Mitochondrial Damage-Associated Molecular Patterns (MTDs) Are Released during Hepatic Ischemia Reperfusion and Induce Inflammatory Responses

Abstract

Ischemia / reperfusion injury (IRI) during the course of liver transplantation enhances the immunogenicity of allografts and thus impacts overall graft outcome. This sterile inflammatory insult is known to activate innate immunity and propagate organ damage through the recognition of damage-associate molecular pattern (DAMP) molecules. The purpose of the present study was to investigate the role of mitochondrial DAMPs (MTDs) in the pathogenesis of hepatic IRI. Using in vitro models we observed that levels of MTDs were significantly higher in both transplantation-associated and warm IR, and that co-culture of MTDs with human and rat hepatocytes significantly increased cell death. MTDs were also released in an in vivo rat model of hepatic IRI and associated with increased secretion of inflammatory cytokines (TNF-α, IL-6, and IL-10) and increased liver injury compared to the sham group. Our results suggest that hepatic IR results in a significant increase of MTDs both in vitro and in vivo suggesting that MTDs may serve as a novel marker in hepatic IRI. Co-culture of MTDs with hepatocytes showed a decrease in cell viability in a concentration dependent manner, which indicates that MTDs is a toxic mediator participating in the pathogenesis of liver IR injury.

Mitochondrial DNA copy number is associated with all‐cause mortality and cardiovascular events in patients with peripheral arterial disease

“…This was most likely caused by a suppression of mitochondrial ROS production . Mitochondrial dysfunction with ROS production seems to play also a major role in the development of intestinal ischaemia reperfusion often observed in haemorrhagic shock, trauma, sepsis, burns and surgical procedures . This disruption of the mucosal barrier opens the route for entrance of bacteria and their antigens resulting in severe infections as well as the amplification of an inflammatory response.…”

Transplantation and Damage-Associated Molecular Patterns (DAMPs)

“…In the field of organ transplantation, the danger/injury model was tackled for the first time in the early 2000s and, more recently, comprehensively addressed in a monograph . According to currently accepted models , any injury to an allograft, in particular, the “canonical” oxidative injury as occurring in the donor under brain death condition and in the recipient during postischemic reperfusion, leads to induction of various classes of DAMPs that activate intragraft PRR‐bearing cells of the donor's and recipient's innate immune system, a process that results in inflammation of the allograft. In parallel, donor‐derived and recipient‐derived dendritic cells (DCs), activated after uptake of alloantigens and recognition of various DAMPs by their corresponding PRRs, elicit—via the process of direct and indirect allorecognition—a robust adaptive anti‐donor alloimmune response ultimately resulting in allograft rejection .…”

“…During the past decade, a large variety of DAMPs generated from various sources and emitted during various injurious scenarios have been discovered. Table summarizes some selected most prominent DAMPs characterized to date in studies on cell death/tissue injury settings including IRI and tumor models as well as their mode of emission . In view of such a plethora of DAMPs, several reasonable approaches to classify them have been reported .…”

Danger signals in regulating the immune response to solid organ transplantation

“…Release of nuclear DNA fragments, mitochondrial DNA (mtDNA) fragments, and other mitochondrial contents can occur upon tissue injury, activating innate immunity to promote downstream adaptive immune responses through ligation of TLR9 or NALP3 (cryopyrin). Such nucleic acid or mitochondrial products accumulate in the extracellular space and enter into the circulation as a consequence of IRI or in the context of acute or chronic allograft rejection (29)(30)(31)(32)(33)(34). Consistent with this idea, recent work in heart, lung, and kidney transplantation has identified accumulation of donor-derived cell-free DNA in the blood of rejecting organ recipients (34).…”