NOX2 Activation of Natural Killer T Cells Is Blocked by the Adenosine A2A Receptor to Inhibit Lung Ischemia–Reperfusion Injury
AK Sharma, DJ LaPar, ML Stone, Y Zhao… - American journal of …, 2016 - atsjournals.org
American journal of respiratory and critical care medicine, 2016•atsjournals.org
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 A2A receptor
(A2AR) agonists are known to potently attenuate lung IR injury and IL-17 production.
However, mechanisms for iNKT cell activation after IR and A2AR agonist–mediated
protection remain unclear. Objectives: We tested the hypothesis that NOX2 mediates IL-17 …
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 A2A receptor
(A2AR) agonists are known to potently attenuate lung IR injury and IL-17 production.
However, mechanisms for iNKT cell activation after IR and A2AR agonist–mediated
protection remain unclear. Objectives: We tested the hypothesis that NOX2 mediates IL-17 …
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 A2A receptor (A2AR) agonists are known to potently attenuate lung IR injury and IL-17 production. However, mechanisms for iNKT cell activation after IR and A2AR agonist–mediated protection remain unclear.
Objectives: We tested the hypothesis that NOX2 mediates IL-17 production by iNKT cells after IR and that A2AR 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 p47phox−/− or NOX2−/− mice to Jα18−/− (iNKT cell-deficient) mice significantly attenuated lung IR injury and IL-17 production. Treatment with an A2AR agonist attenuated IR injury and IL-17 production in wild-type (WT) mice and in Jα18−/− mice reconstituted with WT, but not A2AR−/−, iNKT cells. Furthermore, the A2AR agonist prevented IL-17 production by murine and human iNKT cells after acute hypoxia–reoxygenation by blocking p47phox 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 A2AR agonist–mediated protection entails inhibition of NOX2 in iNKT cells. Therefore, agonism of A2ARs on iNKT cells may be a novel therapeutic strategy to prevent primary graft dysfunction after lung transplantation.
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