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Human PSC-derived hepatocytes express low levels of viral pathogen recognition receptors but are capable of mounting an effective innate immune response

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  • Fischer L, Lucendo-Villarin B, Hay DC, O'Farelly C

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  • Fischer et al 2020 R1 for PURE

    764 KB, Word document

Original languageEnglish
JournalInternational Journal of Molecular Sciences
Publication statusAccepted/In press - 24 May 2020

Abstract

Hepatocytes are key players in the innate immune response to liver pathogens but are challenging to study because of inaccessibility and short half-life. Recent advances in in vitro differentiation of hepatocyte-like cells (HLCs) facilitated studies of hepatocyte-pathogen interactions. Here we aimed to define the anti-viral innate immune potential of human HLCs with a focus on toll-like receptor (TLR)-expression and the presence of a metabolic switch. We analysed cytoplasmic pattern recognition receptor (PRR)- and endosomal TLR-expression and activity and adaptation of HLCs to an inflammatory environment. We found that transcript levels of RIG-I, MDA5 and TLR3 became downregulated during differentiation, indicating the acquisition of a more tolerogenic phenotype as expected in healthy hepatocytes. HLCs responded to activation of RIG-I by producing interferons (IFN) and IFN-stimulated genes. Despite low-level expression of TLR3, receptor expression was upregulated in an inflammatory environment. TLR3 signaling induced expression of proinflammatory cytokines at the gene level indicating that several PRRs need to interact for successful innate immune activation. The inflammatory responsiveness of HLCs was accompanied by the downregulation of cytochrome P450 3A and 1A2 activity and decreased serum protein production showing that the metabolic switch seen in primary hepatocytes during anti-viral responses, is also present in HLCs.

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