Chemokine receptors on neutrophils: functionality and involvement in chronic lung disease
Final Report Abstract
Chronic lung diseases such as cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD) are characterized by an accumulation of airway neutrophils. Chemokines recruit and activate neutrophils via chemokine receptors. As G-protein-coupled receptors (GPCRs), chemokine receptors are highly relevant for therapeutic approaches. Therefore, a precise knowledge on the involvement of specific chemokine receptors in chronic lung diseases is required. We previously identified the chemokine receptor CXCR1 on neutrophils as a critical target in chronic lung disease, since we found that CXCR1 mediates key antibacterial neutrophil functions, but is cleaved proteolytically in protease-dominated airway microenvironments. We further found that airway neutrophils in chronic lung diseases adapt their chemokine receptor expression profile through translocation of intracellular chemokine receptors, such as CXCR4. Based on these previous studies, our aims were to address the following issues in the proposed research group: To investigate specific cellular pathways in neutrophils engaged through chemokine receptors, to identify the genetic and molecular mechanisms involved in the regulation of chemokine receptor expression and to characterize the functional role of chemokines and chemokine receptors in neutrophilic lung disease in vivo. Our published studies demonstrate (i) that genetic CXCR1/CXCR2 haplotypes are associated with CF lung disease, (ii) that CXCR1 cleavage involves a novel interactive network of elastase, secretases and PAR-2 and (iii) that CXCR1 is involved in anti-Pseudomonas aeruginosa host defence in vivo. These studies add to our understanding how neutrophils are involved in CF lung disease, which could pave the way for further diagnostic and/or therapeutic strategies in the field.
Publications
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CXCR1 and CXCR2 haplotypes synergistically modulate cystic fibrosis lung disease. Eur Respir J. 2011. Nov 16
Kormann M, Hector A, Marcos V, Mays L, Kappler M, Illig T, Klopp N, Carevic M, Rieber N, Eickmeier O, Zielen S, Gaggar A, Moepps B, Griese M and Hartl D
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Neutrophils express distinct RNA receptors in a non-canonical way. J Biol Chem. 2012 Apr 24
Berger M, Hsieh CY, Bakele M, Marcos V, Rieber N, Kormann M, Mays L, Hofer L, Neth O, Vitkov L, Krautgartner WD, von Schweinitz D, Kappler R, Hector A, Weber A, Hartl D
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Expression and regulation of interferon-related development regulator 1 (IFRD1) in cystic fibrosis neutrophils. Am J Resp Cell Mol Biol. 2013 Jan;48(1):71-7
Hector A, Kormann M, Kammermeier J, Burdi S, Marcos V, Rieber N, Mays L, Illig T, Klopp N, Falkenstein F, Kappler M, Riethmueller J, Graepler-Mainka U, Stern M, Döring G, Griese M and Hartl D
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Flagellin induces myeloid-derived suppressor cells: implications for Pseudomonas aeruginosa infection in cystic fibrosis lung disease. The Journal of Immunology. 2013; Feb 1
Rieber N, Brand A, Hector A, Graepler-Mainka U, Ost M, Schäfer I, Wecker I, Wirth A, Mays L, Zundel S, Fuchs J, Handgretinger R, Stern M, Hogardt M, Döring G, Riethmüller J, Kormann M and Hartl D
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An interactive network of elastase, secretases and PAR-2 regulates CXCR1 surface expression on neutrophils. J Biol Chem 2014 Jun 9
Bakele M, Lotz-Havla A, Jakowetz A, Carevic M, Marcos V, Muntau A, Gersting S, Hartl D
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The chemokine CCL18 characterizes Pseudomonas infections in cystic fibrosis lung disease. European Respiratory Journal 2014 Aug 19
Hector A, Kroner C, Carevic M, Bakele M, Rieber N, Riethmuller J, Griese M, Zissel G, Hartl D
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CXCR4+ granulocytes reflect fungal cystic fibrosis lung disease. European Respiratory Journal 2015, Apr 30
Carevic M, Singh A, Rieber N, Eickmeier O, Griese M, Hector A, Hartl D
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Regulatory T cell impairment in cystic fibrosis patients with chronic Pseudomonas infection. American Journal of Respiratory and Critical Care Medicine, 2015 Jan 29
Hector A, Schäfer H, Pöschel S, Fischer A, Fritzsching B, Ralhan A, Carevic M, Öz H, Zundel S, Hogardt M, Bakele M, Rieber N, Riethmueller J, Graepler-Mainka U, Stahl M, Bender A, Frick JS, Mall M and Hartl D
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CXCR1 regulates pulmonary anti- Pseudomonas host defense. Journal of Innate Immunity. 2016 Mar 8
Carevic M, H. Öz, K. Fuchs, J. Laval, C. Schroth, N. Frey, A. Hector, T. Bilich, M. Haug, A. Schmidt, S. E. Autenrieth, K. Bucher, S. Beer-Hammer, A. Gaggar, M. Kneilling, C. Benarafa, J. Gao, P. Murphy, S. Schwarz, B. Moepps, Hartl D
