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Prolonged pharmacological inhibition of cathepsin C results in elimination of neutrophil serine proteases.

Authors
  • Guarino, Carla1
  • Hamon, Yveline2
  • Croix, Cécile3
  • Lamort, Anne-Sophie2
  • Dallet-Choisy, Sandrine1
  • Marchand-Adam, Sylvain1
  • Lesner, Adam4
  • Baranek, Thomas1
  • Viaud-Massuard, Marie-Claude3
  • Lauritzen, Conni5
  • Pedersen, John5
  • Heuzé-Vourc'h, Nathalie1
  • Si-Tahar, Mustapha1
  • Fıratlı, Erhan6
  • Jenne, Dieter E7
  • Gauthier, Francis1
  • Horwitz, Marshall S8
  • Borregaard, Niels9
  • Korkmaz, Brice10
  • 1 INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, Tours, France. , (France)
  • 2 INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, Tours, France; Comprehensive Pneumology Center, Institute of Lung Biology and Disease, German Center for Lung Research (DZL), Munich, and Max Planck Institute of Neurobiology, Planegg-Martinsried, Germany. , (Germany)
  • 3 CNRS UMR-7292, "GICC, Innovation Moléculaire et Thérapeutique", Université de Tours, 31 Avenue Monge, Tours, France. , (France)
  • 4 Faculty of Chemistry, University of Gdansk, Gdansk, Poland. , (Poland)
  • 5 Unizyme Laboratories A/S, Hörsholm, Denmark. , (Denmark)
  • 6 Department of Periodontology, Faculty of Dentistry, University of Istanbul, Istanbul, Turkey. , (Turkey)
  • 7 Comprehensive Pneumology Center, Institute of Lung Biology and Disease, German Center for Lung Research (DZL), Munich, and Max Planck Institute of Neurobiology, Planegg-Martinsried, Germany. , (Germany)
  • 8 Department of Pathology, University of Washington, Seattle, WA, USA.
  • 9 The Granulocyte Research Laboratory, National University Hospital, Rigshospitalet, University of Copenhagen, Denmark. , (Denmark)
  • 10 INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, Tours, France; Department of Pathology, University of Washington, Seattle, WA, USA. Electronic address: [email protected] , (France)
Type
Published Article
Journal
Biochemical pharmacology
Publisher
New York, NY : Elsevier Science Inc
Publication Date
May 01, 2017
Volume
131
Pages
52–67
Identifiers
DOI: 10.1016/j.bcp.2017.02.009
PMID: 28193451
Source
Medline
Keywords
License
Unknown

Abstract

Cathepsin C (CatC) is a tetrameric cysteine dipeptidyl aminopeptidase that plays a key role in activation of pro-inflammatory serine protease zymogens by removal of a N-terminal pro-dipeptide sequence. Loss of function mutations in the CatC gene is associated with lack of immune cell serine protease activities and cause Papillon-Lefèvre syndrome (PLS). Also, only very low levels of elastase-like protease zymogens are detected by proteome analysis of neutrophils from PLS patients. Thus, CatC inhibitors represent new alternatives for the treatment of neutrophil protease-driven inflammatory or autoimmune diseases. We aimed to experimentally inactivate and lower neutrophil elastase-like proteases by pharmacological blocking of CatC-dependent maturation in cell-based assays and in vivo. Isolated, immature bone marrow cells from healthy donors pulse-chased in the presence of a new cell permeable cyclopropyl nitrile CatC inhibitor almost totally lack elastase. We confirmed the elimination of neutrophil elastase-like proteases by prolonged inhibition of CatC in a non-human primate. We also showed that neutrophils lacking elastase-like protease activities were still recruited to inflammatory sites. These preclinical results demonstrate that the disappearance of neutrophil elastase-like proteases as observed in PLS patients can be achieved by pharmacological inhibition of bone marrow CatC. Such a transitory inhibition of CatC might thus help to rebalance the protease load during chronic inflammatory diseases, which opens new perspectives for therapeutic applications in humans.

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