Unlocking the Potential of Purinergic Signaling in Transplantation

Abstract

Purinergic signaling has been recognized as playing an important role in inflammation, angiogenesis, malignancy, diabetes and neural transmission. Activation of signaling pathways downstream from purinergic receptors may also be implicated in transplantation and related vascular injury. Following transplantation, the proinflammatory “danger signal” adenosine triphosphate (ATP) is released from damaged cells and promotes proliferation and activation of a variety of immune cells. Targeting purinergic signaling pathways may promote immunosuppression and ameliorate inflammation. Under pathophysiological conditions, nucleotide-scavenging ectonucleotidases CD39 and CD73 hydrolyze ATP, ultimately, to the anti-inflammatory mediator adenosine. Adenosine suppresses proinflammatory cytokine production and is associated with improved graft survival and decreased severity of graft-versus-host disease. Furthermore, purinergic signaling is involved both directly and indirectly in the mechanism of action of several existing immunosuppressive drugs, such as calcineurin inhibitors and mammalian target of rapamycin inhibitors. Targeting of purinergic receptor pathways, particularly in the setting of combination therapies, could become a valuable immunosuppressive strategy in transplantation. This review focuses on the role of the purinergic signaling pathway in transplantation and immunosuppression and explores possible future applications in clinical practice.

ATP mediates the interaction between human blastocyst and endometrium

“…P2YRs are G‐protein–coupled transmembrane receptors that increase the concentration of either intracellular Ca2 + or cyclic adenosine monophosphate (cAMP) ). ATP is related to a variety of physiological processes, including inflammation, angiogenesis and the wound‐healing response . It has been shown that many inflammation‐related genes, such as prostaglandin E2 (PGE2), TNF, IL6 and IL1β, are involved in embryo implantation and decidualization .…”

P2X7R mutation disrupts the NLRP3-mediated Th program and predicts poor cardiac allograft outcomes

“…Purinergic receptor-7 (P2X7R), primarily expressed on lymphocytes, senses adenosine 5′-triphosphate (ATP) (1) released extracellularly during cell damage (2,3) and has been shown to regulate T cell activation (4)(5)(6). In particular, P2X7R signaling favors T helper 1 (Th1) and Th17 generation and differentiation (7)(8)(9), which are involved in alloimmune responses and allograft rejection (10)(11)(12)(13)(14).…”

Extracellular nucleotide signaling in solid organ transplantation

“…A comprehensive review by Zeiser et al in 2016 provides in‐depth information on the role of purinergic signaling in the setting of transplantation. In addition, Boros et al recently provided a concise review on adenosine regulation of the immune response to ischemia‐reperfusion injury.…”

“…Numerous intra-and extracellular factors contribute to the success or failure of solid-organ transplants, and the contribution of purinergic signaling mediated by purine nucleotides and nucleosides such as adenosine and adenosine triphosphate (ATP) is now recognized to be important in all stages of the transplant process. 1 For example, acute graft dysfunction as a result of ischemia-reperfusion injury (IRI) after transplant causes damage to graft tissues, involving the release of ATP that acts as a danger signal and promotes immune cell activation and infiltration. 2 Because the purinergic system is important to T cell biology, it has also been a therapeutic target for the prevention of acute rejection and the promotion of long-term graft survival.…”