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


Namineni, Sukumar; O'Connor, Tracy; Faure-Dupuy, Suzanne; Johansen, Pål; et al; Weber, Achim (2020). A dual role for hepatocyte-intrinsic canonical NF-κB signaling in virus control. Journal of Hepatology, 72(5):960-975.

Abstract

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 immunological 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 (IKKβ$^{ΔHep}$) specifically in hepatocytes. In addition, mice lacking hepatocyte-specific interferon-α/β signaling-(IFNAR$^{ΔHep}$), or interferon-α/β signaling in myeloid cells-(IFNAR$^{ΔMyel}$) 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- but rather on TLR-signaling. LCMV-infected IKKβ$^{ΔHep}$ 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 IKKβ$^{ΔHep}$ mice, enhanced hepatocytic LCMV accumulation was observed in livers of IFNAR$^{ΔHep}$, whereas IFNAR$^{ΔMyel}$ 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 pivotal for early, strong ISG responses, influx of immune cells and hepatic viral clearance.

Abstract

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 immunological 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 (IKKβ$^{ΔHep}$) specifically in hepatocytes. In addition, mice lacking hepatocyte-specific interferon-α/β signaling-(IFNAR$^{ΔHep}$), or interferon-α/β signaling in myeloid cells-(IFNAR$^{ΔMyel}$) 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- but rather on TLR-signaling. LCMV-infected IKKβ$^{ΔHep}$ 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 IKKβ$^{ΔHep}$ mice, enhanced hepatocytic LCMV accumulation was observed in livers of IFNAR$^{ΔHep}$, whereas IFNAR$^{ΔMyel}$ 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 pivotal for early, strong ISG responses, influx of immune cells and hepatic viral clearance.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Pathology and Molecular Pathology
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Hepatology
Language:English
Date:1 May 2020
Deposited On:18 Mar 2020 14:41
Last Modified:29 Jul 2020 14:54
Publisher:Elsevier
ISSN:0168-8278
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.jhep.2019.12.019
PubMed ID:31954207

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