Dataset Information

TNF-alpha inhibition ameliorates HDV-induced liver damage in a mouse model of acute severe infection.

ABSTRACT: Background & Aims:HDV infection induces the most severe form of human viral hepatitis. However, the specific reasons for the severity of the disease remain unknown. Recently, we developed an HDV replication mouse model in which, for the first time, liver damage was detected. Methods:HDV and HBV replication-competent genomes and HDV antigens were delivered to mouse hepatocytes using adeno-associated vectors (AAVs). Aminotransferase elevation, liver histopathology, and hepatocyte death were evaluated and the immune infiltrate was characterized. Liver transcriptomic analysis was performed. Mice deficient for different cellular and molecular components of the immune system, as well as depletion and inhibition studies, were employed to elucidate the causes of HDV-mediated liver damage. Results:AAV-mediated HBV/HDV coinfection caused hepatocyte necrosis and apoptosis. Activated T lymphocytes, natural killer cells, and proinflammatory macrophages accounted for the majority of the inflammatory infiltrate. However, depletion studies and the use of different knockout mice indicated that neither T cells, natural killer cells nor macrophages were necessary for HDV-induced liver damage. Transcriptomic analysis revealed a strong activation of type I and II interferon (IFN) and tumor necrosis factor (TNF)-? pathways in HBV/HDV-coinfected mice. While the absence of IFN signaling had no effect, the use of a TNF-? antagonist resulted in a significant reduction of HDV-associated liver injury. Furthermore, hepatic expression of HDAg resulted in the induction of severe liver damage, which was T cell- and TNF-?-independent. Conclusions:Both host (TNF-?) and viral (HDV antigens) factors play a relevant role in HDV-induced liver damage. Importantly, pharmacological inhibition of TNF-? may offer an attractive strategy to aid control of HDV-induced acute liver damage. Lay summary:Chronic hepatitis delta constitutes the most severe form of viral hepatitis. There is limited data on the mechanism involved in hepatitis delta virus (HDV)-induced liver pathology. Our data indicate that a cytokine (TNF-?) and HDV antigens play a relevant role in HDV-induced liver damage.

SUBMITTER: Usai C

PROVIDER: S-EPMC7200939 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

TNF-alpha inhibition ameliorates HDV-induced liver damage in a mouse model of acute severe infection.

Usai Carla C Maestro Sheila S Camps Gracian G Olague Cristina C Suárez-Amaran Lester L Vales Africa A Aragon Tomas T Hommel Mirja M Aldabe Rafael R Gonzalez-Aseguinolaza Gloria G

JHEP reports : innovation in hepatology 20200310 3

<h4>Background & aims</h4>HDV infection induces the most severe form of human viral hepatitis. However, the specific reasons for the severity of the disease remain unknown. Recently, we developed an HDV replication mouse model in which, for the first time, liver damage was detected.<h4>Methods</h4>HDV and HBV replication-competent genomes and HDV antigens were delivered to mouse hepatocytes using adeno-associated vectors (AAVs). Aminotransferase elevation, liver histopathology, and hepatocyte de ...[more]

PMID: 32382723

Similar Datasets

Project description:BACKGROUND:Acute liver failure (ALF) is a complicated condition that is characterized by global hepatocyte death and often requires immediate liver transplantation. However, this therapy is limited by shortage of donor organs. Mesenchymal stem cells (MSCs) and hepatocytes are two attractive sources of cell-based therapies to treat ALF. The combined transplantation of hepatocytes and MSCs is considered to be more effective for the treatment of ALF than single-cell transplantation. We have previously demonstrated that HNF4?-overexpressing human umbilical cord MSCs (HNF4?-UMSCs) promoted the expression of hepatic-specific genes. In addition, microencapsulation allows exchange of nutrients, forming a protective barrier to the transplanted cells. Moreover, encapsulation of hepatocytes improves the viability and synthetic ability of hepatocytes and circumvents immune rejection. This study aimed to investigate the therapeutic effect of microencapsulation of hepatocytes and HNF4?-UMSCs in ALF mice. METHODS:Human hepatocytes and UMSCs were obtained separately from liver and umbilical cord, followed by co-encapsulation and transplantation into mice by intraperitoneal injection. LPS/D-gal was used to induce ALF by intraperitoneal injection 24?h after transplantation. In addition, Raw 264.7 cells (a macrophage cell line) were used to elucidate the effect of HNF4?-UMSCs-hepatocyte microcapsules on polarization of macrophages. The protein chip was used to define the important paracrine factors in the conditioned mediums (CMs) of UMSCs and HNF4?-UMSCs and investigate the possible mechanism of HNF4?-UMSCs for the treatment of ALF in mice. RESULTS:HNF4?-UMSCs can enhance the function of primary hepatocytes in alginate-poly-L-lysine-alginate (APA) microcapsules. The co-encapsulation of both HNF4?-UMSCs and hepatocytes achieved better therapeutic effects in ALF mice by promoting M2 macrophage polarization and reducing inflammatory response mainly mediated by the paracrine factor HB-EGF secreted by HNF4?-UMSCs. CONCLUSIONS:The present study confirms that the co-encapsulation of HNF4?-UMSC and hepatocytes could exert therapeutic effect on ALF mainly by HB-EGF secreted by HNF4?-UMSCs and provides a novel strategy for the treatment of ALF.

Dataset Information

TNF-alpha inhibition ameliorates HDV-induced liver damage in a mouse model of acute severe infection.

Publications

TNF-alpha inhibition ameliorates HDV-induced liver damage in a mouse model of acute severe infection.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure