NOX2 activation of natural killer T cells is blocked by the adenosine A2A receptor to inhibit lung ischemia-reperfusion injury

Ashish K. Sharma, Damien J. LaPar, Matthew L. Stone, Yunge Zhao, Christopher K. Mehta, Irving L. Kron, Victor E. Laubach

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


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 p47phox2/2 or NOX22/2 mice to Jα182/2 (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 Jα182/2 mice reconstituted with WT, but not A2AR2/2, iNKT cells. Furthermore, theA2AR 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.

Original languageEnglish (US)
Pages (from-to)988-999
Number of pages12
JournalAmerican journal of respiratory and critical care medicine
Issue number9
StatePublished - May 1 2016


  • Adenosine A2A receptor
  • IL-17
  • Invariant natural killer T cells
  • NADPH oxidase
  • NOX2

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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