Thorac Cardiovasc Surg 2020; 68(S 01): S1-S72
DOI: 10.1055/s-0040-1705467
Short Presentations
Sunday, March 1st, 2020
Cardiovascular Basic Sciences
Georg Thieme Verlag KG Stuttgart · New York

RNA Release Triggers Ischemia/Reperfusion Injury in Cardiac Transplantation

C. Gollmann-Tepeköylü
1   Innsbruck, Austria
,
M. Graber
1   Innsbruck, Austria
,
L. Pölzl
1   Innsbruck, Austria
,
F. Nägele
1   Innsbruck, Austria
,
J. Hirsch
1   Innsbruck, Austria
,
N. Bonaros
1   Innsbruck, Austria
,
M. Grimm
1   Innsbruck, Austria
,
S. Schneeberger
1   Innsbruck, Austria
,
T. Resch
1   Innsbruck, Austria
,
J. Holfeld
1   Innsbruck, Austria
› Author Affiliations
Further Information

Publication History

Publication Date:
13 February 2020 (online)

Objectives: Ischemia and the consecutive restoration of blood flow during cardiac transplantation triggers excessive inflammation resulting in graft dysfunction. Toll-like receptor 3 (TLR3) initiates acute inflammation upon tissue injury, as it recognizes released danger associated with molecular patterns, in particular released RNA. We hypothesized that ischemia/reperfusion injury (IRI) causes RNA release with subsequent activation of TLR3 in transplanted hearts.

Methods: Human endothelial cells were subjected to ischemia/reperfusion injury (IRI) and treated with TLR3 agonist poly (I:C) or a TLR3/dsRNA complex inhibitor. Gene expression was analyzed via next-generation sequencing. Neutrophil adhesion was assessed in vitro. In order to investigate the detailed effects of TLR3 on cardiac IRI in vivo, syngeneic heart transplantation was performed in either C57BL/6 wild-type (WT) or TLR3 knockout (TLR3−/−) mice following 9 hours of cold ischemia.

Results: IRI caused release of RNA with subsequent activation of innate immune receptor TLR3. Gene expression profiling revealed excessive inflammation upon TLR3 activation, an effect abrogated by a TLR3 inhibitor. Inflammation resulted in enhanced neutrophil adhesion. In vivo,TLR3 knockout significantly diminished IRI-related injury 48 hours after reperfusion and protected from cardiac damage, apoptosis, and leucocyte infiltration after cardiac transplantation. In particular, epicardial and myocardial damage was alleviated. Furthermore, the presence of infiltrating lymphocytes significantly decreased. This was accompanied by reduced intragraft (CCL3, CCL4) and splenic mRNA expression of proinflammatory cytokines (TNFα, IL1b, CCL4, and CXCL10).

Conclusion: We uncover the release of RNA by injured cells with subsequent activation of TLR3 as crucial pathomechanism of IRI. Our data indicate that TLR3 represents a novel target for the prevention of IRI in solid organ transplantation.