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

Carla Guarino , Yveline Hamon , Cécile Croix , Anne-Sophie Lamort , Sandrine Dallet-Choisy , Sylvain Marchand-Adam , Adam Lesner , Thomas Baranek , Marie-Claude Viaud-Massuard , Conni Lauritzen , John Pedersen , Nathalie Heuzé-Vourc’h , Mustapha Si-Tahar , Erhan Fıratlı , Dieter E. Jenne , Francis Gauthier , Marshall S. Horwitz , Niels Borregaard , Brice Korkmaz

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.
Author Carla Guarino
Carla Guarino,,
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, Yveline Hamon
Yveline Hamon,,
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, Cécile Croix
Cécile Croix,,
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, Anne-Sophie Lamort
Anne-Sophie Lamort,,
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, Sandrine Dallet-Choisy
Sandrine Dallet-Choisy,,
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, Sylvain Marchand-Adam
Sylvain Marchand-Adam,,
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, Adam Lesner PAB
Adam Lesner,,
- Laboratory of Biochemical Analytics
, Thomas Baranek
Thomas Baranek,,
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, Marie-Claude Viaud-Massuard
Marie-Claude Viaud-Massuard,,
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, Conni Lauritzen
Conni Lauritzen,,
-
et al.
Other language title versions
Journal seriesBiochemical Pharmacology, ISSN 0006-2952
Issue year2017
Vol131
Pages52-67
Publication size in sheets0.75
Keywords in Englishcathepsin C, neutrophil, serine protease, cysteine protease, inhibitor, Papillon-Lefèvre syndrome
DOIDOI:10.1016/j.bcp.2017.02.009
URL https://doi.org/10.1016/j.bcp.2017.02.009
Languageen angielski
Score (nominal)40
ScoreMinisterial score = 40.0, 20-12-2017, ArticleFromJournal
Ministerial score (2013-2016) = 40.0, 20-12-2017, ArticleFromJournal
Publication indicators WoS Impact Factor: 2016 = 4.581 (2) - 2016=4.624 (5)
Citation count*8 (2018-04-23)
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* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.
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