X-11-5-27, a daidzein derivative, inhibits NLRP3 inflammasome activity via promoting autophagy
X-11-5-27, a daidzein derivative, inhibits NLRP3 inflammasome activity via promoting autophagy
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X-11-5-27 是一种黄豆苷元衍生物，通过促进自噬抑制 NLRP3 炎性体活性
DOI：
10.1016/j.yexcr.2017.09.022
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发表时间：
2017
影响因子：
3.7
通讯作者：
Hu Rong
中科院分区：
文献类型：
--
作者：
Zhou Wei;Liu Xiuting;Cheng Kunpeng;Zhang Xin;Lu Jinrong;Hu Rong
NLRP3炎症体是一种胞质多蛋白复合体，在感染或损伤的反应中起着关键作用，然而，NLRP3炎症体的异常激活是有害的。在我们的研究中，我们研究了大豆苷元衍生物X-11-5-27对NLRP3炎症体的抑制作用。结果表明，X-11-5-27可剂量依赖性地抑制NLRP3炎症体的激活，进而抑制Caspase-1的裂解和IL-1β的成熟。此外，我们还发现X-11-5-27对NLRP3炎症小体的形成有明显的抑制作用。同时，X-11-5-27呈时间和剂量依赖性地抑制ROS和超氧化物歧化酶的产生。此外，X-11-5-27还增强了超氧化物歧化酶清除ROS释放的活性。X-11-5-27的这种抑制作用是由于保护线粒体的动态平衡，并在鱼藤酮处理后被消除。值得注意的是，X-11-5-27被发现在巨噬细胞中触发自噬，进而抑制NLRP3炎症体的激活。此外，X-11-5-27处理后，PI3K/AKT/mTOR信号通路中蛋白的磷酸化状态显著降低。综上所述，我们的结果表明自噬介导的ROS减少是X-11-5-27诱导的NLRP3火焰体失活的原因。这些结果可能有助于指导关于使用X-11-5-27缓解炎症小体驱动的高炎症的决定。
NLRP3 inflammasome is a cytoplasmic multiprotein complex which plays a critical role in response to infection or injury, however, aberrant NLRP3 inflammasome activation is deleterious. In our study, we investigate the inhibitory effect of X-11-5-27, a daidzein derivative, on the NLRP3 inflammasome. The results showed that the activation of NLRP3 inflammasome was inhibited by X-11-5-27 in a dose-dependent manner, followed by a decrease in the cleavage of caspase-1 and maturation of IL-1β. Furthermore, we found that X-11-5-27 significantly restrained the formation of NLRP3 inflammasome. At the same time, X-11-5-27 time- and dose-dependently decreased the production of ROS and superoxide. In addition, X-11-5-27 enhanced the activity of SOD to scavenge ROS release. This inhibitory effect of X-11-5-27 was due to the protection of mitochondrial homeostasis and was abolished after the treatment of rotenone. Notably, X-11-5-27 was found to trigger autophagy in macrophages, which in turn inhibited the NLRP3 inflammasome activation. Moreover, the phosphorylation states of the proteins in PI3K/AKT/mTOR signaling pathway were dramatically decreased after X-11-5-27 treatment. In conclusion, our results demonstrate that autophagy-mediated ROS reduction is responsible for X-11-5-27-induced NLRP3 flammasome inactivation. And these results may help guide decisions regarding the use of X-11-5-27 in relieving the inflammasome-driven hyper-inflammation.