作者: Moss, Celia ; Lamort, Anne-Sophie ; McKaig, Sarah J ; Schreiber, Adrian ; Łȩgowska, Monika ; Roberts, Helen ; Marchand-Adam, Sylvain ; Gauthier, Francis ; Caughey, George H ; Lauritzen, Conni ; Chapple, Iain ; Hirschfeld, Josefine ; Lesner, Adam ; Jenne, Dieter E ; Korkmaz, Brice ; Kettritz, Ralph ; Lalmanach, Gilles ; Thakker, Nalin S ; Pedersen, John ; Seren, Seda

Cathepsin C (CatC) is a highly conserved tetrameric lysosomal cysteine dipeptidyl aminopeptidase. The best characterized physiological function of CatC is the activation of pro-inflammatory granule-associated serine proteases. These proteases are synthesized as inactive zymogens containing an N-terminal pro-dipeptide, which maintains the zymogen in its inactive conformation and prevents premature activation, which is potentially toxic to the cell. The activation of serine protease zymogens occurs through cleavage of the N-terminal dipeptide by CatC during cell maturation in the bone marrow. In vivo data suggest that pharmacological inhibition of pro-inflammatory serine proteases would suppress or attenuate deleterious effects mediated by these proteases in inflammatory/auto-immune disorders. The pathological deficiency in CatC is associated with Papillon-Lefèvre syndrome (PLS). The patients however do not present marked immunodeficiency despite the absence of active serine proteases in immune defense cells. Hence, the transitory pharmacological blockade of CatC activity in the precursor cells of the bone marrow may represent an attractive therapeutic strategy to regulate activity of serine proteases in inflammatory and immunologic conditions. A variety of CatC inhibitors have been developed both by pharmaceutical companies and academic investigators, some of which are currently being employed and evaluated in preclinical/clinical trials.

2018-08-01·Journal of Biological Chemistry2区 · 生物学

Consequences of cathepsin C inactivation for membrane exposure of proteinase 3, the target antigen in autoimmune vasculitis

2区 · 生物学

Article

作者: Goizet, Cyril ; Gauthier, Francis ; Rashed Abouzaid, Maha ; Dallet-Choisy, Sandrine ; Lorette, Gérard ; N'Guessan, Koffi ; Ibrahim Mostafa, Mostafa ; Lauritzen, Conni ; Croix, Cécile ; Al Farraj Aldosari, Abdullah ; Jenne, Dieter E ; Viaud-Massuard, Marie-Claude ; Ragunatha, Shivanna ; Stephan, Jean-Louis ; Pedersen, John ; Nagy, Nikoletta ; Battino, Maurizio ; Seren, Seda ; Eulenberg-Gustavus, Claudia ; Kettritz, Ralph ; Cornillier, Hélène ; Marchand-Adam, Sylvain ; Szell, Marta ; Lesner, Adam ; Chapple, Iain L ; Giampieri, Francesca ; Korkmaz, Brice ; Schacher, Beate ; Nasr Soliman, Hala ; Hirschfeld, Josefine ; Eickholz, Peter ; Jerke, Uwe

Membrane-bound proteinase 3 (PR3^m) is the main target antigen of anti-neutrophil cytoplasmic autoantibodies (ANCA) in granulomatosis with polyangiitis, a systemic small-vessel vasculitis. Binding of ANCA to PR3^m triggers neutrophil activation with the secretion of enzymatically active PR3 and related neutrophil serine proteases, thereby contributing to vascular damage. PR3 and related proteases are activated from pro-forms by the lysosomal cysteine protease cathepsin C (CatC) during neutrophil maturation. We hypothesized that pharmacological inhibition of CatC provides an effective measure to reduce PR3^m and therefore has implications as a novel therapeutic approach in granulomatosis with polyangiitis. We first studied neutrophilic PR3 from 24 patients with Papillon-Lefèvre syndrome (PLS), a genetic form of CatC deficiency. PLS neutrophil lysates showed a largely reduced but still detectable (0.5-4%) PR3 activity when compared with healthy control cells. Despite extremely low levels of cellular PR3, the amount of constitutive PR3^m expressed on the surface of quiescent neutrophils and the typical bimodal membrane distribution pattern were similar to what was observed in healthy neutrophils. However, following cell activation, there was no significant increase in the total amount of PR3^m on PLS neutrophils, whereas the total amount of PR3^m on healthy neutrophils was significantly increased. We then explored the effect of pharmacological CatC inhibition on PR3 stability in normal neutrophils using a potent cell-permeable CatC inhibitor and a CD34⁺ hematopoietic stem cell model. Human CD34⁺ hematopoietic stem cells were treated with the inhibitor during neutrophil differentiation over 10 days. We observed strong reductions in PR3^m, cellular PR3 protein, and proteolytic PR3 activity, whereas neutrophil differentiation was not compromised.

2017-05-01·Biochemical Pharmacology2区 · 医学

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

2区 · 医学

Article

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

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.

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