Hepatitis B virus X protein promotes liver cell pyroptosis under oxidative stress through NLRP3 inflammasome activation
Open Access
- 27 April 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Inflammation Research
- Vol. 69 (7), 683-696
- https://doi.org/10.1007/s00011-020-01351-z
Abstract
Objective Hepatitis B virus X protein (HBx) is a pivotal factor for HBV-induced hepatitis. Herein, we sought to investigate HBx-mediated NLR pyrin domain containing 3 (NLRP3) inflammasome activation and pyroptosis under oxidative stress. Methods The effect of HBx on the NLRP3 inflammasome was analyzed by enzyme-linked immunosorbent assays, quantitative reverse transcription-polymerase chain reaction, western blotting, and immunofluorescence in hepatic HL7702 cells. Pyroptosis was evaluated by western blotting, lactate dehydrogenase release, propidium iodide staining, and transmission electron microscopy. NLRP3 expression in the inflammasome from liver tissues was assessed by immunohistochemistry. Results In hydrogen peroxide (H2O2)-stimulated HL7702 cells, HBx triggered the release of pro-inflammatory mediators apoptosis-associated speck-like protein containing a CARD (ASC), interleukin (IL)-1 beta, IL-18, and high-mobility group box 1 (HMGB1); activated NLRP3; and initiated pro-inflammatory cell death (pyroptosis). HBx localized to the mitochondria, where it induced mitochondrial damage and production of mitochondrial reactive oxygen species (mitoROS). Treatment of HL7702 cells with a mitoROS scavenger attenuated HBx-induced NLRP3 activation and pyroptosis. Expression levels of NLRP3, ASC, and IL-1 beta in liver tissues from patients were positively correlated with HBV DNA concentration. Conclusions The NLRP3 inflammasome was activated by elevated mitoROS levels and mediated HBx-induced liver inflammation and hepatocellular pyroptosis under H2O2-stress conditions.Funding Information
- Natural Science Foundation of Fujian Province (2018J01314)
- the Fujian Province health and family planning research talent training project (2018-CX-21)
- the Joint Funds for the innovation of science and Technology, Fujian province (2017Y9048)
- the Fujian Minimally Invasive Medical Center (Health Office Medical Care Administration File of South Fujian [2017] No.171)
This publication has 52 references indexed in Scilit:
- Oxidized Mitochondrial DNA Activates the NLRP3 Inflammasome during ApoptosisImmunity, 2012
- Relationship of Oxidative Stress in Hepatitis B Infection Activity with HBV DNA and FibrosisAnnals of Laboratory Medicine, 2012
- HBx Sensitizes Cells to Oxidative Stress-induced Apoptosis by Accelerating the Loss of Mcl-1 Protein via Caspase-3 CascadeMolecular Cancer, 2011
- Occult hepatitis B virus infection with low viremia induces DNA damage, apoptosis and oxidative stress in peripheral blood lymphocytesVirus Research, 2010
- Inflammasome-Dependent Release of the Alarmin HMGB1 in EndotoxemiaThe Journal of Immunology, 2010
- Cutting Edge: NF-κB Activating Pattern Recognition and Cytokine Receptors License NLRP3 Inflammasome Activation by Regulating NLRP3 ExpressionThe Journal of Immunology, 2009
- Inflammasome-mediated regulation of hepatic stellate cellsAmerican Journal of Physiology-Gastrointestinal and Liver Physiology, 2009
- Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasomeJCI Insight, 2009
- Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanismsProceedings of the National Academy of Sciences of the United States of America, 2008
- The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwideJournal of Hepatology, 2006