RGD Reference Report - CXCR2 mediates NADPH oxidase-independent neutrophil extracellular trap formation in cystic fibrosis airway inflammation. - Rat Genome Database

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

Authors: Marcos, V  Zhou, Z  Yildirim, AO  Bohla, A  Hector, A  Vitkov, L  Wiedenbauer, EM  Krautgartner, WD  Stoiber, W  Belohradsky, BH  Rieber, N  Kormann, M  Koller, B  Roscher, A  Roos, D  Griese, M  Eickelberg, O  Doring, G  Mall, MA  Hartl, D 
Citation: Marcos V, etal., Nat Med. 2010 Sep;16(9):1018-23. Epub 2010 Sep 5.
RGD ID: 5135034
Pubmed: PMID:20818377   (View Abstract at PubMed)
DOI: DOI:10.1038/nm.2209   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
cystic fibrosis  ISOCxcl1 (Mus musculus)5135034; 5135034protein:increased expression:respiratory system fluid/secretionRGD 
cystic fibrosis  IEP 5135034; 5135034; 5135034protein:increased expression:sputumRGD 
cystic fibrosis  ISOCxcl2 (Mus musculus)5135034; 5135034protein:increased expression:respiratory system fluid/secretionRGD 
cystic fibrosis  ISOCxcr2 (Mus musculus)5135034; 5135034 RGD 
cystic fibrosis  ISOCXCL1 (Homo sapiens)5135034; 5135034protein:increased expression:sputumRGD 
cystic fibrosis  IEP 5135034; 5135034protein:increased expression:respiratory system fluid/secretionRGD 
cystic fibrosis  ISOCXCL2 (Homo sapiens)5135034; 5135034protein:increased expression:sputumRGD 
cystic fibrosis  IMP 5135034 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Cxcl1  (C-X-C motif chemokine ligand 1)
Cxcl2  (C-X-C motif chemokine ligand 2)
Cxcr2  (C-X-C motif chemokine receptor 2)

Genes (Mus musculus)
Cxcl1  (C-X-C motif chemokine ligand 1)
Cxcl2  (C-X-C motif chemokine ligand 2)
Cxcr2  (C-X-C motif chemokine receptor 2)

Genes (Homo sapiens)
CXCL1  (C-X-C motif chemokine ligand 1)
CXCL2  (C-X-C motif chemokine ligand 2)
CXCL8  (C-X-C motif chemokine ligand 8)
CXCR2  (C-X-C motif chemokine receptor 2)


Additional Information