Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3
The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tum...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-01-01
|
| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/14/2/218 |
| _version_ | 1797476032389840896 |
|---|---|
| author | Melanie Werner Stefan Schefczyk Martin Trippler Juergen W. Treckmann Hideo A. Baba Guido Gerken Joerg F. Schlaak Ruth Broering |
| author_facet | Melanie Werner Stefan Schefczyk Martin Trippler Juergen W. Treckmann Hideo A. Baba Guido Gerken Joerg F. Schlaak Ruth Broering |
| author_sort | Melanie Werner |
| collection | DOAJ |
| description | The role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1–9 ligands for 6–24 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-κB, AKT, JNK, p38 and ERK1/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection. |
| first_indexed | 2024-03-09T20:52:11Z |
| format | Article |
| id | doaj.art-075b8a1bdb704ceca5b88dd01c481c13 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-09T20:52:11Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-075b8a1bdb704ceca5b88dd01c481c132023-11-23T22:29:24ZengMDPI AGViruses1999-49152022-01-0114221810.3390/v14020218Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3Melanie Werner0Stefan Schefczyk1Martin Trippler2Juergen W. Treckmann3Hideo A. Baba4Guido Gerken5Joerg F. Schlaak6Ruth Broering7Department of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, GermanyDepartment of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, GermanyDepartment of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, GermanyDepartment of General-, Visceral- and Transplantation-Surgery, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, GermanyInstitute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, GermanyDepartment of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, GermanyDepartment of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, GermanyDepartment of Gastroenterology, Hepatology and Transplant Medicine, University Hospital of Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, GermanyThe role of non-parenchymal liver cells as part of the hepatic, innate immune system in the defense against hepatotropic viruses is not well understood. Here, primary human Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells were isolated from liver tissue obtained after tumor resections or liver transplantations. Cells were stimulated with Toll-like receptor 1–9 ligands for 6–24 h. Non-parenchymal liver cells expressed and secreted inflammatory cytokines (IL6, TNF and IL10). Toll-like receptor- and cell type-specific downstream signals included the phosphorylation of NF-κB, AKT, JNK, p38 and ERK1/2. However, only supernatants of TLR3-activated Kupffer cells, liver sinusoidal endothelial cells and hepatic stellate cells contained type I and type III interferons and mediated an antiviral activity in the interferon-sensitive subgenomic hepatitis C virus replicon system. The antiviral effect could not be neutralized by antibodies against IFNA, IFNB nor IFNL, but could be abrogated using an interferon alpha receptor 2-specific neutralization. Interestingly, TLR3 responsiveness was enhanced in liver sinusoidal endothelial cells isolated from hepatitis C virus-positive donors, compared to uninfected controls. In conclusion, non-parenchymal liver cells are potent activators of the hepatic immune system by mediating inflammatory responses. Furthermore, liver sinusoidal endothelial cells were identified to be hyperresponsive to viral stimuli in chronic hepatitis C virus infection.https://www.mdpi.com/1999-4915/14/2/218primary human non-parenchymal liver cellshepatitis C virusToll-like receptorsinterferonsKupffer cellsliver sinusoidal endothelial cells |
| spellingShingle | Melanie Werner Stefan Schefczyk Martin Trippler Juergen W. Treckmann Hideo A. Baba Guido Gerken Joerg F. Schlaak Ruth Broering Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3 Viruses primary human non-parenchymal liver cells hepatitis C virus Toll-like receptors interferons Kupffer cells liver sinusoidal endothelial cells |
| title | Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3 |
| title_full | Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3 |
| title_fullStr | Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3 |
| title_full_unstemmed | Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3 |
| title_short | Antiviral Toll-like Receptor Signaling in Non-Parenchymal Liver Cells Is Restricted to TLR3 |
| title_sort | antiviral toll like receptor signaling in non parenchymal liver cells is restricted to tlr3 |
| topic | primary human non-parenchymal liver cells hepatitis C virus Toll-like receptors interferons Kupffer cells liver sinusoidal endothelial cells |
| url | https://www.mdpi.com/1999-4915/14/2/218 |
| work_keys_str_mv | AT melaniewerner antiviraltolllikereceptorsignalinginnonparenchymallivercellsisrestrictedtotlr3 AT stefanschefczyk antiviraltolllikereceptorsignalinginnonparenchymallivercellsisrestrictedtotlr3 AT martintrippler antiviraltolllikereceptorsignalinginnonparenchymallivercellsisrestrictedtotlr3 AT juergenwtreckmann antiviraltolllikereceptorsignalinginnonparenchymallivercellsisrestrictedtotlr3 AT hideoababa antiviraltolllikereceptorsignalinginnonparenchymallivercellsisrestrictedtotlr3 AT guidogerken antiviraltolllikereceptorsignalinginnonparenchymallivercellsisrestrictedtotlr3 AT joergfschlaak antiviraltolllikereceptorsignalinginnonparenchymallivercellsisrestrictedtotlr3 AT ruthbroering antiviraltolllikereceptorsignalinginnonparenchymallivercellsisrestrictedtotlr3 |