Adenosine A2A receptors induced on iNKT and NK cells reduce pulmonary inflammation and injury in mice with sickle cell disease.
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.
Wallace
Kori L
KL
Department of Microbiology, University of Virginia, Charlottesville, VA, USA.
Linden
Joel
J
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*
D043705:Receptor, Adenosine A2A
N Engl J Med. 2004 Feb 26;350(9):886-95
14985486
Proc Natl Acad Sci U S A. 2001 Dec 18;98(26):15215-20
11752464
Med Hypotheses. 2009 Jun;72(6):713-9
19237250
JAMA. 2003 Mar 5;289(9):1136-42
12622584
Anesthesiology. 1997 Oct;87(4):988-90
9357905
Science. 2004 Dec 3;306(5702):1786-9
15539565
Br J Pharmacol. 2000 Jan;129(1):2-11
10694196
Blood. 2010 Aug 5;116(5):687-92
20395414
Infect Immun. 2001 Sep;69(9):5294-304
11500398
J Clin Invest. 2000 Aug;106(3):411-20
10930444
Am J Physiol Lung Cell Mol Physiol. 2007 Jun;292(6):L1335-44
17293374
J Clin Pathol. 1991 Jun;44(6):459-63
2066423
J Immunol. 2007 Jul 15;179(2):1254-63
17617618
J Immunol. 2007 Mar 1;178(5):2706-13
17312112
Am J Physiol Lung Cell Mol Physiol. 2006 May;290(5):L1036-43
16339780
Blood. 2000 Jul 1;96(1):314-20
10891467
Am J Respir Crit Care Med. 2001 Dec 1;164(11):2016-9
11739128
Blood. 2009 Jul 16;114(3):667-76
19433855
J Clin Invest. 2000 Aug;106(3):337-8
10930436
J Pharmacol Exp Ther. 1997 Jan;280(1):301-9
8996210
Hum Pathol. 2002 Oct;33(10):1037-43
12395378
Blood. 2003 May 15;101(10):3953-9
12543857
Am J Respir Crit Care Med. 2004 Mar 15;169(6):687-95
14684557
Br J Haematol. 1996 May;93(2):333-40
8639425
Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12155-9
1465455
J Exp Med. 2006 Nov 27;203(12):2639-48
17088433
N Engl J Med. 1994 Jun 9;330(23):1639-44
7993409
Proc Natl Acad Sci U S A. 2002 Mar 5;99(5):3047-51
11880644
Circulation. 1998 Aug 18;98(7):711-8
9715864
Kidney Int. 1988 Jul;34(1):117-20
3172632
J Clin Invest. 1982 Dec;70(6):1253-9
6294138
Circulation. 2006 Nov 7;114(19):2056-64
17060376
Am J Hematol. 2008 Jan;83(1):19-25
17724699
J Heart Lung Transplant. 1999 Oct;18(10):994-1002
10561110
Am J Physiol Renal Physiol. 2000 Nov;279(5):F809-18
11053040
Am J Physiol. 1989 Apr;256(4 Pt 1):C799-806
2539728
Immunity. 2000 Feb;12(2):211-21
10714687
Eur J Pharmacol. 2002 Mar 8;438(3):183-8
11909610
PLoS Biol. 2008 Jul 15;6(7):e172
18630988
Proc Natl Acad Sci U S A. 1992 Dec 15;89(24):12150-4
1465454
Blood. 2007 Apr 1;109(7):3088-98
17158223
Am J Physiol Gastrointest Liver Physiol. 2004 Feb;286(2):G285-93
14715520
Br J Haematol. 2006 Jul;134(1):109-15
16803576
N Engl J Med. 1995 May 18;332(20):1317-22
7715639
J Pharmacol Exp Ther. 2000 Sep;294(3):1034-42
10945856
Drug Discov Today. 2004 May 1;9(9):403-9
15081957
Crit Care Med. 1999 Nov;27(11):2563-8
10579281
J Immunol. 2007 May 1;178(9):5899-911
17442974
Microbes Infect. 2003 May;5(6):515-26
12758281
Blood. 1996 May 15;87(10):4440-7
8639806
J Clin Invest. 2003 Sep;112(6):883-91
12975473
Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5977-82
17372206