Berberine suppresses influenza virus-triggered NLRP3 inflammasome activation in macrophages by inducing mitophagy and decreasing mitochondrial ROS
Berberine suppresses influenza virus-triggered NLRP3 inflammasome activation in macrophages by inducing mitophagy and decreasing mitochondrial ROS
复制标题
小檗碱通过诱导线粒体自噬和减少线粒体 ROS 来抑制巨噬细胞中流感病毒触发的 NLRP3 炎症小体激活
DOI：
10.1002/jlb.3ma0320-358rr
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发表时间：
2020-07-01
影响因子：
5.5
通讯作者：
Hao, Yu
中科院分区：
文献类型：
--
作者：
Liu, Hui;You, Leiming;Hao, Yu
小檗碱（BBR）是从几种常用的中草药中提取的异喹啉生物碱。我们以前的研究表明，BBR介导的减轻由于炎症引起的肺损伤，并降低流感病毒性肺炎小鼠的死亡率。近年来自噬对抗炎症反应的观点引起了广泛关注。本研究主要通过活性氧-Nod样受体蛋白3（ROS-NLRP 3）通路来探讨BBR是否通过诱导线粒体自噬来抑制NLRP 3炎性小体的活化。我们的研究结果表明，BBR和靶向超氧化物歧化酶模拟物（Mito-TEMPO;一种特异性线粒体ROS清除剂）显着限制NLRP 3炎性体激活，增加线粒体膜电位（MMP），并减少线粒体ROS（mtROS）在感染PR 8流感病毒的J774A.1巨噬细胞的产生。这些观察结果表明，BBR对NLRP 3炎性小体活化的抑制作用与mtROS产生的改善有关。BBR治疗诱导正常的线粒体自噬，从微管相关蛋白1轻链3 II的增加、p62的减少、LC 3和线粒体的共定位以及自噬体的形成可以看出。然而，自噬抑制剂3-甲基腺嘌呤逆转了BBR对流感病毒感染的巨噬细胞中线粒体损伤和NLRP 3炎性体激活的抑制作用，表明线粒体自噬参与介导BBR对NLRP 3炎性体激活的抑制作用。此外，Bcl-2/腺病毒E18-19-kDa相互作用蛋白3（BNIP 3）表达的敲低在一定程度上减弱了BBR对线粒体自噬诱导的作用，这表明BBR诱导的线粒体自噬可能至少部分地以BNIP 3依赖的方式介导。使用给予BBR的流感病毒性肺炎小鼠模型在体内获得了类似的结果。综上所述，这些发现表明，通过线粒体自噬诱导减少ROS产生来限制NLRP 3炎性小体活化可能对BBR介导的流感病毒诱导的炎性病变的缓解至关重要。
Berberine (BBR) is an isoquinoline alkaloid extracted from several commonly used Chinese herbs. Our previous studies demonstrated BBR-mediated alleviation of lung injury due to inflammation and decrease in the mortality of mice with influenza viral pneumonia. The recent argument of autophagy against inflammatory responses has aroused wide concerns. This study focuses on the reactive oxygen species-Nod-like receptor protein 3 (ROS-NLRP3) pathway to investigate whether BBR inhibits NLRP3 inflammasome activation by inducing mitophagy. Our results demonstrate that BBR and mitochondrion-targeted superoxide dismutase mimetic (Mito-TEMPO; a specific mitochondrial ROS scavenger) significantly restricted NLRP3 inflammasome activation, increased mitochondrial membrane potential (MMP), and decreased mitochondrial ROS (mtROS) generation in J774A.1 macrophages infected with PR8 influenza virus. These observations suggest that the inhibitory effects of BBR on NLRP3 inflammasome activation were associated with the amelioration of mtROS generation. BBR treatment induced regular mitophagy, as evident from the increase in microtubule-associated protein 1 light chain 3 II, decrease in p62, colocalization of LC3 and mitochondria, and formation of autophagosomes. However, 3-methyladenine, an autophagy inhibitor, reversed the inhibitory effects of BBR on mitochondrial damage and NLRP3 inflammasome activation in influenza virus-infected macrophages, indicating the involvement of mitophagy in mediating the inhibitory effects of BBR on NLRP3 inflammasome activation. Furthermore, the knockdown of Bcl-2/adenovirus E18-19-kDa interacting protein 3 (BNIP3) expression attenuated the effects of BBR on mitophagy induction to some extent, suggesting that the BBR-induced mitophagy may be, at least in part, mediated in a BNIP3-dependent manner. Similar results were obtained in vivo using a mouse model of influenza viral pneumonia that was administered with BBR. Taken together, these findings suggest that restricting NLRP3 inflammasome activation by decreasing ROS generation through mitophagy induction may be crucial for the BBR-mediated alleviation of influenza virus-induced inflammatory lesions.