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| Item Type: | Article |
|---|---|
| Title: | Pharmacological inhibition of cathepsin S and of NSPs-AAP-1 (a novel, alternative protease driving the activation of neutrophil serine proteases) |
| Creators Name: | Domain, R., Seren, S., Jerke, U., Makridakis, M., Chen, K.J., Zoidakis, J., Rhimi, M., Zhang, X., Bonvent, T., Croix, C., Gonzalez, L., Li, D., Basso, J., Paget, C., Viaud-Massuard, M.C., Lalmanach, G., Shi, G.P., Aghdassi, A., Vlahou, A., McDonald, P.P., Couillin, I., Williams, R., Kettritz, R. and Korkmaz, B. |
| Abstract: | An uncontrolled activity of neutrophil serine proteases (NSPs) contributes to inflammatory diseases. Cathepsin C (CatC) is known to activate NSPs during neutrophilic differentiation and represents a promising pharmacological target in NSP-mediated diseases. In humans, Papillon-Lefèvre syndrome (PLS) patients have mutations in their CTSC gene, resulting in the complete absence of CatC activity. Despite this, low residual NSP activities are detected in PLS neutrophils (<10% vs healthy individuals), suggesting the involvement of CatC-independent proteolytic pathway(s) in the activation of proNSPs. This prompted us to characterize CatC-independent NSP activation pathways by blocking proCatC maturation. In this study, we show that inhibition of intracellular CatS almost completely blocked CatC maturation in human promyeloid HL-60 cells. Despite this, NSP activation was not significantly reduced, confirming the presence of a CatC-independent activation pathway involving a CatC-like protease that we termed NSPs-AAP-1. Similarly, when human CD34+ progenitor cells were treated with CatS inhibitors during neutrophilic differentiation in vitro, CatC activity was nearly abrogated but ∼30% NSP activities remained, further supporting the existence of NSPs-AAP-1. Our data indicate that NSPs-AAP-1 is a cysteine protease that is inhibited by reversible nitrile compounds designed for CatC inhibition. We further established a proof of concept for the indirect, although incomplete, inhibition of NSPs by pharmacological targeting of CatC maturation using CatS inhibitors. This emphasizes the potential of CatS as a therapeutic target for inflammatory diseases. Thus, preventing proNSP maturation using a CatS inhibitor, alone or in combination with a CatC/NSPs-AAP-1 inhibitor, represents a promising approach to efficiently control the extent of tissue injury in neutrophil-mediated inflammatory diseases. |
| Keywords: | Cathepsin C, Cysteine Cathepsin, Neutrophil Serine Protease, Zymogen, Synthetic Inhibitor, Therapeutic Approach, Animals, Mice |
| Source: | Biochemical Pharmacology |
| ISSN: | 0006-2952 |
| Publisher: | Elsevier |
| Volume: | 229 |
| Page Range: | 116114 |
| Number of Pages: | 1 |
| Date: | November 2024 |
| Official Publication: | https://doi.org/10.1016/j.bcp.2024.116114 |
| PubMed: | View item in PubMed |
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