1. A dual role for hepatocyte-intrinsic canonical NF-κB signaling in virus control
- Author
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Indrabahadur Singh, Zeinab Abdullah, Bernhard Holzmann, Karl S. Lang, Percy A. Knolle, Thomas M. Kündig, Julie Lucifora, Sukumar Namineni, Philipp A. Lang, Pål Johansen, Jacob Nattermann, Kai Breuhahn, Peter Staeheli, Haifeng Xu, Katharina Borst, Sandra Lampl, Fanghui Li, Rayan Farhat, Achim Weber, Patrick Blank, Suzanne Faure-Dupuy, Ulrich Kalinke, Emmanuel Dejardin, Michael Karin, Ulrike Protzer, Kaijing Liu, Lisa Mareike Assmus, Dirk Wohlleber, Daniela Lenggenhager, Andreas Muschaweckh, Prashant V. Shinde, Aleksandra A. Pandyra, Mathias Heikenwalder, Maude Rolland, Piyush Sharma, Marc Ringelhan, Tracy O'Connor, Tobias Riedl, Katharina Neuhaus, Marco Binder, David Durantel, TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany., and Institut National de la Santé et de la Recherche Médicale (INSERM)
- Subjects
Male ,0301 basic medicine ,Medizin ,Hepacivirus ,Virus Replication ,Gene Knockout Techniques ,0302 clinical medicine ,Interferon ,Lymphocytic choriomeningitis virus ,Cells, Cultured ,Liver infection ,Innate immune responses ,virus diseases ,Acquired immune system ,I-kappa B Kinase ,ddc ,3. Good health ,Cell biology ,medicine.anatomical_structure ,Hepatocyte ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,Female ,030211 gastroenterology & hepatology ,Signal Transduction ,medicine.drug ,Adult ,Genotype ,NF-kB signaling ,Mice, Transgenic ,Cytotoxic T cells ,Lymphocytic Choriomeningitis ,Biology ,Innate Immune responses ,Lymphocytic choriomeningitis ,Polymorphism, Single Nucleotide ,Young Adult ,03 medical and health sciences ,Immune system ,medicine ,Animals ,Humans ,PRRs ,Interferon-stimulated genes ,Innate immune system ,Hepatology ,Interferon Stimulated Genes ,Transcription Factor RelA ,NF-kappa B p50 Subunit ,Hepatitis C, Chronic ,medicine.disease ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Viral replication ,Hepatocytes - Abstract
Background & Aims Hepatic innate immune control of viral infections has largely been attributed to Kupffer cells, the liver-resident macrophages. However, hepatocytes, the parenchymal cells of the liver, also possess potent immunological functions in addition to their known metabolic functions. Owing to their abundance in the liver and known immunological functions, we aimed to investigate the direct antiviral mechanisms employed by hepatocytes. Methods Using lymphocytic choriomeningitis virus (LCMV) as a model of liver infection, we first assessed the role of myeloid cells by depletion prior to infection. We investigated the role of hepatocyte-intrinsic innate immune signaling by infecting mice lacking canonical NF-κB signaling (IkkβΔHep) specifically in hepatocytes. In addition, mice lacking hepatocyte-specific interferon-α/β signaling-(IfnarΔHep), or interferon-α/β signaling in myeloid cells-(IfnarΔMyel) were infected. Results Here, we demonstrate that LCMV activates NF-κB signaling in hepatocytes. LCMV-triggered NF-κB activation in hepatocytes did not depend on Kupffer cells or TNFR1 signaling but rather on Toll-like receptor signaling. LCMV-infected IkkβΔHep livers displayed strongly elevated viral titers due to LCMV accumulation within hepatocytes, reduced interferon-stimulated gene (ISG) expression, delayed intrahepatic immune cell influx and delayed intrahepatic LCMV-specific CD8+ T cell responses. Notably, viral clearance and ISG expression were also reduced in LCMV-infected primary hepatocytes lacking IKKβ, demonstrating a hepatocyte-intrinsic effect. Similar to livers of IkkβΔHep mice, enhanced hepatocytic LCMV accumulation was observed in livers of IfnarΔHep mice, whereas IfnarΔMyel mice were able to control LCMV infection. Hepatocytic NF-κB signaling was also required for efficient ISG induction in HDV-infected dHepaRG cells and interferon-α/β-mediated inhibition of HBV replication in vitro. Conclusions Together, these data show that hepatocyte-intrinsic NF-κB is a vital amplifier of interferon-α/β signaling, which is pivotal for strong early ISG responses, immune cell infiltration and hepatic viral clearance. Lay summary Innate immune cells have been ascribed a primary role in controlling viral clearance upon hepatic infections. We identified a novel dual role for NF-κB signaling in infected hepatocytes which was crucial for maximizing interferon responses and initiating adaptive immunity, thereby efficiently controlling hepatic virus replication.
- Published
- 2020