title: Prolonged pharmacological inhibition of cathepsin C results in elimination of neutrophil serine proteases.
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.
authors.affiliation: INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, Tours, France.
authors.forename: Carla
authors.initials: C
authors.lastname: Guarino
authors.affiliation: 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.
authors.forename: Yveline
authors.initials: Y
authors.lastname: Hamon
authors.affiliation: CNRS UMR-7292, "GICC, Innovation Moléculaire et Thérapeutique", Université de Tours, 31 Avenue Monge, Tours, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Croix
authors.affiliation: 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.
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Lamort
authors.affiliation: INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, Tours, France.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Dallet-Choisy
authors.affiliation: INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, Tours, France.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Marchand-Adam
authors.affiliation: Faculty of Chemistry, University of Gdansk, Gdansk, Poland.
authors.forename: Adam
authors.initials: A
authors.lastname: Lesner
authors.affiliation: INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, Tours, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Baranek
authors.affiliation: CNRS UMR-7292, "GICC, Innovation Moléculaire et Thérapeutique", Université de Tours, 31 Avenue Monge, Tours, France.
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Viaud-Massuard
authors.affiliation: Unizyme Laboratories A/S, Hörsholm, Denmark.
authors.forename: Conni
authors.initials: C
authors.lastname: Lauritzen
authors.affiliation: Unizyme Laboratories A/S, Hörsholm, Denmark.
authors.forename: John
authors.initials: J
authors.lastname: Pedersen
authors.affiliation: INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, Tours, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Heuzé-Vourc'h
authors.affiliation: INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, Tours, France.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Si-Tahar
authors.affiliation: Department of Periodontology, Faculty of Dentistry, University of Istanbul, Istanbul, Turkey.
authors.forename: Erhan
authors.initials: E
authors.lastname: Fıratlı
authors.affiliation: 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.
authors.forename: Dieter E
authors.initials: DE
authors.lastname: Jenne
authors.affiliation: INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, Tours, France.
authors.forename: Francis
authors.initials: F
authors.lastname: Gauthier
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA, USA.
authors.forename: Marshall S
authors.initials: MS
authors.lastname: Horwitz
authors.affiliation: The Granulocyte Research Laboratory, National University Hospital, Rigshospitalet, University of Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Borregaard
authors.affiliation: 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: brice.korkmaz@inserm.fr.
authors.forename: Brice
authors.initials: B
authors.lastname: Korkmaz
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D016022:Case-Control Studies; D020789:Cathepsin C / Q000037:antagonists & inhibitors*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D019272:Leukocyte Elastase / Q000097:blood; D008252:Macaca fascicularis; D009504:Neutrophils / Q000201:enzymology*; D010214:Papillon-Lefevre Disease / Q000201:enzymology; D057057:Serine Proteases / Q000378:metabolism*
chemical_list: D015853:Cysteine Proteinase Inhibitors; D057057:Serine Proteases; D020789:Cathepsin C; D019272:Leukocyte Elastase
keywords: Cathepsin C; Cysteine protease; Inhibitor; Neutrophil; Papillon-Lefèvre syndrome; Serine protease