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

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 α1-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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Figure 1: Blocking of CXCR1 impairs IL-8–mediated antibacterial functions of neutrophils.
Figure 2: CXCR1 expression on airway neutrophils is associated with bacterial-killing capacity and free elastase in individuals with chronic neutrophilic lung diseases.
Figure 3: Stratification of subjects with cystic fibrosis (CF).
Figure 4: Serine proteases cleave CXCR1 and release soluble CXCR1 fragments.
Figure 5: Soluble CXCR1 fragments induce cytokine production via TLR2.
Figure 6: α1-antitrypsin inhalation in subjects with cystic fibrosis (CF).

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Acknowledgements

We thank E. Remold-O'Donnell, M. Ennis, J. Elias, C. Sommerhoff, F. Ebel, A. Luster, M. Mall and B. Walzog for helpful discussions, and J. Miller for proofreading. This work is supported by the German Federal Ministry of Education and Research in the program BioFuture FKZ0311898 (C.R.), the German Society of Pediatric Pneumology (D.H.), Präventions-und Informationsnetzwerk Allergie/Asthma e.V. (D.H.) and the German Research Society DFG GR970-7.2 (M.G., M.W.).

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D.H. designed the main research concept, performed experiments and wrote the manuscript. A.A.R., D.R. and M.G. supervised the study, codesigned the research concept and wrote the manuscript; P.L. contributed to study design, performed statistical analyses and wrote the manuscript; D.R. provided funding and cosupervised the project.; P.H., V.M., C.R., M.W., B.K. and S.K.-E. performed experiments and/or provided scientific and technical knowledge.

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Correspondence to Dominik Hartl.

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Hartl, D., Latzin, P., Hordijk, P. et al. Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease. Nat Med 13, 1423–1430 (2007). https://doi.org/10.1038/nm1690

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