Tolerizing CTL by sustained hepatic PD-L1 expression provides a new therapy spproach in mouse sepsis

Cytotoxic T lymphocyte (CTL) activation contributes to liver damage during sepsis, but the mechanisms involved are largely unknown. Understanding the underlying principle will permit interference with CTL activation and 
Cytotoxic T lymphocyte (CTL) activation contributes to liver damage during sepsis, but the mechanisms involved are largely unknown. Understanding the underlying principle will permit interference with CTL activation and thus, provide a new therapeutic option.
Methods: To elucidate the mechanism leading to CTL activation we used the Hepa1-6 cell line in vitro and the mouse model of in vivo polymicrobial sepsis, following cecal-ligation and -puncture (CLP) in wildtype, myeloid specific NOX-2, global NOX2 and NOX4 knockout mice, and their survival as a final readout. In this in vivo setting, we also determined hepatic mRNA and protein expression as well as clinical parameters of liver damage - aspartate- and alanine amino-transaminases. Hepatocyte specific overexpression of PD-L1 was achieved in vivo by adenoviral infection and transposon-based gene transfer using hydrodynamic injection.
Results: We observed downregulation of PD-L1 on hepatocytes in the murine sepsis model. Adenoviral and transposon-based gene transfer to restore PD-L1 expression, significantly improved survival and reduced the release of liver damage, as PD-L1 is a co-receptor that negatively regulates T cell function. Similar protection was observed during pharmacological intervention using recombinant PD-L1-Fc. N-acetylcysteine blocked the downregulation of PD-L1 suggesting the involvement of reactive oxygen species. This was confirmed in vivo, as we observed significant upregulation of PD-L1 expression in NOX4 knockout mice, following sham operation, whereas its expression in global as well as myeloid lineage NOX2 knockout mice was comparable to that in the wild type animals. PD-L1 expression remained high following CLP only in total NOX2 knockouts, resulting in significantly reduced release of liver damage markers.
Conclusion: These results suggest that, contrary to common assumption, maintaining PD-L1 expression on hepatocytes improves liver damage and survival of mice during sepsis. We conclude that administering recombinant PD-L1 or inhibiting NOX2 activity might offer a new therapeutic option in sepsis.
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Metadaten
Author:Andreas von Knethen, Anne Schäfer, Laura Kuchler, Tilo Knape, Urs Christen, Edith Hintermann, Beate Fißlthaler, Katrin Schröder, Ralf Peter Louis Brandes, Berit Genz, Kerstin Abshagen, Brigitte M. Pützer, Lisa K. Sha, Andreas Weigert, Shahzad Nawaz Syed, Martin Schulz, Ajay M. Shah, Andreas Erns, Mateusz Putyrski, Fabian Finkelmeier, Marina Pesic, Florian Greten, Michael Hogardt, Volkhard A. J. Kempf, Sandra Gunne, Michael J. Parnham, Bernhard Brüne
URN:urn:nbn:de:hebis:30:3-499486
DOI:http://dx.doi.org/10.7150/thno.28057
Parent Title (English):Theranostics
Document Type:Article
Language:English
Year of Completion:2019
Date of first Publication:2019/03/16
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/04/11
Tag:PD-L1; cytotoxic T cells; liver; reactive oxygen species; sepsis
Volume:9
Pagenumber:14
First Page:2003
Last Page:2016
Note:
This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
HeBIS PPN:45101569X
Institutes:Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (English):License LogoCreative Commons - Namensnennung-Nicht kommerziell 4.0

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