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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\u03b2), 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>Until now, it remains a mystery that chronic hepatitis B virus (HBV)-infected patients in the \u201cimmune tolerance phase\u201d will transition to the \u201cimmune activation phase\u201d 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.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/mbio.03068-23","type":"journal-article","created":{"date-parts":[[2024,3,5]],"date-time":"2024-03-05T14:00:23Z","timestamp":1709647223000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":16,"title":["Stat3 activation-triggered transcriptional networks govern the early stage of HBV-induced hepatic inflammation"],"prefix":"10.1128","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-7418-4205","authenticated-orcid":true,"given":"Jinglin","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China"},{"name":"Department of Transfusion Medicine, West China Hospital of Sichuan University, Chengdu, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China"},{"name":"Department of Laboratory Medicine, Bishan Hospital of Chongqing Medical University, Bishan Hospital of Chongqing, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gaoli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhui","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Ling","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingzhi","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Infection, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongmei","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Infection, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Ren","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9996-5149","authenticated-orcid":false,"given":"Min","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Second Affiliated Hospital of Chongqing Medical University, Chongqing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_4_2_2","unstructured":"World Health Organization. 2021. 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