Danger signals released during cold ischemia storage activate NLRP3 inflammasome in myeloid cells and influence early allograft function in liver transplantation.
Cold ischemia
DAMPs
DBD
DCD
Inflammasome
Liver transplantation
NLRP3
Journal
EBioMedicine
ISSN: 2352-3964
Titre abrégé: EBioMedicine
Pays: Netherlands
ID NLM: 101647039
Informations de publication
Date de publication:
Jan 2023
Jan 2023
Historique:
received:
14
07
2022
revised:
04
11
2022
accepted:
01
12
2022
pubmed:
22
12
2022
medline:
21
1
2023
entrez:
21
12
2022
Statut:
ppublish
Résumé
Innate immunity plays a fundamental role in solid organ transplantation. Myeloid cells can sense danger signals or DAMPs released after tissue or cell damage, such as during ischemia processes. This study aimed to identify DAMPs released during cold ischemia storage of human liver and analyze their ability to activate the inflammasome in myeloid cells and the possible implications in terms of short-term outcomes of liver transplantation. 79 samples of organ preservation solution (OPS) from 79 deceased donors were collected after cold static storage. We used different analytical methods to measure DAMPs in these end-ischemic OPS (eiOPS) samples. We also used eiOPS in the human macrophage THP-1 cell line and primary monocyte cultures to study inflammasome activation. Different DAMPs were identified in eiOPS, several of which induced both priming and activation of the NLRP3 inflammasome in human myeloid cells. Cold ischemia time and donation after circulatory death negatively influenced the DAMP signature. Moreover, the presence of oligomeric inflammasomes and interleukin-18 in eiOPS correlated with early allograft dysfunction in liver transplant patients. DAMPs released during cold ischemia storage prime and activate the NLRP3 inflammasome in liver macrophages after transplantation, inducing a pro-inflammatory environment that will complicate the outcome of the graft. The use of pharmacological blockers targeting DAMPs or the NLRP3 inflammasome in liver ischemia during static cold storage or through extracorporeal organ support could be a suitable strategy to increase the success of liver transplantation. Fundación Mutua Madrileña and Instituto de Salud Carlos III, Madrid, Spain.
Sections du résumé
BACKGROUND
BACKGROUND
Innate immunity plays a fundamental role in solid organ transplantation. Myeloid cells can sense danger signals or DAMPs released after tissue or cell damage, such as during ischemia processes. This study aimed to identify DAMPs released during cold ischemia storage of human liver and analyze their ability to activate the inflammasome in myeloid cells and the possible implications in terms of short-term outcomes of liver transplantation.
METHODS
METHODS
79 samples of organ preservation solution (OPS) from 79 deceased donors were collected after cold static storage. We used different analytical methods to measure DAMPs in these end-ischemic OPS (eiOPS) samples. We also used eiOPS in the human macrophage THP-1 cell line and primary monocyte cultures to study inflammasome activation.
FINDINGS
RESULTS
Different DAMPs were identified in eiOPS, several of which induced both priming and activation of the NLRP3 inflammasome in human myeloid cells. Cold ischemia time and donation after circulatory death negatively influenced the DAMP signature. Moreover, the presence of oligomeric inflammasomes and interleukin-18 in eiOPS correlated with early allograft dysfunction in liver transplant patients.
INTERPRETATION
CONCLUSIONS
DAMPs released during cold ischemia storage prime and activate the NLRP3 inflammasome in liver macrophages after transplantation, inducing a pro-inflammatory environment that will complicate the outcome of the graft. The use of pharmacological blockers targeting DAMPs or the NLRP3 inflammasome in liver ischemia during static cold storage or through extracorporeal organ support could be a suitable strategy to increase the success of liver transplantation.
FUNDING
BACKGROUND
Fundación Mutua Madrileña and Instituto de Salud Carlos III, Madrid, Spain.
Identifiants
pubmed: 36543018
pii: S2352-3964(22)00601-6
doi: 10.1016/j.ebiom.2022.104419
pmc: PMC9794897
pii:
doi:
Substances chimiques
Inflammasomes
0
NLR Family, Pyrin Domain-Containing 3 Protein
0
NLRP3 protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
104419Informations de copyright
Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests P.P. is scientific consultant of Glenmak Ltd, FirstThought, Donation and Transplantation Institute and Viva in vitro diagnostics. P.P. is co-inventor on patent application to use NLRP3 inflammasome as biomarker of disease, which have been licensed to Viva in vitro diagnostics S.L, a company co-funded by P.P., A.B.-M. and L.M-A. A.B-M. is co-inventor on provisional patent application of an in vitro method for predicting organ transplant rejection, but declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The rest of authors declare no competing interests.