title: Adenosine A2A receptors induced on iNKT and NK cells reduce pulmonary inflammation and injury in mice with sickle cell disease.
abstract: We showed previously that pulmonary function and arterial oxygen saturation in NY1DD mice with sickle cell disease (SCD) are improved by depletion of invariant natural killer T (iNKT) cells or blockade of their activation. Here we demonstrate that SCD causes a 9- and 6-fold induction of adenosine A(2A) receptor (A(2A)R) mRNA in mouse pulmonary iNKT and natural killer (NK) cells, respectively. Treating SCD mice with the A(2A)R agonist ATL146e produced a dose-dependent reversal of pulmonary dysfunction with maximal efficacy at 10 ng/kg/minute that peaked within 3 days and persisted throughout 7 days of continuous infusion. Crossing NY1DD mice with Rag1(-/-) mice reduced pulmonary injury that was restored by adoptive transfer of 10(6) purified iNKT cells. Reconstituted injury was reversed by ATL146e unless the adoptively transferred iNKT cells were pretreated with the A(2A)R alkylating antagonist, FSPTP (5-amino-7-[2-(4-fluorosulfonyl)phenylethyl]-2-(2-furyl)-pryazolo[4,3-ε]-1,2,4-triazolo[1,5-c]pyrimidine), which completely prevented pro-tection. In NY1DD mice exposed to hypoxia-reoxygenation, treatment with ATL146e at the start of reoxygenation prevented further lung injury. Together, these data indicate that activation of induced A(2A)Rs on iNKT and NK cells in SCD mice is sufficient to improve baseline pulmonary function and prevent hypoxia-reoxygenation-induced exacerbation of pulmonary injury. A(2A) agonists have promise for treating diseases associated with iNKT or NK cell activation.
authors.affiliation: Department of Microbiology, University of Virginia, Charlottesville, VA, USA.
authors.forename: Kori L
authors.initials: KL
authors.lastname: Wallace
authors.forename: Joel
authors.initials: J
authors.lastname: Linden
mesh_terms: D000755:Anemia, Sickle Cell / Q000276:immunology* / Q000378:metabolism; D000818:Animals; D002469:Cell Separation; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D055370:Lung Injury / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000096:biosynthesis / Q000276:immunology*
chemical_list: D043705:Receptor, Adenosine A2A
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