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

Biochem Pharmacol. 2017 May 1:131:52-67. doi: 10.1016/j.bcp.2017.02.009.

Carla Guarino ¹, Yveline Hamon ², Cécile Croix ³, Anne-Sophie Lamort ², Sandrine Dallet-Choisy ¹, Sylvain Marchand-Adam ¹, Adam Lesner ⁴, Thomas Baranek ¹, Marie-Claude Viaud-Massuard ³, Conni Lauritzen ⁵, John Pedersen ⁵, Nathalie Heuzé-Vourc'h ¹, Mustapha Si-Tahar ¹, Erhan Fıratlı ⁶, Dieter E Jenne ⁷, Francis Gauthier ¹, Marshall S Horwitz ⁸, Niels Borregaard ⁹, Brice Korkmaz ¹⁰

Affiliations

1 INSERM U-1100, "Centre d'Etude des Pathologies Respiratoires" and Université François Rabelais, Tours, 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.
3 CNRS UMR-7292, "GICC, Innovation Moléculaire et Thérapeutique", Université de Tours, 31 Avenue Monge, Tours, France.
4 Faculty of Chemistry, University of Gdansk, Gdansk, Poland.
5 Unizyme Laboratories A/S, Hörsholm, Denmark.
6 Department of Periodontology, Faculty of Dentistry, University of Istanbul, Istanbul, 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.
8 Department of Pathology, University of Washington, Seattle, WA, USA.
9 The Granulocyte Research Laboratory, National University Hospital, Rigshospitalet, University of Copenhagen, 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].

PMID: 28193451 DOI: 10.1016/j.bcp.2017.02.009

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.

Keywords

Cathepsin C; Cysteine protease; Inhibitor; Neutrophil; Papillon-Lefèvre syndrome; Serine protease.

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