Z Gastroenterol 2020; 58(01): e57-e58
DOI: 10.1055/s-0039-3402260
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

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

S Namineni
1   DKFZ, F180, Heidelberg, Germany
2   Institute of Molecular Immunology and Experimental Oncology, Munich, Germany
,
T O'Connor
1   DKFZ, F180, Heidelberg, Germany
2   Institute of Molecular Immunology and Experimental Oncology, Munich, Germany
,
S Faure-Dupuy
1   DKFZ, F180, Heidelberg, Germany
,
P Johansen
3   Department of Dermatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
,
T Riedl
1   DKFZ, F180, Heidelberg, Germany
,
K Liu
4   Institute of Pathology, Heidelberg, Germany
,
H Xu
5   Department of Molecular Medicine II, Düsseldorf, Germany
,
I Singh
1   DKFZ, F180, Heidelberg, Germany
,
P Shinde
5   Department of Molecular Medicine II, Düsseldorf, Germany
,
F Li
6   Institute of Immunology, Essen, Germany
,
A Pandyra
6   Institute of Immunology, Essen, Germany
,
P Sharma
6   Institute of Immunology, Essen, Germany
,
M Ringelhan
1   DKFZ, F180, Heidelberg, Germany
7   Departement of Internal Medicine II, Munich, Germany
,
A Muschaweckh
1   DKFZ, F180, Heidelberg, Germany
8   Klinikum rechts der Isar, Munich, Germany
,
K Borst
1   DKFZ, F180, Heidelberg, Germany
9   Institute for Experimental Infection Research, Brunswick, Germany
,
P Blank
1   DKFZ, F180, Heidelberg, Germany
9   Institute for Experimental Infection Research, Brunswick, Germany
,
S Lampl
2   Institute of Molecular Immunology and Experimental Oncology, Munich, Germany
,
D Durantel
10   Cancer Research Center of Lyon, Lyon, France
,
R Farhat
10   Cancer Research Center of Lyon, Lyon, France
,
A Weber
11   Department of Pathology and Molecular Pathology, Zurich, Switzerland
,
D Lenggenhager
11   Department of Pathology and Molecular Pathology, Zurich, Switzerland
,
TM Kündig
3   Department of Dermatology, University Hospital Zurich and University of Zurich, Zurich, Switzerland
,
P Stäheli
12   Institute of Virology, Freiburg, Germany
,
U Protzer
1   DKFZ, F180, Heidelberg, Germany
,
D Wohlleber
1   DKFZ, F180, Heidelberg, Germany
2   Institute of Molecular Immunology and Experimental Oncology, Munich, Germany
,
B Holzmann
13   Department of Surgery, Munich, Germany
2   Institute of Molecular Immunology and Experimental Oncology, Munich, Germany
,
M Binder
1   DKFZ, F180, Heidelberg, Germany
13   Department of Surgery, Munich, Germany
,
K Breuhahn
4   Institute of Pathology, Heidelberg, Germany
,
Z Abdullah
4   Institute of Pathology, Heidelberg, Germany
14   Institute of Experimental Immunology, Bonn, Germany
,
M Rolland
15   Laboratory of Molecular Immunology and Signal Transduction, Liège, Belgium
,
E Dejardin
15   Laboratory of Molecular Immunology and Signal Transduction, Liège, Belgium
,
PA Lang
5   Department of Molecular Medicine II, Düsseldorf, Germany
,
KS Lang
6   Institute of Immunology, Essen, Germany
,
M Karin
16   Laboratory of Gene Regulation and Signal Transduction, La Jolla, United States
,
J Lucifora
10   Cancer Research Center of Lyon, Lyon, France
,
U Kalinke
9   Institute for Experimental Infection Research, Brunswick, Germany
,
PA Knolle
2   Institute of Molecular Immunology and Experimental Oncology, Munich, Germany
,
M Heikenwalder
1   DKFZ, F180, Heidelberg, Germany
2   Institute of Molecular Immunology and Experimental Oncology, Munich, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2020 (online)

Also available at
 

Background & Aims:

Hepatic innate immune control of viral infections has largely been attributed to Kupffer cells, the liver macrophages. However, also hepatocytes, the parenchymal cells of the liver, possess potent immunological functions in addition to their known metabolic functions. Owing to their abundance in the liver and known functions, we aimed to investigate the direct anti-viral 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 with LCMV.

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. 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, whereas IFNARΔMyel mice were able to control LCMV-infection. Hepatocytic NF-κB signaling was also required for efficient ISG induction and interferonα/β-mediated inhibition of HBV replication in vitro, in HBV- or HDV-infected HepaRGs.

Conclusions:

Together, these data show that hepatocyte-intrinsic NF-κB is a vital amplifier of interferonα/β signaling pivotal for early, strong ISG responses, influx of immune cells and hepatic viral clearance.