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Mesoporous silica nanoparticles induced hepatotoxicity via NLRP3 inflammasome activation and caspase-1-dependent pyroptosis

Abstract

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 the NOD-like receptor protein 3 (NLRP3) inflammasomes activation in hepatocytes, leading to caspase-1-dependent pyroptosis, a novel manner of cell death. In vivo, MSNs 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, MSNs-induced liver inflammation and hepatotoxicity could be abolished. Furthermore, experiments indicated that MSNs induced mitochondrial reactive oxygen species (ROS) generation, and ROS scavenger could attenuate the MSNs-activated NLRP3 inflammasomes and pyroptosis in liver. Collectively, these data suggested that MSNs triggered liver inflammation and hepatocyte pyroptosis through NLRP3 inflammasomes activation, which was caused by MSNs-induced ROS generation. Our study provided novel insights into hepatotoxicity of MSNs and the underlying mechanisms, and facilitated the potential approach to increase of the biosafety of MSNs.

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Publication details

The article was received on 20 Jan 2018, accepted on 05 Apr 2018 and first published on 06 Apr 2018


Article type: Paper
DOI: 10.1039/C8NR00554K
Citation: Nanoscale, 2018, Accepted Manuscript
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    Mesoporous silica nanoparticles induced hepatotoxicity via NLRP3 inflammasome activation and caspase-1-dependent pyroptosis

    X. Zhang, J. Luan, W. Chen, J. Fan, Y. Nan, Y. Wang, Y. Liang, G. Meng and D. Ju, Nanoscale, 2018, Accepted Manuscript , DOI: 10.1039/C8NR00554K

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