Mesoporous silica nanoparticles induced hepatotoxicity via NLRP3 inflammasome activation and caspase-1-dependent pyroptosis
Mesoporous silica nanoparticles induced hepatotoxicity via NLRP3 inflammasome activation and caspase-1-dependent pyroptosis
复制标题
介孔二氧化硅纳米颗粒通过 NLRP3 炎性体激活和 caspase-1 依赖性细胞焦亡诱导肝毒性
DOI：
10.1039/c8nr00554k
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发表时间：
2018-05-21
期刊：
影响因子：
6.7
通讯作者：
Ju, Dianwen
中科院分区：
文献类型：
--
作者：
Zhang, Xuyao;Luan, Jingyun;Ju, Dianwen
介孔二氧化硅纳米颗粒（MSNs）在生物医学上的应用越来越广泛，引起了人们对其毒理学效应的极大关注；msn的毒性仍不明确，其潜在机制也不清楚。我们进行了这项研究，以确定持续给药的肝毒性和潜在的机制。MSNs以剂量和时间依赖的方式引起肝L02细胞的细胞毒性。然后，msn在肝细胞中引发nod样受体蛋白3 （NLRP3）炎性体活化，导致caspase-1依赖性焦亡，这是一种新的细胞死亡方式。通过组织损伤、血清丙氨酸转氨酶和血清天冬氨酸转氨酶的增加，在体内给药可引起肝毒性。值得注意的是，NLRP3炎性体和焦亡在治疗期间也被激活。同时，在NLRP3基因敲除小鼠和caspase-1基因敲除小鼠中，msn诱导的肝脏炎症和肝毒性可以被消除。此外，实验表明，msn诱导线粒体！活性氧（reactive oxygen species， ROS）的产生和活性氧清除剂可以减弱msn激活的NLRP3炎性小体和肝脏的焦亡。综上所述，这些数据表明msn通过NLRP3炎性体激活引发肝脏炎症和肝细胞焦亡，而NLRP3炎性体是由msn诱导的ROS生成引起的。我们的研究为MSNs的肝毒性及其潜在机制提供了新的见解，并为提高MSNs的生物安全性提供了潜在的方法。
Increased biomedical applications of mesoporous silica nanoparticles (MSNs) raise considerable attention concerning their toxicological effects; the toxicities of MSNs are still undefined and the underlying mechanisms are unknown. We conducted this study to determine the hepatotoxicity of continuous administration of MSNs and the potential mechanisms. MSNs caused cytotoxicity in hepatic L02 cells in a dose- and time-dependent manner. Then, MSNs were shown to elicit NOD-like receptor protein 3 (NLRP3) inflammasome activation in hepatocytes, leading to caspase-1-dependent pyroptosis, a novel manner of cell death. In vivo MSN administration triggered hepatotoxicity as indicated by increased histological injury, serum alanine aminotransferase and serum aspartate aminotransferase. Notably, NLRP3 inflammasome and pyroptosis were also activated during the treatment. Meanwhile, in NLRP3 knockout mice and caspase-1 knockout mice, MSN-induced liver inflammation and hepatotoxicity could be abolished. Furthermore, experiments indicated that MSNs induced mitochondria! reactive oxygen species (ROS) generation, and the ROS scavenger could attenuate the MSN-activated NLRP3 inflammasomes and pyroptosis in the liver. Collectively, these data suggested that MSNs triggered liver inflammation and hepatocyte pyroptosis through NLRP3 inflammasome activation, which was caused by MSN-induced ROS generation. Our study provided novel insights into the hepatotoxicity of MSNs and the underlying mechanisms, and facilitated the potential approach to increase the biosafety of MSNs.