Stat3 activation-triggered transcriptional networks govern the early stage of HBV-induced hepatic inflammation

作者全名："Tang, Jinglin; Zhang, Jiaxuan; Zhang, Gaoli; Peng, Wenhui; Ling, Ning; Zhou, Yingzhi; Xu, Hongmei; Ren, Hong; Chen, Min"

作者地址："[Tang, Jinglin; Zhang, Jiaxuan; Zhang, Gaoli; Peng, Wenhui; Ling, Ning; Ren, Hong; Chen, Min] Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Infect Dis,Minist, Chongqing, Peoples R China; [Zhou, Yingzhi; Xu, Hongmei] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Dept Infect, Minist Educ,Key Lab Child Dev & Disorders,Children, Chongqing, Peoples R China"

通信作者："Chen, M (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Inst Viral Hepatitis, Dept Infect Dis,Key Lab Mol Biol Infect Dis,Minist, Chongqing, Peoples R China."

来源：MBIO

ESI学科分类：MICROBIOLOGY

WOS号：WOS:001178582300001

JCR分区：Q1

影响因子：5.1

年份：2024

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：chronic hepatitis B; chronic HBV carriers; liver inflammation; Stat3; immune responses

摘要："The chronic carrier state of the hepatitis B virus (HBV) often leads to the development of liver inflammation as carriers age. However, the exact mechanisms that trigger this hepatic inflammation remain poorly defined. We analyzed the sequential processes during the onset of liver inflammation based on time-course transcriptome and transcriptional regulatory networks in an HBV transgenic (HBV-Tg) mice model and chronic HBV-infected (CHB) patients (data from GSE83148). The key transcriptional factor (TF) responsible for hepatic inflammation occurrence was identified and then validated both in HBV-Tg mice and liver specimens from young CHB patients. By time-course analysis, an early stage of hepatic inflammation was demonstrated in 3-month-old HBV-Tg mice: a marked upregulation of genes related to inflammation (Saa1/2, S100a8/9/11, or Il1 beta), innate immunity (Tlr2, Tlr7, or Tlr8), and cells chemotaxis (Ccr2, Cxcl1, Cxcl13, or Cxcl14). Within CHB samples, a unique early stage of inflammation activation was discriminated from immune tolerance and immune activation groups based on distinct gene expression patterns. Enhanced activation of TF Stat3 was strongly associated with increased inflammatory gene expression in this early stage of inflammation. Expression of phosphorylated Stat3 was higher in liver specimens from young CHB patients with relatively higher alanine aminotransferase levels. Specific inhibition of Stat3 activation significantly attenuated the degree of liver inflammation, the expression of inflammation-related genes, and the inflammatory monocytes and macrophages in 3-month-old HBV-Tg mice. Stat3 activation is essential for hepatic inflammation occurrence and is a novel indicator of early-stage immune activation in chronic HBV carriers.IMPORTANCEUntil now, it remains a mystery that chronic hepatitis B virus (HBV)-infected patients in the ""immune tolerance phase"" will transition to the ""immune activation phase"" as they age. In this study, we reveal that Stat3 activation-triggered hepatic transcriptional alterations are distinctive characteristics of the early stage of immune/inflammation activation in chronic HBV infection. For the first time, we discover a mechanism that might trigger the transition from immune tolerance to immune activation in chronic HBV carriers. Until now, it remains a mystery that chronic hepatitis B virus (HBV)-infected patients in the ""immune tolerance phase"" will transition to the ""immune activation phase"" as they age. In this study, we reveal that Stat3 activation-triggered hepatic transcriptional alterations are distinctive characteristics of the early stage of immune/inflammation activation in chronic HBV infection. For the first time, we discover a mechanism that might trigger the transition from immune tolerance to immune activation in chronic HBV carriers."

基金机构："MOST | National Natural Science Foundation of China (NSFC) [81772198]; National Natural Science Foundation of China [2018ZX10302206]; National Science and Technology Major Project of China [cstc2020jcyj-msxmX0389]; Natural Science Foundation of Chongqing, China [2022]; Second Affiliated Hospital of Chongqing Medical University"

基金资助正文："This work was supported by the National Natural Science Foundation of China (81772198), National Science and Technology Major Project of China (2018ZX10302206), and Natural Science Foundation of Chongqing, China (cstc2020jcyj-msxmX0389) to M.C. This work was also supported by Remarkable Innovation-Clinical Research Project, The Second Affiliated Hospital of Chongqing Medical University (2022) to H.R."