Cargando…

Human PSC-Derived Hepatocytes Express Low Levels of Viral Pathogen Recognition Receptors, but Are Capable of Mounting an Effective Innate Immune Response

Hepatocytes are key players in the innate immune response to liver pathogens but are challenging to study because of inaccessibility and a short half-life. Recent advances in in vitro differentiation of hepatocyte-like cells (HLCs) facilitated studies of hepatocyte–pathogen interactions. Here, we ai...

Descripción completa

Detalles Bibliográficos
Autores principales: Fischer, Lena, Lucendo-Villarin, Baltasar, Hay, David C., O’Farrelly, Cliona
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312201/
https://www.ncbi.nlm.nih.gov/pubmed/32481600
http://dx.doi.org/10.3390/ijms21113831
_version_ 1783549678588002304
author Fischer, Lena
Lucendo-Villarin, Baltasar
Hay, David C.
O’Farrelly, Cliona
author_facet Fischer, Lena
Lucendo-Villarin, Baltasar
Hay, David C.
O’Farrelly, Cliona
author_sort Fischer, Lena
collection PubMed
description Hepatocytes are key players in the innate immune response to liver pathogens but are challenging to study because of inaccessibility and a 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 pattern recognition receptor (PRR)-expression and the presence of a metabolic switch. We analysed cytoplasmic PRR and endosomal toll-like receptor (TLR)-expression, as well as activity and adaptation of HLCs to an inflammatory environment. We found that transcript levels of retinoic acid inducible gene I (RIG-I), melanoma differentiation antigen 5 (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 (IFNs) and IFN-stimulated genes. Despite low-level levels of TLR3, receptor expression was upregulated in an inflammatory environment. TLR3 signalling 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.
format Online
Article
Text
id pubmed-7312201
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-73122012020-06-26 Human PSC-Derived Hepatocytes Express Low Levels of Viral Pathogen Recognition Receptors, but Are Capable of Mounting an Effective Innate Immune Response Fischer, Lena Lucendo-Villarin, Baltasar Hay, David C. O’Farrelly, Cliona Int J Mol Sci Article Hepatocytes are key players in the innate immune response to liver pathogens but are challenging to study because of inaccessibility and a 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 pattern recognition receptor (PRR)-expression and the presence of a metabolic switch. We analysed cytoplasmic PRR and endosomal toll-like receptor (TLR)-expression, as well as activity and adaptation of HLCs to an inflammatory environment. We found that transcript levels of retinoic acid inducible gene I (RIG-I), melanoma differentiation antigen 5 (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 (IFNs) and IFN-stimulated genes. Despite low-level levels of TLR3, receptor expression was upregulated in an inflammatory environment. TLR3 signalling 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. MDPI 2020-05-28 /pmc/articles/PMC7312201/ /pubmed/32481600 http://dx.doi.org/10.3390/ijms21113831 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Fischer, Lena
Lucendo-Villarin, Baltasar
Hay, David C.
O’Farrelly, Cliona
Human PSC-Derived Hepatocytes Express Low Levels of Viral Pathogen Recognition Receptors, but Are Capable of Mounting an Effective Innate Immune Response
title Human PSC-Derived Hepatocytes Express Low Levels of Viral Pathogen Recognition Receptors, but Are Capable of Mounting an Effective Innate Immune Response
title_full Human PSC-Derived Hepatocytes Express Low Levels of Viral Pathogen Recognition Receptors, but Are Capable of Mounting an Effective Innate Immune Response
title_fullStr Human PSC-Derived Hepatocytes Express Low Levels of Viral Pathogen Recognition Receptors, but Are Capable of Mounting an Effective Innate Immune Response
title_full_unstemmed Human PSC-Derived Hepatocytes Express Low Levels of Viral Pathogen Recognition Receptors, but Are Capable of Mounting an Effective Innate Immune Response
title_short Human PSC-Derived Hepatocytes Express Low Levels of Viral Pathogen Recognition Receptors, but Are Capable of Mounting an Effective Innate Immune Response
title_sort human psc-derived hepatocytes express low levels of viral pathogen recognition receptors, but are capable of mounting an effective innate immune response
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312201/
https://www.ncbi.nlm.nih.gov/pubmed/32481600
http://dx.doi.org/10.3390/ijms21113831
work_keys_str_mv AT fischerlena humanpscderivedhepatocytesexpresslowlevelsofviralpathogenrecognitionreceptorsbutarecapableofmountinganeffectiveinnateimmuneresponse
AT lucendovillarinbaltasar humanpscderivedhepatocytesexpresslowlevelsofviralpathogenrecognitionreceptorsbutarecapableofmountinganeffectiveinnateimmuneresponse
AT haydavidc humanpscderivedhepatocytesexpresslowlevelsofviralpathogenrecognitionreceptorsbutarecapableofmountinganeffectiveinnateimmuneresponse
AT ofarrellycliona humanpscderivedhepatocytesexpresslowlevelsofviralpathogenrecognitionreceptorsbutarecapableofmountinganeffectiveinnateimmuneresponse