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Protective role of RIPK1 scaffolding against HDV-induced hepatocyte cell death and the significance of cytokines in mice.
Camps, Gracián; Maestro, Sheila; Torella, Laura; Herrero, Diego; Usai, Carla; Bilbao-Arribas, Martin; Aldaz, Ana; Olagüe, Cristina; Vales, Africa; Suárez-Amarán, Lester; Aldabe, Rafael; Gonzalez-Aseguinolaza, Gloria.
Afiliação
  • Camps G; DNA & RNA Medicine Division, CIMA, University of Navarra, Instituto de Investigación Sanitaria de Navarra, IdisNA, Pamplona, Spain.
  • Maestro S; DNA & RNA Medicine Division, CIMA, University of Navarra, Instituto de Investigación Sanitaria de Navarra, IdisNA, Pamplona, Spain.
  • Torella L; DNA & RNA Medicine Division, CIMA, University of Navarra, Instituto de Investigación Sanitaria de Navarra, IdisNA, Pamplona, Spain.
  • Herrero D; DNA & RNA Medicine Division, CIMA, University of Navarra, Instituto de Investigación Sanitaria de Navarra, IdisNA, Pamplona, Spain.
  • Usai C; DNA & RNA Medicine Division, CIMA, University of Navarra, Instituto de Investigación Sanitaria de Navarra, IdisNA, Pamplona, Spain.
  • Bilbao-Arribas M; DNA & RNA Medicine Division, CIMA, University of Navarra, Instituto de Investigación Sanitaria de Navarra, IdisNA, Pamplona, Spain.
  • Aldaz A; DNA & RNA Medicine Division, CIMA, University of Navarra, Instituto de Investigación Sanitaria de Navarra, IdisNA, Pamplona, Spain.
  • Olagüe C; DNA & RNA Medicine Division, CIMA, University of Navarra, Instituto de Investigación Sanitaria de Navarra, IdisNA, Pamplona, Spain.
  • Vales A; DNA & RNA Medicine Division, CIMA, University of Navarra, Instituto de Investigación Sanitaria de Navarra, IdisNA, Pamplona, Spain.
  • Suárez-Amarán L; DNA & RNA Medicine Division, CIMA, University of Navarra, Instituto de Investigación Sanitaria de Navarra, IdisNA, Pamplona, Spain.
  • Aldabe R; DNA & RNA Medicine Division, CIMA, University of Navarra, Instituto de Investigación Sanitaria de Navarra, IdisNA, Pamplona, Spain.
  • Gonzalez-Aseguinolaza G; DNA & RNA Medicine Division, CIMA, University of Navarra, Instituto de Investigación Sanitaria de Navarra, IdisNA, Pamplona, Spain.
PLoS Pathog ; 20(5): e1011749, 2024 May.
Article em En | MEDLINE | ID: mdl-38739648
ABSTRACT
Hepatitis delta virus (HDV) infection represents the most severe form of human viral hepatitis; however, the mechanisms underlying its pathology remain incompletely understood. We recently developed an HDV mouse model by injecting adeno-associated viral vectors (AAV) containing replication-competent HBV and HDV genomes. This model replicates many features of human infection, including liver injury. Notably, the extent of liver damage can be diminished with anti-TNF-α treatment. Here, we found that TNF-α is mainly produced by macrophages. Downstream of the TNF-α receptor (TNFR), the receptor-interacting serine/threonine-protein kinase 1 (RIPK1) serves as a cell fate regulator, playing roles in both cell survival and death pathways. In this study, we explored the function of RIPK1 and other host factors in HDV-induced cell death. We determined that the scaffolding function of RIPK1, and not its kinase activity, offers partial protection against HDV-induced apoptosis. A reduction in RIPK1 expression in hepatocytes through CRISPR-Cas9-mediated gene editing significantly intensifies HDV-induced damage. Contrary to our expectations, the protective effect of RIPK1 was not linked to TNF-α or macrophage activation, as their absence did not alter the extent of damage. Intriguingly, in the absence of RIPK1, macrophages confer a protective role. However, in animals unresponsive to type-I IFNs, RIPK1 downregulation did not exacerbate the damage, suggesting RIPK1's role in shielding hepatocytes from type-I IFN-induced cell death. Interestingly, while the damage extent is similar between IFNα/ßR KO and wild type mice in terms of transaminase elevation, their cell death mechanisms differ. In conclusion, our findings reveal that HDV-induced type-I IFN production is central to inducing hepatocyte death, and RIPK1's scaffolding function offers protective benefits. Thus, type-I IFN together with TNF-α, contribute to HDV-induced liver damage. These insights may guide the development of novel therapeutic strategies to mitigate HDV-induced liver damage and halt disease progression.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Vírus Delta da Hepatite / Citocinas / Hepatócitos / Proteína Serina-Treonina Quinases de Interação com Receptores Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Vírus Delta da Hepatite / Citocinas / Hepatócitos / Proteína Serina-Treonina Quinases de Interação com Receptores Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article