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Marcos, V.* ; Zhou, Z.* ; Yildirim, A.Ö. ; Bohla, A. ; Hector, A.* ; Vitkov, L.* ; Wiedenbauer, E.M.* ; Krautgartner, W.D.* ; Stoiber, W.* ; Belohradsky, B.H.* ; Rieber, N.* ; Kormann, M.* ; Koller, B.* ; Roscher, A.* ; Roos, D.* ; Griese, M.* ; Eickelberg, O. ; Döring, G.* ; Mall, M.A.* ; Hartl, D.*

CXCR2 mediates NADPH oxidase-independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation.

J. Nat. Med. 16, 1018-1023 (2010)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords CF LUNG-DISEASE; MITOCHONDRIAL-DNA; INTERLEUKIN-8; RELEASE; DEFENSE; MICE; INDUCTION; BACTERIA; IMMUNITY; LIGANDS
ISSN (print) / ISBN 1340-3443
e-ISSN 1861-0293
Journal Journal of natural medicines
Quellenangaben Volume: 16, Issue: 9, Pages: 1018-1023 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Tokyo [u.a.]
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Lung Biology (LHI)
Lung Health and Immunity (LHI)