The Immunosuppressive Role of Adenosine A2A Receptors in Ischemia Reperfusion Injury and Islet Transplantation

Abstract

Activation of adenosine A2A receptors (A2AR) reduces inflammation by generally inhibiting the activation of pro-inflammatory cells, decreasing endothelial adhesion molecule expression and reducing the release of proinflammatory cytokine mediators. Numerous preclinical studies using selective A2AR agonists, antagonists, A2AR knockout as well as chimeric mice have suggested the therapeutic potential of A2AR agonists for the treatment of ischemia reperfusion injury (IRI) and autoimmune diseases. This review summarizes the immunosuppressive actions of A2AR agonists in murine IRI models of liver, kidney, heart, lung and CNS, and gives details on the cellular effects of A2AR activation in neutrophils, macrophages, dendritic cells, natural killer cells, NKT cells, T effector cells and CD4+CD25+FoxP3+ T regulatory cells. This is discussed in the context of cytokine mediators involved in inflammatory cascades. Whilst the role of adenosine receptor agonists in various models of autoimmune disease has been well-documented, very little information is available regarding the role of A2AR activation in type 1 diabetes mellitus (T1DM). An overview of the pathogenesis of T1DM as well as early islet graft rejection in the immediate peri-transplantation period offers insight regarding the use of A2AR agonists as a beneficial intervention in clinical islet transplantation, promoting islet graft survival, minimizing early islet loss and reducing the number of islets required for successful transplantation, thereby increasing the availability of this procedure to a greater number of recipients. In summary, the use of A2AR agonists as a clinical intervention in IRI and as an adjunct to clinical immunesuppressive regimen in islet transplantation is highlighted.

The Inflammasome in Liver Injury and Non-Alcoholic Fatty Liver Disease

“…On initial inspection the ability of adenosine to increase IL-1β production seems counter to the vast amount of experimental evidence suggesting adenosine is anti-inflammatory, particularly in relation to inhibition of TNF-α and IL-6 [46]. In this context it is important to note that even in the above setting the adenosine response is selective.…”

NOX2 Activation of Natural Killer T Cells Is Blocked by the Adenosine A2A Receptor to Inhibit Lung Ischemia–Reperfusion Injury

“…A 2A R activation leads to increased cAMP production that culminates in the attenuation of transcriptional signaling that leads to inflammation. In response to inflammatory stimuli such as IR, activation of innate immune cells leads to robust production of proinflammatory cytokines (e.g., tumor necrosis factor-a [TNF-a], IL-17, and IFN-g), which can be blocked by treatment with A 2A R agonists (3,(20)(21)(22)(23). However, the mechanism of A 2A R agonist-mediated prevention of lung IR injury, especially in the context of iNKT cell-mediated IL-17 production, remains to be elucidated.…”

Anti-inflammatory Interventional Strategies to Promote Islet Transplantation Outcomes

“…Factors contributing to the eventual decline in graft function and survival include, amongst others, a) innate non-specific inflammatory reactions in the microenvironment of the graft during the peritransplant period that mediate early loss of nearly 50% of the transplanted islets; b) ischemiareperfusion injury (IRI) following transplantation; c) relative hypoxia and poor vascularization of islets resulting in inefficient engraftment and primary dysfunction of islets, d) progressive destruction of the graft by innate and adaptive immune mechanisms and the recurrence of autoimmunity; e) metabolic distress from exhaustion of a marginal β-cell mass and f) drug toxicity associated with immunosuppressive regimens [1,7]. The detrimental effects of the instant blood mediated inflammatory reaction (IBMIR) as well as IRI-induced inflammation contribute to peritransplant loss of a significant proportion of transplanted islet mass, likely promoting alloantigen presentation and accelerating subsequent cell-mediated allogeneic immune responsiveness [7][8][9]. Therefore, the discovery of novel antiinflammatory pharmacologic agents or strategies that can be inducted into standard immunosuppressive regimens to effectively inhibit inflammatory cascades in the period immediately following transplantation will significantly impact longitudinal clinical islet transplant outcomes.…”

“…Therefore, the discovery of novel antiinflammatory pharmacologic agents or strategies that can be inducted into standard immunosuppressive regimens to effectively inhibit inflammatory cascades in the period immediately following transplantation will significantly impact longitudinal clinical islet transplant outcomes. To this end, numerous preclinical studies using selective adenosine A2A receptor (A2AR) agonists, antagonists, A2AR knockout as well as chimeric mice have suggested the therapeutic potential of A2AR agonists for the treatment of ischemia reperfusion injury (IRI) and promoting graft survival outcomes [9]. Activation of adenosine A2A receptors (A2AR) reduces inflammation by inhibiting the activation of pro-inflammatory cells, decreasing endothelial adhesion molecule expression and reducing the release of proinflammatory cytokine mediators [7,9].…”

“…To this end, numerous preclinical studies using selective adenosine A2A receptor (A2AR) agonists, antagonists, A2AR knockout as well as chimeric mice have suggested the therapeutic potential of A2AR agonists for the treatment of ischemia reperfusion injury (IRI) and promoting graft survival outcomes [9]. Activation of adenosine A2A receptors (A2AR) reduces inflammation by inhibiting the activation of pro-inflammatory cells, decreasing endothelial adhesion molecule expression and reducing the release of proinflammatory cytokine mediators [7,9]. Our studies conducted in both the murine sub-kidney capsule as well as the clinically-relevant hepatic intra-portal islet transplantation models indicate that infusion of A2AR agonist ATL146e and ATL313 in diabetic recipient mice during the peritransplant period resulted in reduction of both, inflammation-mediated early loss of a minimal dose islet graft as well as in the time taken to achieve sustained normoglycemia [7].…”