title: NOX2 Activation of Natural Killer T Cells Is Blocked by the Adenosine A2A Receptor to Inhibit Lung Ischemia-Reperfusion Injury.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  Adoptive transfer of iNKT cells from p47(phox-/-) 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 p47(phox) phosphorylation, a critical step for NOX2 activation.
  
  
  
  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.
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia.
authors.forename: Ashish K
authors.identifier: 0000-0002-1234-6039
authors.initials: AK
authors.lastname: Sharma
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia.
authors.forename: Damien J
authors.initials: DJ
authors.lastname: LaPar
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Stone
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia.
authors.forename: Yunge
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia.
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Mehta
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia.
authors.forename: Irving L
authors.initials: IL
authors.lastname: Kron
authors.affiliation: Department of Surgery, University of Virginia, Charlottesville, Virginia.
authors.forename: Victor E
authors.identifier: 0000-0001-9673-5383
authors.initials: VE
authors.lastname: Laubach
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D008168:Lung / Q000503:physiopathology; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000276:immunology / Q000378:metabolism*; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism*; D043705:Receptor, Adenosine A2A / Q000276:immunology / Q000378:metabolism*; D015427:Reperfusion Injury / Q000517:prevention & control*
chemical_list: D008562:Membrane Glycoproteins; D043705:Receptor, Adenosine A2A; C488842:Cybb protein, mouse; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: IL-17; NADPH oxidase; NOX2; adenosine A2A receptor; invariant natural killer T cells