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Research article

HMGB1-induced autophagy: a new pathway to maintain Treg function during chronic hepatitis B virus infection

Li-sha Cheng, Jing Li, Yun Liu, Fu-ping Wang, Si-qi Wang, Wei-min She, Sheng-di Wu, Xiao-long Qi, Yong-ping Zhou, Wei Jiang
Clinical Science Feb 15, 2017, 131 (5) 381-394; DOI: 10.1042/CS20160704
Li-sha Cheng
Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
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Jing Li
Department of Gastroenterology, Tongji Hospital, Tongji University, Shanghai, China
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Yun Liu
Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
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Fu-ping Wang
Department of Gastroenterology, Children's Hospital, Capital Institute of Pediatrics, Beijing, China
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Si-qi Wang
Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
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Wei-min She
Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
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Sheng-di Wu
Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
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Xiao-long Qi
Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Yong-ping Zhou
Department of Hepatobiliary Surgery, Second People's Hospital, Nanjing Medical University, Wuxi, China
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Wei Jiang
Department of Gastroenterology, Zhongshan Hospital, Fudan University, Shanghai, China
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  • For correspondence: jiang.wei@zs-hospital.sh.cn
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Abstract

High-mobility group box-1 (HMGB1) protein, as one of the well-known damage-associated molecular pattern molecules (DAMPs), is enriched in chronic hepatitis B virus (HBV) infection and has a context-dependent role in autophagy, a highly conserved self-digestive process in response to environmental stress. Recent mouse studies indicate that autophagy is highly active in regulatory T (Treg)-cells. In the present study, we evaluated spontaneous and induced autophagy of peripheral Treg cells from 98 patients with chronic hepatitis B (CHB), by measuring levels of lipidated form of microtubule-associated light chain 3 (LC3-II, marker for closed autophagosomes) and observing autophagic vacuoles (AV) with transmission electron microscope. No significant difference was found in spontaneous autophagy of either Treg or CD4+ naive cells when comparing CHB patients with healthy subjects, apart from CHB-Treg showed significantly higher autophagic activity after activation by anti-CD3–CD28 beads. Besides, incubation of CHB-Treg cells with CHB-serum greatly maintained their autophagic behaviour, which could be significantly diminished by blocking HMGB1 with the neutralizing antibody. Further, we characterized time- and dose-dependent effects by recombinant HMGB1 protein on autophagy of CHB-Treg cells. We also documented a significant up-regulation of HMGB1 and its receptors [toll-like receptor (TLR4), receptor for advanced glycation end-product (RAGE)] in both peripheral and intra-hepatic microenvironments of CHB patients. Moreover, the RAGE–extracellular regulated protein kinases (ERK) axis and rapamycin-sensitive components of mammalian target of rapamycin (mTOR) pathways were demonstrated in vitro to be involved in HMGB1-induced autophagy of Treg cells. Additionally, HMGB1-induced autophagy could maintain cell survival and functional stability of CHB-Treg cells. Our findings could open new perspectives in developing therapeutic strategies to activate specific anti-HBV immunity by diminishing Treg autophagy.

  • autophagy
  • chronic hepatitis B
  • high-mobility group box-1
  • regulatory T-cells
  • Abbreviations

    ALT,
    alanine aminotransferase;
    7-AAD,
    7-Aminoactinomycin D;
    AMPK,
    AMP-activated protein kinase;
    APC,
    allophycocyanin;
    Atg,
    autophagy-related genes;
    AST,
    aspartate aminotransferase;
    AV,
    annexin V;
    AVs,
    autophagic vacuoles;
    CCK-8,
    cell counting kit 8;
    CHB,
    chronic hepatitis B;
    CQ,
    chloroquine;
    CTLA-4,
    cytotoxic T-lymphocyte antigen-4;
    DAMP,
    damage-associated molecular pattern molecule;
    ERK,
    extracellular regulated protein kinases;
    Foxp3,
    forkhead box P3;
    HBc,
    HBV core;
    HBeAg,
    HBV e antigen;
    HBsAg,
    HBV surface antigen;
    HBV,
    hepatitis B virus;
    HBX,
    HBV X protein;
    HC,
    healthy controls;
    HMGB1,
    high-mobility group box-1;
    HRP,
    horseradish peroxidase;
    IFN,
    interferon;
    IL,
    interleukin;
    JNK,
    c-Jun N-terminal kinase;
    LAL,
    limulus amebocyte lysate;
    LC3,
    microtubule-associated light chain 3;
    mAb,
    monoclonal antibody;
    MAPK,
    mitogen-activated protein kinases;
    MFI,
    mean fluorescence intensity;
    mTOR,
    mammalian target of rapamycin;
    mTORC,
    mTOR complex;
    PAMPs,
    pathogen-associated molecular patterns;
    PBMCs,
    peripheral blood mononuclear cells;
    PE,
    phosphatidylethanolamine;
    PRR,
    pattern recognition receptor;
    RAGE,
    receptor for advanced glycation end-products;
    rHMGB1,
    recombinant HMGB1;
    rIL-2,
    recombinant human IL-2;
    RT,
    reverse transcription;
    SAPK,
    stress-activated protein kinase;
    TGF,
    transforming growth factor;
    TLR,
    toll-like receptor;
    Treg,
    regulatory T;
    ULK1,
    unc-51-like kinase;
    ULN,
    upper limit of normal
    • © 2017 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
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    March 2017

    Volume: 131 Issue: 5

    Clinical Science: 131 (5)
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    HMGB1-induced autophagy: a new pathway to maintain Treg function during chronic hepatitis B virus infection
    Li-sha Cheng, Jing Li, Yun Liu, Fu-ping Wang, Si-qi Wang, Wei-min She, Sheng-di Wu, Xiao-long Qi, Yong-ping Zhou, Wei Jiang
    Clinical Science Mar 2017, 131 (5) 381-394; DOI: 10.1042/CS20160704
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    HMGB1-induced autophagy: a new pathway to maintain Treg function during chronic hepatitis B virus infection
    Li-sha Cheng, Jing Li, Yun Liu, Fu-ping Wang, Si-qi Wang, Wei-min She, Sheng-di Wu, Xiao-long Qi, Yong-ping Zhou, Wei Jiang
    Clinical Science Mar 2017, 131 (5) 381-394; DOI: 10.1042/CS20160704

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    Keywords

    autophagy
    Chronic hepatitis B
    high-mobility group box-1
    regulatory T-cells

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