A dual role for hepatocyte-intrinsic canonical NF-κB signaling in virus control

• DOI: 10.1016/j.jhep.2019.12.019
• Publication Date: 2020-01-15T06:53:50Z
• Authors: Sukumar Namineni; Tracy O'Connor; Suzanne Faure-Dupuy; Pål Johansen; Tobias Riedl; Kaijing Liu; Haifeng Xu; Indrabahadur Singh; Prashant Shinde; Fanghui Li; Aleksandra Pandyra; Piyush Sharma; Marc Ringelhan; Andreas Muschaweckh; Katharina Borst; Patrick Blank; Sandra Lampl; Katharina Neuhaus; David Durantel; Rayan Farhat; Achim Weber; Daniela Lenggenhager; Thomas M. Kündig; Peter Staeheli; Ulrike Protzer; Dirk Wohlleber; Bernhard Holzmann; Marco Binder; Kai Breuhahn; Lisa Mareike Assmus; Jacob Nattermann; Zeinab Abdullah; Maude Rolland; Emmanuel Dejardin; Philipp A. Lang; Karl S. Lang; Michael Karin; Julie Lucifora; Ulrich Kalinke; Percy A. Knolle; Mathias Heikenwalder
• Keywords: Adult; Male; 0301 basic medicine; Genotype; Medizin; 610; NF-kB signaling; Cytotoxic T cells; Mice, Transgenic; Hepacivirus; Innate Immune responses; Lymphocytic Choriomeningitis; Polymorphism, Single Nucleotide; Gene Knockout Techniques; 03 medical and health sciences; Animals; Humans; Lymphocytic choriomeningitis virus; PRRs; Interferon-stimulated genes; Cells, Cultured; [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology; Interferon Stimulated Genes; Innate immune responses; NF-kappa B p50 Subunit; Hepatitis C, Chronic; ddc:; I-kappa B Kinase; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology; Hepatocytes; Female; Signal Transduction

•LCMV infection activates NF-κB signaling in hepatocytes.•Macrophages, TNFR1 do not induce LCMV-driven hepatocyte NF-κB-activation.•IkkβΔHep mice display increased viral infection/replication and lower ISG induction.•IfnarΔHep recapitulate aberrant virus replication as observed IkkβΔHep mice.•NF-κB is required for efficient induction HBV-/HDV-infected HepaRG. Background & AimsHepatic innate immune control of infections has largely been attributed to Kupffer cells, the liver-resident macrophages. However, hepatocytes, parenchymal cells liver, also possess potent immunological functions addition their known metabolic functions. Owing abundance liver functions, we aimed investigate direct antiviral mechanisms employed by hepatocytes.MethodsUsing lymphocytic choriomeningitis (LCMV) a model infection, first assessed role myeloid depletion prior infection. We investigated hepatocyte-intrinsic infecting lacking canonical (IkkβΔHep) specifically hepatocytes. In addition, hepatocyte-specific interferon-α/β signaling-(IfnarΔHep), or cells-(IfnarΔMyel) were infected.ResultsHere, demonstrate that LCMV LCMV-triggered activation hepatocytes did depend on but rather Toll-like receptor signaling. LCMV-infected livers displayed strongly elevated titers due accumulation within reduced interferon-stimulated gene (ISG) expression, delayed intrahepatic cell influx LCMV-specific CD8+ T responses. Notably, clearance expression primary IKKβ, demonstrating effect. Similar mice, enhanced hepatocytic was IfnarΔHep whereas IfnarΔMyel able Hepatocytic HDV-infected dHepaRG interferon-α/β-mediated inhibition HBV vitro.ConclusionsTogether, these data show vital amplifier signaling, which pivotal strong early responses, infiltration hepatic clearance.Lay summaryInnate have ascribed controlling upon infections. identified novel dual infected crucial maximizing interferon responses initiating adaptive immunity, thereby efficiently replication. Hepatic Using infected. Here, vitro. Together, clearance.