HBV inhibits LPS-induced NLRP3 inflammasome activation and IL-1β production via suppressing the NF-κB pathway and ROS production

Background & Aims: Hepatitis B virus (HBV) has developed strategies to evade immune responses. However, the mechanisms involved remain unclear. The NLRP3 inflammasome plays crucial roles in antiviral host defense and its downstream factor IL-1 beta has been shown to inhibit HBV infection in vivo. This study aims to assess whether HBV can affect the NLRP3 inflammasome signaling pathways and shed light on the underlying mechanisms HBV utilizes to evade host innate immune responses. Methods: HBV inhibition of the lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation was evaluated by Western blot, quantitative RT-PCR, flow cytometry and immunofluorescence. Results: Kupffer cells expressed significantly more NLRP3 and IL-1 beta after LPS stimulation; whereas, chronic HBV infection suppressed LPS-induced NLRP3 and pro-IL-1 beta expression as well as IL-1 beta maturation. This inhibitory activity is mediated by HBeAg, and is involved in the inhibition of NF-kappa B signal pathway and reactive oxygen species (ROS) production. The inhibitory effect of HBeAg was confirmed in patients with chronic hepatitis B (CHB) and hepatocellular carcinoma by comparing the levels of IL-1 beta and NLRP3-related proteins in para-carcinoma tissues from HBeAg-positive or negative patients. Moreover, chronic HBV infection increases the susceptibility of mice to S. typhimurium infection, possibly via inhibiting the NLRP3 inflammasome activation and IL-1b production. Conclusions: HBeAg inhibits LPS-induced NLRP3 inflammasome activation and IL-1 beta production via suppressing NF-kappa B pathway and ROS production. This finding provides a novel mechanism for HBV-mediated suppression of innate immune responses, and identifies new therapeutic targets for chronic HBV infection and related diseases. Lay summary: HBeAg suppresses LPS-induced NLRP3 inflammasome activation and IL-1 beta production in two ways, one is to repress NLRP3 and pro-IL-1 beta expression via inhibiting NF-kappa B phosphorylation, and the other is to repress caspase-1 activation and IL-1 beta maturation via inhibiting ROS production. This effect contributes to the HBV persistence and immune tolerance. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B. V. All rights reserved.