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
AbstractCathepsin 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.
|Other language title versions|
|Journal series||Biochemical Pharmacology, ISSN 0006-2952, (A 40 pkt)|
|Publication size in sheets||0.75|
|Keywords in English||cathepsin C, neutrophil, serine protease, cysteine protease, inhibitor, Papillon-Lefèvre syndrome|
|Score|| = 40.0, ArticleFromJournal|
= 40.0, ArticleFromJournal
|Publication indicators||= 10; : 2017 = 4.235 (2) - 2017=4.752 (5)|
|Citation count*||20 (2019-08-13)|
* presented citation count is obtained through Internet information analysis and it is close to the number calculated by the Publish or Perish system.