Journal
BIOCHEMICAL PHARMACOLOGY
Volume 131, Issue -, Pages 52-67Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2017.02.009
Keywords
Cathepsin C; Neutrophil; Serine protease; Cysteine protease; Inhibitor; Papillon-Lefevre syndrome
Categories
Funding
- INSERM
- University Francois Rabelais de Tours
- Association Vaincre la Mucoviscidose (VLM) [RF20130500913]
- Region Centre-Val de Loire (Project BPCO-Lyse)
- National Institute of Health (NIH) [R01 HL130472]
- Vilhelm Petersen's Fund [7221]
- Danish Council for Independ Research [4183-00024]
- European Union's Horizon research and innovation programme [668036]
- Alexandre von Humboldt Foundation
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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-Lefevre 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. (C) 2017 Elsevier Inc. All rights reserved.
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