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

[en] 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-kappaB signaling (IKKbeta(DeltaHep)) specifically in hepatocytes. In addition, mice lacking hepatocyte-specific interferon-alpha/beta signaling-(IFNAR(DeltaHep)), or interferon-alpha/beta signaling in myeloid cells-(IFNAR(DeltaMyel)) were infected. RESULTS: Here, we demonstrate that LCMV activates NF-kappaB signaling in hepatocytes. LCMV-triggered NF-kappaB activation in hepatocytes did not depend on Kupffer cells or TNFR1- but rather on TLR-signaling. LCMV-infected IKKbeta(DeltaHep) 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 IKKbeta, demonstrating a hepatocyte-intrinsic effect. Similar to livers of IKKbeta(DeltaHep) mice, enhanced hepatocytic LCMV accumulation was observed in livers of IFNAR(DeltaHep), whereas IFNAR(DeltaMyel) mice were able to control LCMV-infection. Hepatocytic NF-kappaB signaling was also required for efficient ISG induction in HDV-infected dHepaRG cells and interferon-alpha/beta-mediated inhibition of HBV replication in vitro. CONCLUSIONS: Together, these data show that hepatocyte-intrinsic NF-kappaB is a vital amplifier of interferon-alpha/beta signaling pivotal for early, strong ISG responses, influx of immune cells and hepatic viral clearance.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Namineni, Sukumar

O'Connor, Tracy

Faure-Dupuy, Suzanne

Johansen, Pal

Riedl, Tobias

Liu, Kaijing

Xu, Haifeng

Singh, Indrabahadur

Shinde, Prashant

Li, Fanghui

More authors (30 more)

Language :

English

Title :

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

Publication date :

January 2020

Journal title :

Journal of Hepatology

ISSN :

0168-8278

eISSN :

1600-0641

Publisher :

Elsevier, Netherlands

Peer reviewed :

Peer Reviewed verified by ORBi

Commentary :

Available on ORBi :

since 28 January 2020

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