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

Area of Science:

• Virology
• Immunology
• Stem Cell Biology

Background:

• Hepatotropic viruses cause significant global health issues.
• Hepatocytes' innate immune responses are critical but understudied.
• Interferon lambda (IFNL) is key in antiviral defense, but its role in hepatocytes is unclear.

Purpose of the Study:

• To investigate hepatic interferon lambda (IFNL) expression using a surrogate system.
• To explore the role of cytoplasmic pattern recognition receptors (PRRs) in hepatocyte antiviral responses.
• To characterize the innate immune response of hepatocyte-like cells (HLCs) to viral RNA.

Main Methods:

• Utilized induced pluripotent stem (iPS)-derived hepatocyte-like cells (HLCs).
• Stimulated HLCs with viral-like RNA ligands.
• Measured gene expression of type III interferon and interferon-stimulated genes (ISGs).
• Investigated the role of cytoplasmic PRRs, including Protein Kinase RNA-dependent (PKR) and RIG-I-like receptors (RLRs).

Main Results:

• HLCs showed a significant, thousand-fold increase in type III interferon gene expression upon stimulation with viral RNA.
• Type I interferon expression was induced to a lesser extent compared to type III.
• Induction of ISG15 and CXCL10 confirmed the activation of interferon-dependent antiviral activity.
• Hepatocytes utilize PRRs like PKR and RLRs for detecting double-stranded RNA.

Conclusions:

• Hepatocyte-like cells effectively mount an innate antiviral response characterized by type III interferon induction.
• iPS-derived HLCs serve as a valuable model for studying hepatic antiviral immunity.
• This study elucidates a critical aspect of the innate immune defense in hepatocytes against viral infections.