CXCR2 mediates NADPH oxidase-independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation.
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.
Marcos
Veronica
V
Research Center, Children's Hospital, Ludwig-Maximilians-University, Munich, Germany.
Zhou
Zhe
Z
Yildirim
Ali Onder
AO
Bohla
Alexander
A
Hector
Andreas
A
Vitkov
Ljubomir
L
Wiedenbauer
Eva-Maria
EM
Krautgartner
Wolf Dietrich
WD
Stoiber
Walter
W
Belohradsky
Bernd H
BH
Rieber
Nikolaus
N
Kormann
Michael
M
Koller
Barbara
B
Roscher
Adelbert
A
Roos
Dirk
D
Griese
Matthias
M
Eickelberg
Oliver
O
Döring
Gerd
G
Mall
Marcus A
MA
Hartl
Dominik
D
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*
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
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