title: CXCR2 mediates NADPH oxidase-independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation.
abstract: Upon activation, neutrophils release DNA fibers decorated with antimicrobial proteins, forming neutrophil extracellular traps (NETs). Although NETs are bactericidal and contribute to innate host defense, excessive NET formation has been linked to the pathogenesis of autoinflammatory diseases. However, the mechanisms regulating NET formation, particularly during chronic inflammation, are poorly understood. Here we show that the G protein-coupled receptor (GPCR) CXCR2 mediates NET formation. Downstream analyses showed that CXCR2-mediated NET formation was independent of NADPH oxidase and involved Src family kinases. We show the pathophysiological relevance of this mechanism in cystic fibrosis lung disease, characterized by chronic neutrophilic inflammation. We found abundant NETs in airway fluids of individuals with cystic fibrosis and mouse cystic fibrosis lung disease, and NET amounts correlated with impaired obstructive lung function. Pulmonary blockade of CXCR2 by intra-airway delivery of small-molecule antagonists inhibited NET formation and improved lung function in vivo without affecting neutrophil recruitment, proteolytic activity or antibacterial host defense. These studies establish CXCR2 as a receptor mediating NADPH oxidase-independent NET formation and provide evidence that this GPCR pathway is operative and druggable in cystic fibrosis lung disease.
authors.affiliation: Research Center, Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Veronica
authors.initials: V
authors.lastname: Marcos
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhou
authors.forename: Ali Onder
authors.initials: AO
authors.lastname: Yildirim
authors.forename: Alexander
authors.initials: A
authors.lastname: Bohla
authors.forename: Andreas
authors.initials: A
authors.lastname: Hector
authors.forename: Ljubomir
authors.initials: L
authors.lastname: Vitkov
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Wiedenbauer
authors.forename: Wolf Dietrich
authors.initials: WD
authors.lastname: Krautgartner
authors.forename: Walter
authors.initials: W
authors.lastname: Stoiber
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Belohradsky
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Rieber
authors.forename: Michael
authors.initials: M
authors.lastname: Kormann
authors.forename: Barbara
authors.initials: B
authors.lastname: Koller
authors.forename: Adelbert
authors.initials: A
authors.lastname: Roscher
authors.forename: Dirk
authors.initials: D
authors.lastname: Roos
authors.forename: Matthias
authors.initials: M
authors.lastname: Griese
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.forename: Gerd
authors.initials: G
authors.lastname: Döring
authors.forename: Marcus A
authors.initials: MA
authors.lastname: Mall
authors.forename: Dominik
authors.initials: D
authors.lastname: Hartl
mesh_terms: D000818:Animals; D016923:Cell Death; D054426:Chemokine CXCL2 / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000502:physiology; D006801:Humans; D007249:Inflammation / Q000503:physiopathology; D016209:Interleukin-8 / Q000494:pharmacology / Q000502:physiology; D008171:Lung Diseases / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018375:Neutrophil Activation / Q000187:drug effects / Q000502:physiology; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009861:Onium Compounds / Q000494:pharmacology; D023063:Receptors, Interleukin-8B / Q000502:physiology*
chemical_list: C499706:CXCL2 protein, human; C508606:CXCL8 protein, human; D054426:Chemokine CXCL2; D004791:Enzyme Inhibitors; D016209:Interleukin-8; D009861:Onium Compounds; D023063:Receptors, Interleukin-8B; C007517:diphenyleneiodonium; D019255:NADPH Oxidases
references.citation: Nat Rev Immunol. 2006 Mar;6(3):173-82
references.pmid: 16498448
references.citation: Nat Med. 2008 Sep;14(9):949-53
references.pmid: 18690244
references.citation: Annu Rev Pharmacol Toxicol. 2008;48:171-97
references.pmid: 17883327
references.citation: Nat Med. 2007 Apr;13(4):403-4
references.pmid: 17415369
references.citation: Clin Rev Allergy Immunol. 2002 Aug;23(1):5-27
references.pmid: 12162106
references.citation: J Biol Chem. 2004 Oct 15;279(42):44123-32
references.pmid: 15302890
references.citation: Cell Death Differ. 2009 Nov;16(11):1438-44
references.pmid: 19609275
references.citation: J Clin Invest. 1992 Oct;90(4):1296-301
references.pmid: 1357002
references.citation: Science. 2004 Mar 5;303(5663):1532-5
references.pmid: 15001782
references.citation: J Biol Chem. 1998 Sep 11;273(37):23830-6
references.pmid: 9726994
references.citation: J Cell Biol. 2009 Jan 26;184(2):205-13
references.pmid: 19153223
references.citation: Nat Med. 2007 Apr;13(4):463-9
references.pmid: 17384648
references.citation: J Biol Chem. 2008 Sep 26;283(39):26538-47
references.pmid: 18662984
references.citation: J Leukoc Biol. 2005 Jul;78(1):279-88
references.pmid: 15831558
references.citation: J Immunol. 2003 Oct 1;171(7):3775-84
references.pmid: 14500678
references.citation: Hum Immunol. 2005 Nov;66(11):1146-54
references.pmid: 16571415
references.citation: J Immunol. 1999 Dec 1;163(11):6086-94
references.pmid: 10570298
references.citation: J Immunol. 2008 Feb 1;180(3):1895-902
references.pmid: 18209087
references.citation: Nat Rev Microbiol. 2007 Aug;5(8):577-82
references.pmid: 17632569
references.citation: Br J Pharmacol. 2008 Oct;155(3):357-64
references.pmid: 18587419
references.citation: Cell Microbiol. 2006 Apr;8(4):668-76
references.pmid: 16548892
references.citation: Infect Immun. 2010 Jun;78(6):2620-30
references.pmid: 20368349
references.citation: J Clin Invest. 2005 May;115(5):1150-62
references.pmid: 15864347
references.citation: Am J Respir Med. 2002;1(1):19-25
references.pmid: 14720072
references.citation: Nat Med. 2007 Dec;13(12):1423-30
references.pmid: 18059279
references.citation: Nat Med. 2004 May;10(5):452-4
references.pmid: 15122239
references.citation: Infect Immun. 2000 Jul;68(7):4289-96
references.pmid: 10858247
references.citation: Pediatr Rev. 2001 Aug;22(8):257-64
references.pmid: 11483851
references.citation: J Intern Med. 2001 Aug;250(2):91-104
references.pmid: 11489059
references.citation: Proc Natl Acad Sci U S A. 1996 Jun 25;93(13):6682-6
references.pmid: 8692878
references.citation: Int J Immunopharmacol. 1995 Feb;17(2):103-8
references.pmid: 7657403
references.citation: Curr Opin Pharmacol. 2008 Jun;8(3):300-7
references.pmid: 18457992
references.citation: J Cell Biol. 2007 Jan 15;176(2):231-41
references.pmid: 17210947
references.citation: Am J Physiol Regul Integr Comp Physiol. 2002 Jul;283(1):R7-28
references.pmid: 12069927
references.citation: Nat Med. 2004 May;10(5):487-93
references.pmid: 15077107
references.citation: Nat Med. 2009 Jun;15(6):623-5
references.pmid: 19448636
references.citation: J Mol Med (Berl). 2009 Aug;87(8):775-83
references.pmid: 19444424
references.citation: J Immunol. 2004 Mar 15;172(6):3860-8
references.pmid: 15004193
references.citation: Pharmacol Ther. 2009 Jan;121(1):55-68
references.pmid: 19026683