TY  - JOUR
A1  - Knethen, Andreas von
A1  - Schäfer, Anne
A1  - Kuchler, Laura
A1  - Knape, Tilo
A1  - Christen, Urs
A1  - Hintermann, Edith
A1  - Fißlthaler, Beate
A1  - Schröder, Katrin
A1  - Brandes, Ralf
A1  - Genz, Berit
A1  - Abshagen, Kerstin
A1  - Pützer, Brigitte M.
A1  - Sha, Lisa K.
A1  - Weigert, Andreas
A1  - Syed, Shahzad Nawaz
A1  - Schulz, Martin
A1  - Shah, Ajay M.
A1  - Erns, Andreas
A1  - Putyrski, Mateusz
A1  - Finkelmeier, Fabian
A1  - Pešić, Marina
A1  - Greten, Florian
A1  - Hogardt, Michael
A1  - Kempf, Volkhard A. J.
A1  - Gunne, Sandra
A1  - Parnham, Michael J.
A1  - Brüne, Bernhard
T1  - Tolerizing CTL by sustained hepatic PD-L1 expression provides a new therapy spproach in mouse sepsis
T2  - Theranostics
N2  - 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.
KW  - sepsis
KW  - cytotoxic T cells
KW  - reactive oxygen species
KW  - PD-L1
KW  - liver
Y1  - 2019
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/49948
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-499486
N1  - 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.
VL  - 9
SP  - 2003
EP  - 2016
ER  -