是由于过量活性氧（ROS）导致NLRP3转录增加所致。此外，NLRP3炎性体的启动对H2O2或鱼烯酮诱导的外源性ROS水平敏感。与脂多糖相比，鱼藤酮与三磷酸腺苷联合激活NLRP3炎性体的活性更高，表明ROS促进了启动步骤。此外，nrf2诱导的NQO1参与了NLRP3炎性小体的抑制。在体内铝诱导的腹膜炎小鼠模型中，Nrf2激活抑制了典型的IL-1信号依赖性炎症，而与野生型小鼠相比，Nrf2-/-小鼠表现出免疫细胞募集和IL-1 β生成的显著增加。创新：我们阐明了Nrf2激活诱导的NQO1表达对NLRP3炎症小体失活的影响及其可能机制，并建立了Nrf2通路在ros诱导的NLRP3启动中的新调控作用。结论：我们证明Nrf2通过抑制启动步骤负向调节NLRP3炎症小体活性，并提示Nrf2可能是一些不受控制的炎症小体激活相关疾病的潜在靶标。
Aims: The NLRP3 inflammasome is a multiprotein complex that protects hosts against a variety of pathogens. However, the molecular mechanisms of modulating NLRP3 inflammasome activation, especially at the priming step, are still poorly understood. This study was designed to elucidate the negative regulation of nuclear factor E2-related factor-2 (Nrf2) on the activation of NLRP3 inflammasome.Results: We reported that Nrf2 activation inhibited NLRP3 expression, caspase-1 cleavage, and subsequent IL-1 beta generation. Compared with normal cells, Nrf2-deficient cells showed upregulated cleaved caspase-1, which were attributed to the increased transcription of NLRP3 caused by excess reactive oxygen species (ROS). Furthermore, priming of the NLRP3 inflammasome was sensitive to the exogenous ROS levels induced by H2O2 or rotenone. Combined with adenosine triphosphate, rotenone triggered higher activity of the NLRP3 inflammasome compared with lipopolysaccharide, suggesting that ROS promoted the priming step. In addition, Nrf2-induced NQO1 was involved in the inhibition of the NLRP3 inflammasome. In an in vivo alum-induced peritonitis mouse model, Nrf2 activation suppressed typical IL-1 signaling-dependent inflammation, whereas Nrf2-/-mice exhibited a significant increase in the recruitment of immune cell and the generation of IL-1 beta compared with wild-type mice.Innovation: We elucidated the effects and possible mechanisms of Nrf2 activation-induced NQO1 expression on NLRP3 inflammasome inactivation and established a novel regulatory role of the Nrf2 pathway in ROS-induced NLRP3 priming.Conclusions: We demonstrated Nrf2 negatively regulating NLRP3 inflammasome activity by inhibiting the priming step and suggested that Nrf2 could be a potential target for some uncontrolled inflammasome activation-associated diseases.