Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity.
Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity.
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Icariside I 特异性促进 ATP 或尼日利亚菌素诱导的 NLRP3 炎性体激活并引起特殊的肝毒性。
DOI：
10.1186/s12964-020-00647-1
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发表时间：
2021-02-11
期刊：
影响因子：
--
通讯作者：
Xiao X
中科院分区：
文献类型：
--
作者：
Gao Y;Xu G;Ma L;Shi W;Wang Z;Zhan X;Qin N;He T;Guo Y;Niu M;Wang J;Bai Z;Xiao X
表皮生长因子（EF）是治疗骨折和关节疾病的常用药物，但其潜在的肝毒性限制了其临床应用。我们前期的研究证实EF可导致特异质药物性肝损伤（IDILI）和肝细胞凋亡，但其机制尚不清楚。研究表明，NLRP 3炎性体在IDILI等多种炎症性疾病的发生中发挥重要作用。特异性刺激诱导的NLRP 3炎性小体活化可能是导致肝损伤的关键策略。因此，选择来自EF的主要化合物来测试EF中的成分是否可以激活NLRP 3炎性体并诱导IDILI。用淫羊藿苷I处理骨髓源性巨噬细胞（BMDM），然后用炎性刺激物刺激BMDM，测定其产生半胱天冬酶1（caspase-1）和白细胞介素1β（IL-1β）以及乳酸脱氢酶（LDH）的释放。通过测定细胞内钾离子浓度、ASC寡聚化和活性氧（ROS）的产生来评价淫羊藿苷I刺激炎性小体活化的机制。使用NLRP 3疾病的小鼠模型来测试淫羊藿苷I是否具有肝细胞凋亡作用并在体内促进NLRP 3炎性体活化。淫羊藿苷I特异性地增强由ATP或尼日利亚菌素触发的NLRP 3炎性体活化，但不增强SiO2、poly（I：C）或胞质LPS触发的NLRP 3炎性体活化。此外，淫羊藿苷I不改变NLRC 4和AIM 2炎性小体的活化。机械上，单独的淫羊藿苷I不诱导线粒体活性氧（mtROS），这是NLRP 3炎性小体激活的关键上游事件之一;然而，淫羊藿苷I增加由ATP或尼日利亚菌素诱导的mtROS产生，而不是SiO2。重要的是，在LPS介导的IDILI易感性小鼠模型中，淫羊藿苷I导致肝损伤和NLRP 3炎性体活化，但在用MCC 950预处理的LPS介导的小鼠模型中不存在淫羊藿苷I的作用，MCC 950用于模拟NLRP 3炎性体活化的敲低。我们的研究表明，淫羊藿苷I特异性地促进ATP或尼日利亚菌素诱导的NLRP 3炎性小体激活，并导致特异性肝毒性。研究结果表明，在患有与ATP或尼日利亚菌素诱导的NLRP 3炎性小体激活相关的疾病的患者中应避免使用淫羊藿苷I或EF，这可能是IDILI的危险因素。视频摘要。在线版本包含补充材料，可通过10.1186/s12964-020-00647-1获取。
Epimedii Folium (EF) is commonly used for treating bone fractures and joint diseases, but the potential hepatotoxicity of EF limits its clinical application. Our previous study confirms that EF could lead to idiosyncratic drug-induced liver injury (IDILI) and hepatocyte apoptosis, but the mechanism remains unknown. Studies have shown that NLRP3 inflammasome plays an important role in the development of various inflammatory diseases such as IDILI. Specific stimulus-induced NLRP3 inflammasome activation may has been a key strategy for lead to liver injury. Therefore, main compounds derived from EF were chosen to test whether the ingredients in EF could activate the NLRP3 inflammasome and to induce IDILI. Bone-marrow-derived macrophages (BMDMs) were treated with Icariside I, and then stimulated with inflammasome stimuli and assayed for the production of caspase-1 and interleukin 1β (IL-1β) and the release of lactate dehydrogenase (LDH). Determination of intracellular potassium, ASC oligomerization as well as reactive oxygen species (ROS) production were used to evaluate the stimulative mechanism of Icariside I on inflammasome activation. Mouse models of NLRP3 diseases were used to test whether Icariside I has hepatocyte apoptosis effects and promoted NLRP3 inflammasome activation in vivo. Icariside I specifically enhances NLRP3 inflammasome activation triggered by ATP or nigericin but not SiO2, poly(I:C) or cytosolic LPS. Additionally, Icariside I does not alter the activation of NLRC4 and AIM2 inflammasomes. Mechanically, Icariside I alone does not induce mitochondrial reactive oxygen species (mtROS), which is one of the critical upstream events of NLRP3 inflammasome activation; however, Icariside I increases mtROS production induced by ATP or nigericin but not SiO2. Importantly, Icariside I leads to liver injury and NLRP3 inflammasome activation in an LPS-mediated susceptibility mouse model of IDILI, but the effect of Icariside I is absent in the LPS-mediated mouse model pretreated with MCC950, which is used to mimic knockdown of NLRP3 inflammasome activation. Our study reveals that Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity. The findings suggest that Icariside I or EF should be avoided in patients with diseases related to ATP or nigericin-induced NLRP3 inflammasome activation, which may be risk factors for IDILI. Video abstract. The online version contains supplementary material available at 10.1186/s12964-020-00647-1.