title: HBV inhibits LPS-induced NLRP3 inflammasome activation and IL-1β production via suppressing the NF-κB pathway and ROS production.
abstract: 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-1β 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.
  
  
  
  HBV inhibition of the lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation was evaluated by Western blot, quantitative RT-PCR, flow cytometry and immunofluorescence.
  
  
  
  Kupffer cells expressed significantly more NLRP3 and IL-1β after LPS stimulation; whereas, chronic HBV infection suppressed LPS-induced NLRP3 and pro-IL-1β expression as well as IL-1β maturation. This inhibitory activity is mediated by HBeAg, and is involved in the inhibition of NF-κB 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-1β 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-1β production.
  
  
  
  HBeAg inhibits LPS-induced NLRP3 inflammasome activation and IL-1β production via suppressing NF-κB 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.
  
  
  
  HBeAg suppresses LPS-induced NLRP3 inflammasome activation and IL-1β production in two ways, one is to repress NLRP3 and pro-IL-1β expression via inhibiting NF-κB phosphorylation, and the other is to repress caspase-1 activation and IL-1β maturation via inhibiting ROS production. This effect contributes to the HBV persistence and immune tolerance.
authors.affiliation: Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.
authors.forename: Peixiang
authors.initials: P
authors.lastname: Lan
authors.affiliation: Department of Medicinal Chemistry, Key Laboratory of Chemical Biology of Natural Products (MOE), School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.
authors.forename: Xuben
authors.initials: X
authors.lastname: Hou
authors.affiliation: Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.
authors.forename: Qiuju
authors.initials: Q
authors.lastname: Han
authors.affiliation: Institute of Diagnostics, School of Medicine, Shandong University, Jinan 250012, Shandong, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Lu
authors.affiliation: Division of Liver Diseases, Shandong Provincial Hospital, Jinan 250001, Shandong, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Department of Pediatric Surgery, Shandong Provincial Hospital, Jinan 250001, Shandong, China.
authors.forename: Chenwei
authors.initials: C
authors.lastname: Jiao
authors.affiliation: Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Immunopharmacology and Immunotherapy, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China. Electronic address: caizhangsd@sdu.edu.cn.
authors.forename: Cai
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei 230027, Anhui, China. Electronic address: tzg@ustc.edu.cn.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tian
mesh_terms: D000818:Animals; D020170:Caspase 1 / Q000378:metabolism; D006514:Hepatitis B Surface Antigens / Q000378:metabolism; D006513:Hepatitis B e Antigens / Q000378:metabolism; D006515:Hepatitis B virus / Q000276:immunology* / Q000472:pathogenicity; D019694:Hepatitis B, Chronic / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000096:biosynthesis*; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012481:Salmonella Infections, Animal / Q000209:etiology / Q000276:immunology; D012486:Salmonella typhimurium; D015398:Signal Transduction
chemical_list: D006514:Hepatitis B Surface Antigens; D006513:Hepatitis B e Antigens; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D016328:NF-kappa B; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D017382:Reactive Oxygen Species; D020170:Caspase 1
keywords: Hepatitis B e antigens; Hepatitis B virus; IL-1β; Inflammasomes; Interleukin-1 beta; NLRP3 inflammasome; Reactive oxygen species