Article abstract
Nature Medicine 13, 1423 - 1430 (2007)
Published online: 2 December 2007 | doi:10.1038/nm1690
Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease
Dominik Hartl1,2, Philipp Latzin3, Peter Hordijk4, Veronica Marcos1, Carsten Rudolph1, Markus Woischnik1, Susanne Krauss-Etschmann1,5, Barbara Koller1, Dietrich Reinhardt1, Adelbert A Roscher1, Dirk Roos4 & Matthias Griese1
Abstract
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 
1-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.
- Children's Hospital Research Center, Ludwig-Maximilians University, Munich 80337, Germany.
- Pulmonary and Critical Care Section, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
- Children's Hospital, University of Berne, Berne 3010, Switzerland.
- Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam 1066, The Netherlands.
- Gesellschaft für Strahlenforschung–National Research Center for Environment and Health, Munich 85764, Germany.
Correspondence to: Dominik Hartl1,2 e-mail: dhartl@med.uni-muenchen.de
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