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Hartl, D.* ; Latzin, P.* ; Hordijk, P.* ; Marcos, V.* ; Rudolph, C.* ; Woischnik, M.* ; Krauss-Etschmann, S. ; Koller, B.* ; Reinhardt, D.* ; Roscher, A.A.* ; Roos, D.* ; Griese, M.

Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease.

J. Nat. Med. 13, 1423-1430 (2007)
DOI
Open Access Green as soon as Postprint is submitted to ZB.
Interleukin-8 (IL-8) activates neutrophils via the chemokine receptors CXCR1 and CXCR2. However, the airways of individuals with cystic fibrosis are frequently colonized by bacterial pathogens, despite the presence of large numbers of neutrophils and IL-8. Here we show that IL-8 promotes bacterial killing by neutrophils through CXCR1 but not CXCR2. Unopposed proteolytic activity in the airways of individuals with cystic fibrosis cleaved CXCR1 on neutrophils and disabled their bacterial-killing capacity. These effects were protease concentration-dependent and also occurred to a lesser extent in individuals with chronic obstructive pulmonary disease. Receptor cleavage induced the release of glycosylated CXCR1 fragments that were capable of stimulating IL-8 production in bronchial epithelial cells via Toll-like receptor 2. In vivo inhibition of proteases by inhalation of alpha1-antitrypsin restored CXCR1 expression and improved bacterial killing in individuals with cystic fibrosis. The cleavage of CXCR1, the functional consequences of its cleavage, and the identification of soluble CXCR1 fragments that behave as bioactive components represent a new pathophysiologic mechanism in cystic fibrosis and other chronic lung diseases.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Animals; Cystic Fibrosis/immunology*; Cystic Fibrosis/microbiology*; Glycosylation;Humans; Interleukin-8/metabolism; Lung/microbiology; Mice; Models; biological;Neutrophils/metabolism*; Neutrophils/microbiology; Receptors; Interleukin-8A/metabolism
ISSN (print) / ISBN 1340-3443
e-ISSN 1861-0293
Journal Journal of natural medicines
Quellenangaben Volume: 13, Issue: 12, Pages: 1423-1430 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Tokyo [u.a.]
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) CCG Immune Regulation in Childhood (IMI-KIK)