NOX2 Activation of Natural Killer T Cells Is Blocked by the Adenosine A_2A Receptor to Inhibit Lung Ischemia–Reperfusion Injury

Abstract

Rationale: Ischemia-reperfusion (IR) injury after lung transplantation, which affects both short-and long-term allograft survival, involves activation of NADPH oxidase 2 (NOX2) and activation of invariant natural killer T (iNKT) cells to produce IL-17. Adenosine A 2A receptor (A 2A R) agonists are known to potently attenuate lung IR injury and IL-17 production. However, mechanisms for iNKT cell activation after IR and A 2A R agonist-mediated protection remain unclear.Objectives: We tested the hypothesis that NOX2 mediates IL-17 production by iNKT cells after IR and that A 2A R agonism prevents IR injury by blocking NOX2 activation in iNKT cells.Methods: An in vivo murine hilar ligation model of IR injury was used, in which left lungs underwent 1 hour of ischemia and 2 hours of reperfusion.Measurements and Main Results: Adoptive transfer of iNKT cells from p47 phox2/2 or NOX2 2/2 mice to Ja18 2/2 (iNKT cell-deficient) mice significantly attenuated lung IR injury and IL-17 production. Treatment with an A 2A R agonist attenuated IR injury and IL-17 production in wild-type (WT) mice and in Ja18 2/2 mice reconstituted with WT, but not A 2A R 2/2, iNKT cells. Furthermore, the A 2A R agonist prevented IL-17 production by murine and human iNKT cells after acute hypoxia-reoxygenation by blocking p47 phox phosphorylation, a critical step for NOX2 activation.Conclusions: NOX2 plays a key role in inducing iNKT cell-mediated IL-17 production and subsequent lung injury after IR. A primary mechanism for A 2A R agonist-mediated protection entails inhibition of NOX2 in iNKT cells. Therefore, agonism of A 2A Rs on iNKT cells may be a novel therapeutic strategy to prevent primary graft dysfunction after lung transplantation.

Adenosine Production by Biomaterial‐Supported Mesenchymal Stromal Cells Reduces the Innate Inflammatory Response in Myocardial Ischemia/Reperfusion Injury

“…These findings have been previously reported in the literature and independently verified by our lab (Figure S3). 51 These findings are purportedly because of signaling between adenosine and the adenosine A2a‐receptor, which regulates NADPH‐oxidase assembly in immune cells 52. To determine whether MSCs were able to disrupt the formation of ROS in vivo, we measured H 2 O 2 formation 1 day following MI/R.…”

“…51 These findings are purportedly because of signaling between adenosine and the adenosine A2a-receptor, which regulates NADPH-oxidase assembly in immune cells. 52 To determine whether MSCs were able to disrupt the formation of ROS in vivo, we measured H 2 O 2 formation 1 day following MI/R. Significant increases in myocardial H 2 O 2 formation were observed in PBS-or hydrogel-treated animals when compared with sham-injured controls.…”

Models of Lung Transplant Research: a consensus statement from the National Heart, Lung, and Blood Institute workshop

“…neutrophil/mononuclear phagocyte activation and infiltration) (30), and proinflammatory cytokines and chemokines (7,8,15,20,24), all exemplifying multiple complex inflammatory pathways involved in PGD.…”

Muscle-derived extracellular superoxide dismutase inhibits endothelial activation and protects against multiple organ dysfunction syndrome in mice

“…Finally, we assessed pulmonary function using an isolated perfused lung system for physiologically relevant respiration and perfusion ex vivo [29]. We observed a significant increase in airway resistance from 1.39 ± 0.06 cm H 2 O/μl/sec in WT-saline mice to 2.18 ± 0.21 in WT-LPS mice ( p < 0.01), which was completely abolished in TG-LPS mice (1.40 ± 0.10; p < 0.01) (Fig.…”