title: Involvement of adenosine A2A receptors in engulfment-dependent apoptotic cell suppression of inflammation.
abstract: Efficient execution of apoptotic cell death followed by efficient clearance mediated by professional macrophages is a key mechanism in maintaining tissue homeostasis. Removal of apoptotic cells usually involves three central elements: 1) attraction of phagocytes via soluble "find me" signals, 2) recognition and phagocytosis via cell surface-presenting "eat me" signals, and 3) suppression or initiation of inflammatory responses depending on additional innate immune stimuli. Suppression of inflammation involves both direct inhibition of proinflammatory cytokine production and release of anti-inflammatory factors, which all contribute to the resolution of inflammation. In the current study, using wild-type and adenosine A(2A) receptor (A2AR) null mice, we investigated whether A2ARs, known to mediate anti-inflammatory signals in macrophages, participate in the apoptotic cell-mediated immunosuppression. We found that macrophages engulfing apoptotic cells release adenosine in sufficient amount to trigger A2ARs, and simultaneously increase the expression of A2ARs, as a result of possible activation of liver X receptor and peroxisome proliferators activated receptor δ. In macrophages engulfing apoptotic cells, stimulation of A2ARs suppresses the NO-dependent formation of neutrophil migration factors, such as macrophage inflammatory protein-2, using the adenylate cyclase/protein kinase A pathway. As a result, loss of A2ARs results in elevated chemoattractant secretion. This was evident as pronounced neutrophil migration upon exposure of macrophages to apoptotic cells in an in vivo peritonitis model. Altogether, our data indicate that adenosine is one of the soluble mediators released by macrophages that mediate engulfment-dependent apoptotic cell suppression of inflammation.
authors: Department of Biochemistry and Molecular Biology, Signaling and Apoptosis Research Group, Hungarian Academy of Sciences, Research Center of Molecular Medicine, University of Debrecen, Debrecen H-4012, Hungary.
authors: Krisztina
authors: K
authors: Köröskényi
authors: Edina
authors: E
authors: Duró
authors: Anna
authors: A
authors: Pallai
authors: Zsolt
authors: Z
authors: Sarang
authors: Doris
authors: D
authors: Kloor
authors: David S
authors: DS
authors: Ucker
authors: Susana
authors: S
authors: Beceiro
authors: Antonio
authors: A
authors: Castrillo
authors: Ajay
authors: A
authors: Chawla
authors: Catherine A
authors: CA
authors: Ledent
authors: László
authors: L
authors: Fésüs
authors: Zsuzsa
authors: Z
authors: Szondy
references: J Immunol. 1999 Dec 1;163(11):6164-72
references: 10570307
references: Immunity. 2009 Aug 21;31(2):245-58
references: 19646905
references: J Biol Chem. 1984 Aug 25;259(16):10020-4
references: 6088478
references: Nature. 1997 Aug 14;388(6643):674-8
references: 9262401
references: FASEB J. 1989 Dec;3(14):2565-73
references: 2687068
references: Nat Immunol. 2005 Dec;6(12):1191-7
references: 16369558
references: J Pharm Biomed Anal. 2001 Mar;24(5-6):1143-6
references: 11248511
references: Nature. 2000 Jan 13;403(6766):199-203
references: 10646605
references: Proc Natl Acad Sci U S A. 1989 Jan;86(2):612-6
references: 2643119
references: Arthritis Res Ther. 2006;8(2):R53
references: 16519795
references: Crit Care Med. 2000 Sep;28(9):3198-202
references: 11008982
references: Nature. 1997 Nov 27;390(6658):350-1
references: 9389474
references: Rheumatology (Oxford). 2005 Sep;44(9):1101-7
references: 15928001
references: Immunol Today. 1993 Mar;14(3):131-6
references: 8385467
references: Autoimmunity. 2007 Jun;40(4):274-80
references: 17516209
references: J Immunol. 2004 Jan 15;172(2):880-9
references: 14707059
references: Pharmacol Rev. 2001 Dec;53(4):527-52
references: 11734617
references: J Clin Invest. 1998 Feb 15;101(4):890-8
references: 9466984
references: J Cell Biol. 2001 Nov 12;155(4):649-59
references: 11706053
references: J Immunol. 2002 Aug 15;169(4):2093-101
references: 12165537
references: Immunobiology. 2007;212(9-10):795-812
references: 18086380
references: Cell. 1986 Oct 10;47(1):3-10
references: 3489530
references: Immunology. 2004 Sep;113(1):1-14
references: 15312130
references: Mol Cell Biol. 1990 Oct;10(10):5596-9
references: 2078213
references: J Chromatogr B Biomed Sci Appl. 1999 Mar 19;724(2):231-8
references: 10219663
references: Pharmacol Rev. 1998 Sep;50(3):413-92
references: 9755289
references: J Leukoc Biol. 2006 Oct;80(4):744-52
references: 16855064
references: Trends Immunol. 2004 Jan;25(1):33-9
references: 14698282
references: Proc Natl Acad Sci U S A. 1981 Jun;78(6):3363-7
references: 6267587
references: Cytokine Growth Factor Rev. 1997 Sep;8(3):207-19
references: 9462486
references: FASEB J. 2001 Mar;15(3):571-3
references: 11259370
references: J Immunol. 1995 Aug 15;155(4):2077-84
references: 7636258
references: Nat Rev Immunol. 2002 Dec;2(12):965-75
references: 12461569
references: Methods Enzymol. 2002;359:158-68
references: 12481568
references: Proc Natl Acad Sci U S A. 1977 Aug;74(8):3307-11
references: 198781
references: Immunity. 2004 Oct;21(4):467-76
references: 15485625
references: FASEB J. 1999 Dec;13(15):2125-37
references: 10593859
references: J Immunol. 1998 Apr 1;160(7):3562-8
references: 9531319
references: Blood. 1997 May 1;89(9):3345-53
references: 9129041
references: Immunity. 2004 Nov;21(5):643-53
references: 15539151
references: J Exp Med. 1993 Aug 1;178(2):605-13
references: 7688028
references: J Biol Chem. 1992 Jun 5;267(16):10976-81
references: 1375933
references: Nat Med. 2009 Nov;15(11):1266-72
references: 19838202
references: Mol Biol Cell. 2001 Apr;12(4):919-30
references: 11294896
references: J Immunol. 2001 Oct 1;167(7):4026-32
references: 11564822
references: Biochim Biophys Acta. 1997 Mar 15;1334(2-3):123-8
references: 9101705
references: FASEB J. 1994 Dec;8(15):1314-25
references: 8001745