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FGL2-MCOLN3-autophagy axis-triggered neutrophil extracellular traps exacerbate liver injury in fulminant viral hepatitis

  • Xitang Li
    Affiliations
    Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    National Medical Center for Major Public Health Events, Wuhan, China

    State Key Laboratory for Zoonotic Diseases
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally: Qiang Gao, Wenhui Wu, Suping Hai
    Qiang Gao
    Footnotes
    # These authors contributed equally: Qiang Gao, Wenhui Wu, Suping Hai
    Affiliations
    Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    National Medical Center for Major Public Health Events, Wuhan, China

    State Key Laboratory for Zoonotic Diseases
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally: Qiang Gao, Wenhui Wu, Suping Hai
    Wenhui Wu
    Footnotes
    # These authors contributed equally: Qiang Gao, Wenhui Wu, Suping Hai
    Affiliations
    Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    National Medical Center for Major Public Health Events, Wuhan, China

    State Key Laboratory for Zoonotic Diseases
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally: Qiang Gao, Wenhui Wu, Suping Hai
    Suping Hai
    Footnotes
    # These authors contributed equally: Qiang Gao, Wenhui Wu, Suping Hai
    Affiliations
    Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    National Medical Center for Major Public Health Events, Wuhan, China

    State Key Laboratory for Zoonotic Diseases
    Search for articles by this author
  • Junjian Hu
    Affiliations
    Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    National Medical Center for Major Public Health Events, Wuhan, China

    State Key Laboratory for Zoonotic Diseases
    Search for articles by this author
  • Jie You
    Affiliations
    Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    National Medical Center for Major Public Health Events, Wuhan, China

    State Key Laboratory for Zoonotic Diseases
    Search for articles by this author
  • Da Huang
    Affiliations
    Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    National Medical Center for Major Public Health Events, Wuhan, China

    State Key Laboratory for Zoonotic Diseases
    Search for articles by this author
  • Hongwu Wang
    Affiliations
    Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    National Medical Center for Major Public Health Events, Wuhan, China

    State Key Laboratory for Zoonotic Diseases
    Search for articles by this author
  • Di Wu
    Affiliations
    Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    National Medical Center for Major Public Health Events, Wuhan, China

    State Key Laboratory for Zoonotic Diseases
    Search for articles by this author
  • Meifang Han
    Affiliations
    Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    National Medical Center for Major Public Health Events, Wuhan, China

    State Key Laboratory for Zoonotic Diseases
    Search for articles by this author
  • Dong Xi
    Affiliations
    Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    National Medical Center for Major Public Health Events, Wuhan, China

    State Key Laboratory for Zoonotic Diseases
    Search for articles by this author
  • Weiming Yan
    Affiliations
    Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    National Medical Center for Major Public Health Events, Wuhan, China

    State Key Laboratory for Zoonotic Diseases
    Search for articles by this author
  • Tao Chen
    Affiliations
    Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    National Medical Center for Major Public Health Events, Wuhan, China

    State Key Laboratory for Zoonotic Diseases
    Search for articles by this author
  • Xiaoping Luo
    Affiliations
    Department and institute of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
    Search for articles by this author
  • Author Footnotes
    ∗ These authors are co-correspondence: Qin Ning, Xiaojing Wang
    Qin Ning
    Correspondence
    Co-Corresponding author: Qin Ning, MD, PhD, Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China. Tel./Fax number: +862783665959;
    Footnotes
    ∗ These authors are co-correspondence: Qin Ning, Xiaojing Wang
    Affiliations
    Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    National Medical Center for Major Public Health Events, Wuhan, China

    State Key Laboratory for Zoonotic Diseases
    Search for articles by this author
  • Author Footnotes
    ∗ These authors are co-correspondence: Qin Ning, Xiaojing Wang
    Xiaojing Wang
    Correspondence
    Corresponding author: Xiaojing Wang, MD, PhD, Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030, Hubei, China Tel. /Fax number: +862783665959;
    Footnotes
    ∗ These authors are co-correspondence: Qin Ning, Xiaojing Wang
    Affiliations
    Department and institute of infectious diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China

    National Medical Center for Major Public Health Events, Wuhan, China

    State Key Laboratory for Zoonotic Diseases
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally: Qiang Gao, Wenhui Wu, Suping Hai
    ∗ These authors are co-correspondence: Qin Ning, Xiaojing Wang
Open AccessPublished:August 01, 2022DOI:https://doi.org/10.1016/j.jcmgh.2022.07.014
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      Abstract

      Background & Aims

      Fulminant viral hepatitis (FVH) is a life-threatening disease, but its pathogenesis is not fully understood. Neutrophil extracellular traps (NETs) were an unrecognized link between inflammation and coagulation, which are two main features of FVH. Here, we aim to investigate the role and mechanism of NETs in the pathogenesis of FVH.

      Methods

      A mice model of FVH was established by murine hepatitis virus strain-3 (MHV-3) infection. Liver leukocytes of infected or uninfected mice were used for single cell RNA sequencing and whole transcriptome sequencing. NETs depletion was achieved using DNase1. Acetaminophen was used to establish a mice model of non-virus caused acute liver failure. Clinically, NETs-related markers in liver, plasma and peripheral neutrophils were assessed in patients with HBV-related acute liver injury (HBV-ALI).

      Results

      Increased hepatic NETs formation was observed in MHV-3-infected mice but not in acetaminophen-treated mice. NETs depletion improved the liver damage and survival rate in FVH by inhibiting hepatic fibrin deposition and inflammation. Adoptive transfer experiment showed that neutrophil-specific FGL2 promoted NETs formation. FGL2 was found to directly interact with mucolipin3 (MCOLN3), which regulated calcium influx and initiated autophagy, leading to NETs formation. Clinically, elevated plasma NETs level was associated with coagulation dysfunction in patients with HBV-ALI. Colocalization of FGL2, NETs and fibrin in liver was observed in these patients.

      Conclusion

      NETs aggravated liver injury in FVH by promoting fibrin deposition and inflammation. NETs formation was regulated by the FGL2-MCOLN3-autophagy axis. Targeting NETs may provide a new strategy for the treatment of FVH.

      Graphical abstract

      Keywords

      List of abbreviations:

      ALT (alanine aminotransferase), AST (aspartate aminotransferase), BM (Bone marrow-derived), Cit-H3 (citrullinated histone-3), DC (dendritic cells), ERK (extracellular regulated protein kinases), FGL2 (fibrinogen-like protein 2), FH (fulminant hepatitis), FVH (fulminant viral hepatitis), HBV (hepatitis B virus), HC (healthy control), MAPK (mitogen-activated protein kinases), MCOLN3 (mucolipin3), MHV-3 (murine hepatitis virus strain-3), MPO (myeloperoxidase), NE (neutrophil elastase), NETs (neutrophil extracellular traps), NK (natural killer cell), PAD4 (peptidyl arginine deiminase type IV), PCA (procoagulant activity), pDC (plasma dendritic cells), RNA-Seq (RNA sequencing), Treg (regulatory T cell)