Intrahepatic T helper 17 cells recruited by hepatitis B virus X antigen‐activated hepatic stellate cells exacerbate the progression of chronic hepatitis B virus infection

Zhang, Hongbin; Xiong, Yan; Yang, Cheng; Zhan, Qian; Fu, Yan; Luo, Huating; Luo, Haitao

doi:10.1111/jvh.13352

Cited by 12 publications

(14 citation statements)

References 45 publications

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“…Besides altering gene expressions in host cells, virus infection often transfers environment. It is reported that HBV infection causes liver fibrosis via activation of HSC (Zan et al, 2013;Gong et al, 2016;Zhang et al, 2020). In our results, we confirmed that HBV enhanced the secretion of ENPP2 in hepatoma cells, and ENPP2 is reported to have the function to activate HSC (Kaffe et al, 2017), these points imply that HBV may activate HSC via ENPP2.…”

Section: Discussionsupporting

confidence: 86%

“…We then designed a series of in vitro and in vivo studies to observe whether HBV induced HCC progression via enhancement of the expression and secretion of ENPP2. Finally, since in liver tissue HBV infection not only transforms host cell hepatocytes and activates HSC through viral antigens (Martin-Vilchez et al, 2008;Zan et al, 2013;Gong et al, 2016;Zhang et al, 2020) and possibly through ENPP2 from hepatocytes (Kaffe et al, 2017), we analyzed the role of activated HSC (aHSC) in HBV-related HCC progression. These data can improve our understanding of the molecular mechanisms in HBV-related HCC malignancy.…”

Section: Introductionmentioning

confidence: 99%

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Hepatitis B Virus Promotes Hepatocellular Carcinoma Progression Synergistically With Hepatic Stellate Cells via Facilitating the Expression and Secretion of ENPP2

Deng

Chen

Zhou

et al. 2021

Front. Mol. Biosci.

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Background: Hepatitis B virus (HBV) infection is a major risk factor causing hepatocellular carcinoma (HCC) development, but the molecular mechanisms are not fully elucidated. It has been reported that virus infection induces ectonucleotide pyrophosphatase-phosphodiesterase 2 (ENPP2) expression, the latter participates in tumor progression. Therefore, the aim of the present study was to investigate whether HBV induced HCC malignancy via ENPP2.Methods: HCC patient clinical data were collected and prognosis was analyzed. Transient transfection and stable ectopic expression of the HBV genome were established in hepatoma cell lines. Immunohistochemical staining, RT-qPCR, western blot, and ELISA assays were used to detect the expression and secretion of ENPP2. Finally, CCK-8, colony formation, and migration assays as well as a subcutaneous xenograft mouse model were used to investigate the influence of HBV infection, ENPP2 expression, and activated hepatic stellate cells (aHSCs) on HCC progression in vitro and in vivo.Results: The data from cancer databases indicated that the level of ENPP2 was significant higher in HCC compared within normal liver tissues. Clinical relevance analysis using 158 HCC patients displayed that ENPP2 expression was positively correlated with poor overall survival and disease-free survival. Statistical analysis revealed that compared to HBV-negative HCC tissues, HBV-positive tissues expressed a higher level of ENPP2. In vitro, HBV upregulated ENPP2 expression and secretion in hepatoma cells and promoted hepatoma cell proliferation, colony formation, and migration via enhancement of ENPP2; downregulation of ENPP2 expression or inhibition of its function suppressed HCC progression. In addition, aHSCs strengthened hepatoma cell proliferation, migration in vitro, and promoted tumorigenesis synergistically with HBV in vivo; a loss-function assay further verified that ENPP2 is essential for HBV/aHSC-induced HCC progression.Conclusion: HBV enhanced the expression and secretion of ENPP2 in hepatoma cells, combined with aHSCs to promote HCC progression via ENPP2.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Hepatitis B Virus Promotes Hepatocellular Carcinoma Progression Synergistically With Hepatic Stellate Cells via Facilitating the Expression and Secretion of ENPP2

Deng

Chen

Zhou

et al. 2021

Front. Mol. Biosci.

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“…It has been described that the Th17-IL-17 axis is simultaneously the fuel and the flame of a sustained proinflammatory and profibrotic environment during CHB infection through a stepwise manner ( Paquissi, 2017 ). During HBV infection, HBxAg-activated hepatic stellate cells (HSCs) recruit more Th17 cells into the liver that could, in turn, stimulate the proliferation and fibrotic marker secretion of the HSCs mediated by IL-17A and IL-22, forming a positive feedback loop that aggravates the progression of chronic liver disease with HBV infection ( Tan et al, 2013 ; Zhang H. et al, 2020 ). In addition, counteraction between Th17 and Treg cell has been attached much attention by scientists ( Su et al, 2013 ).…”

Section: Cytokines In Hepatitis B Virus Infectionmentioning

confidence: 99%

Cytokines and Chemokines in HBV Infection

Zhong

Zhang

Tang

et al. 2021

Front. Mol. Biosci.

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Chronic hepatitis B virus (HBV) infection remains a leading cause of hepatic inflammation and damage. The pathogenesis of chronic hepatitis B (CHB) infection is predominantly mediated by persistent intrahepatic immunopathology. With the characterization of unique anatomical and immunological structure, the liver is also deemed an immunological organ, which gives rise to massive cytokines and chemokines under pathogenesis conditions, having significant implications for the progression of HBV infection. The intrahepatic innate immune system is responsible for the formidable source of cytokines and chemokines, with the latter also derived from hepatic parenchymal cells. In addition, systemic cytokines and chemokines are disturbed along with the disease course. Since HBV is a stealth virus, persistent exposure to HBV-related antigens confers to immune exhaustion, whereby regulatory cells are recruited by intrahepatic chemokines and cytokines, including interleukin-10 and transforming growth factor β, are involved in such series of causal events. Although the considerable value of two types of available approved treatment, interferons and nucleos(t)ide analogues, effectively suppress HBV replication, neither of them is sufficient for optimal restoration of the immunological attrition state to win the battle of the functional or virological cure of CHB infection. Notably, cytokines and chemokines play a crucial role in regulating the immune response. They exert effects by directly acting on HBV or indirectly manipulating target immune cells. As such, specific cytokines and chemokines, with a potential possibility to serve as novel immunological interventions, combined with those that target the virus itself, seem to be promising prospects in curative CHB infection. Here, we systematically review the recent literature that elucidates cytokine and chemokine-mediated pathogenesis and immune exhaustion of HBV infection and their dynamics triggered by current mainstream anti-HBV therapy. The predictive value of disease progression or control and the immunotherapies target of specific major cytokines and chemokines in CHB infection will also be delineated.

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“…In patients with chronic viral hepatitis, neutrophils accounted for most of the IL-17A + cells, especially in the late fibrosis stage, but the frequency of CD45 + IL-17A + lymphocytes in liver tissue was independent of the stage of fibrosis (F0-F3) (104). However, an increase in IL-17A expression has been shown in the advanced stages of HBV-related liver disease by the immunohistochemistry on fresh biopsies of HBV + patients (12,15,(105)(106)(107) or patients with non-alcoholic steatohepatitis (99).…”

Section: Il-17amentioning

confidence: 99%

Retinoic Acid: A New Old Friend of IL-17A in the Immune Pathogeny of Liver Fibrosis

2021

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Despite all the medical advances mortality due to cirrhosis and hepatocellular carcinoma, the end stages of fibrosis, continuously increases. Recent data suggest that liver fibrosis is guided by type 3 inflammation with IL-17A at the top of the line. The storage of vitamin A and its active metabolites, as well as genetics, can influence the development and progression of liver fibrosis and inflammation. Retinoic acid (active metabolite of vitamin A) is able to regulate the differentiation of IL-17A+/IL-22–producing cells as well as the expression of profibrotic markers. IL-17A and its pro-fibrotic role in the liver is the most studied, while the interaction and communication between IL-17A, IL-22, and vitamin A–active metabolites has not been investigated. We aim to update what is known about IL-17A, IL-22, and retinoic acid in the pathobiology of liver diseases.

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Intrahepatic T helper 17 cells recruited by hepatitis B virus X antigen‐activated hepatic stellate cells exacerbate the progression of chronic hepatitis B virus infection

Cited by 12 publications

References 45 publications

Hepatitis B Virus Promotes Hepatocellular Carcinoma Progression Synergistically With Hepatic Stellate Cells via Facilitating the Expression and Secretion of ENPP2

Hepatitis B Virus Promotes Hepatocellular Carcinoma Progression Synergistically With Hepatic Stellate Cells via Facilitating the Expression and Secretion of ENPP2

Cytokines and Chemokines in HBV Infection

Retinoic Acid: A New Old Friend of IL-17A in the Immune Pathogeny of Liver Fibrosis

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