Z Gastroenterol 2020; 58(01): e59
DOI: 10.1055/s-0039-3402265
Poster Visit Session V Viral Hepatitis and Immunology: Saturday, February 15, 2020, 11:00 am – 11:45 am, Lecture Hall P1
Georg Thieme Verlag KG Stuttgart · New York

Hippo signaling counter regulates early innate immunity in hepatocytes exposed to Hepatitis B virus

X Luo
1   University Duisburg-Essen, Medical Faculty, Dept. of Gastroenterology and Hepatology, Essen, Germany
,
M Lu
2   University Duisburg-Essen, Medical Faculty, Institute for Virology, Essen, Germany
,
HA Baba
3   University Duisburg-Essen, Medical Faculty, Institute for Pathology, Essen, Germany
,
G Gerken
1   University Duisburg-Essen, Medical Faculty, Dept. of Gastroenterology and Hepatology, Essen, Germany
,
H Wedemeyer
1   University Duisburg-Essen, Medical Faculty, Dept. of Gastroenterology and Hepatology, Essen, Germany
,
R Broering
1   University Duisburg-Essen, Medical Faculty, Dept. of Gastroenterology and Hepatology, Essen, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2020 (online)

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    Background & Aims:

    Chronic hepatitis B virus (HBV) infection is a key risk factor for the development of hepatocellular carcinoma. Recent studies indicate potential relationships among HBV infection, Hippo signaling and innate immunity. Here, we investigated the interaction between Hippo signaling and HBV-triggered innate immune responses.

    Methods:

    Eligible pathways associated with HBV infection were analyzed using GSE69590 and GSE83148 data. Primary murine and human hepatocytes (PMHs and PHHs, respectively) were isolated and exposed to cell culture-derived HBV. Quantitative PCR, Western blotting and immunocytochemistry illustrated the activation and intracellular localization of YAP and NF-κB. Dual-luciferase reporter assay, chromatin immunoprecipitation, electrophoretic mobility shift assay and loss/gain of function experiments addressed the underlying mechanisms of this activation.

    Results:

    Reanalysis of gene arrays (GSE69590) identified HBV-related changes in Hippo and NF-κB signaling in HBV-infected PHH. Immunocytochemical staining and Western blot analysis showed a time-dependent nuclear translocation of YAP and NF-κB after HBV exposure in PMH. The application of TLR2 and MST1/2 inhibitors confirmed the involvement of the TLR2 and Hippo pathways in this model. PMHs isolated from Irak4-/- and Myd88-/- mice confirmed the relationship between TLR2 and Hippo signaling. Loss/gain of function experiments implied that YAP regulates IκBα expression. Functional investigations confirmed the regulation of Nfkbia promoter activity by the YAP/TEAD4 complex. IκBα fluctuation is a rapid innate immune control mechanism. Furthermore, administration of Pam3CSK4 or LPS to mice and the exposure of PHHs to HBV confirmed the relevance of the TLR2-MyD88-IRAK4-Hippo axis in innate immunity. Interestingly, gene array data (GSE83148) of HBV-infected patients and uninfected controls indicated that this TLR2-MyD88-IRAK4-Hippo axis is also relevant during chronic infection.

    Conclusions:

    In summary, we demonstrated that HBV is recognized by TLR2 which leads to increased NF-κB signaling and Hippo pathway activity to initiate and regulate rapid innate immune responses, respectively. The present data clearly indicate the importance of the TLR2-MyD88-IRAK4-Hippo axis in hepatic innate immune responses against HBV infection.


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