Neutrophilic Cathepsin C Is Maturated by a Multistep Proteolytic Process and Secreted by Activated Cells during Inflammatory Lung Diseases

Abstract

The cysteine protease cathepsin C (CatC) activates granuleassociated proinflammatory serine proteases in hematopoietic precursor cells. Its early inhibition in the bone marrow is regarded as a new therapeutic strategy for treating proteolysisdriven chronic inflammatory diseases, but its complete inhibition is elusive in vivo. Controlling the activity of CatC may be achieved by directly inhibiting its activity with a specific inhibitor or/and by preventing its maturation. We have investigated immunochemically and kinetically the occurrence of CatC and its proform in human hematopoietic precursor cells and in differentiated mature immune cells in lung secretions. The maturation of proCatC obeys a multistep mechanism that can be entirely managed by CatS in neutrophilic precursor cells. CatS inhibition by a cell-permeable inhibitor abrogated the release of the heavy and light chains from proCatC and blocked ϳ80% of CatC activity. Under these conditions the activity of neutrophil serine proteases, however, was not abolished in precursor cell cultures. In patients with neutrophilic lung inflammation, mature CatC is found in large amounts in sputa. It is secreted by activated neutrophils as confirmed through lipopolysaccharide administration in a nonhuman primate model. CatS inhibitors currently in clinical trials are expected to decrease the activity of neutrophilic CatC without affecting those of elastase-like serine proteases.

Dipeptidyl Peptidase 1 Inhibitor AZD7986 Induces a Sustained, Exposure‐Dependent Reduction in Neutrophil Elastase Activity in Healthy Subjects

“…We did not directly measure the level of DPP1 inhibition in the present study, but our NE and safety data strongly suggest that AZD7986 inhibits DPP1 to a significant extent. Both NSP inhibition and the development of skin symptoms appear to require high inhibition of DPP1 . Unaffected PLS family members (heterozygotes), with no apparent skin symptoms, have been described to have DPP1 activity ranging from 13–47% compared to controls, suggesting >80–90% inhibition is required before symptoms develop.…”

“…Subject demographics can be found in Table S1. In Part I, five different doses (5,15,35,50, or 65 mg) of AZD7986 were administered in cohorts of nine subjects (of which three subjects received placebo). In Part II, three different doses (10, 25, or 40 mg) were administered once daily in cohorts of 9, 11, and 16 subjects, respectively (of which three, three, and six subjects received placebo).…”

Proteome-wide Map of Targets of T790M-EGFR-Directed Covalent Inhibitors

“…The cathepsin off-targets of osimertinib (inhibitor 1 ), in particular CTSC, play critical roles in protein processing, specifically in the activation of immune-related serine proteases (Furber et al, 2014, Hamon et al, 2016). These off-targets were identified not only in human cancer cell lines, but also in liver tissue from mice treated with doses of osimertinib that match those used in the literature to block T790M-EGFR-driven tumor growth in xenograft models (Cross et al, 2014).…”

Abrogation of cathepsin C by Helicobacter pylori impairs neutrophil activation to promote gastric infection

“…Our findings showed that the supernatants of gastric epithelial cells contained mature subunits of active CtsC, and the past reports about mature CtsC secreted by nonhematopoietic cells were rare. Some previous studies reported only 60 kDa zymogen of CtsC was found in the supernatants of various nonhematopoietic cells, including lung epithelial cells (37), thyroid cells (38), and microglia (39), and none of these studies had clarified the function of extracellular CtsC.…”