Early interferon lambda production is induced by double-stranded RNA in iPS-derived hepatocyte-like cells

TL;DR

This study shows that iPS-derived hepatocyte-like cells produce high levels of interferon lambda when exposed to viral-like RNA, suggesting they can be used to study antiviral responses in liver cells.

Contribution

The novel finding is that HLCs produce a strong type III interferon response to viral-like RNA, contrasting with weaker type I IFN induction.

Findings

HLCs show thousand-fold increase in type III interferon gene expression when stimulated with viral-like RNA.

Interferon-stimulated genes like ISG15 and CXCL10 are concomitantly induced in HLCs.

HLCs rely on cytoplasmic PRRs such as PKR and RLR for detecting double-stranded RNA.

Abstract

Hepatotropic viruses are amongst the most ubiquitous pathogens worldwide, causing significant morbidity and mortality. As hepatocytes are among the primary targets of these viruses, their ability to mount early effective innate defence responses is of major research interest. Interferon lambda (IFNL) is produced early in response to viral stimulation in other cell types, but hepatocyte production of this interferon is little investigated. Due to the difficulty and significant costs in obtaining and culturing human primary hepatocytes, surrogate systems are widely sought. Here we used induced pluripotent stem (iPS)-derived hepatocyte-like cells (HLCs) to investigate hepatic IFNL expression in response to viral-like ligands. We demonstrate that hepatocytes rely on cytoplasmic pattern recognition receptors (PRRs) such as Protein Kinase RNA-dependent (PKR) and retinoic acid-inducible gene-I (RIG-I)-like receptors (RLR) for the detection of double stranded RNA. Stimulation of HLCs by viral-like RNA ligands activating cytosolic RNA sensors resulted in thousand fold increase of type III interferon gene expression. These results are in contrast with type I IFN expression, which was induced to a lower extent. Concomitant induction of interferon stimulated genes, such as interferon-stimulated gene 15 (ISG15) and CXCL10, indicated the ability of HLCs to activate interferon-dependent activity. These results demonstrate that HLCs mount an innate antiviral response upon stimulation with viral-like RNA characterized by the induction of type III IFN.

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