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

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.

• Guarino, C.
• Hamon, Y.
• Croix, C.
• Lamort, A. S.
• Dallet-Choisy, S.
• Marchand-Adam, S.
• Lesner, A.
• Baranek, T.
• Viaud-Massuard, M. C.
• Lauritzen, C.
• Pedersen, J.
• Heuze-Vourc'h, N.
• Si-Tahar, M.
• Firatli, E.
• Jenne, D. E.
• Gauthier, F.
• Horwitz, M. S.
• Borregaard, N.
• Korkmaz, B.