Pharmacological inhibition of cathepsin S and of NSPs-AAP-1 (a novel, alternative protease driving the activation of neutrophil serine proteases)

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 theirCTSC 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<sup>+</sup> 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.

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Journal
Biochemical Pharmacology
Published
2024-09-16
DOI
https://doi.org/10.1016/j.bcp.2024.116114
Citations
1
Primary Topic
Protease and Inhibitor Mechanisms
Type
article
Field-Weighted Citation Impact
0.29

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article

Pharmacological inhibition of cathepsin S and of NSPs-AAP-1 (a novel, alternative protease driving the activation of neutrophil serine proteases)

Richard D. Williams, Jérôme Zoidakis, Brice Korkmaz, Moez Rhimi et al.
1 citations
Biochemical Pharmacology
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article

Pharmacological inhibition of cathepsin S and of NSPs-AAP-1 (a novel, alternative protease driving the activation of neutrophil serine proteases)

Richard D. Williams, Jérôme Zoidakis, Brice Korkmaz, Moez Rhimi, Patrick P. McDonald, Antonia Vlahou, Guo‐Ping Shi, Gilles Lalmanach, Roxane Domain, Seda Seren, Manousos Makridakis, Isabelle Couillin, Dedong Li, Marie‐Claude Viaud‐Massuard, Jessica Basso, Ali A. Aghdassi, Loïc Gonzalez, Ralph Kettritz, Christophe Paget, Uwe Jerke, Cécile Croix, Xian Zhang, Kuan‐Ju Chen, Tillia Bonvent
article en
1 citations

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 theirCTSC 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<sup>+</sup> 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.

Biochemical PharmacologyVol. 229
Université de Tours (FR), Queen's University Belfast (GB), Brigham and Women's Hospital (US), Centre National de la Recherche Scientifique (FR), Harvard University (US), Inserm (FR), Hefei University of Technology (CN), Max Delbrück Center (DE), Academy of Athens (GR), AgroParisTech (FR), Université Paris-Saclay (FR), Universitätsmedizin Greifswald (DE), Microbiologie de l’alimentation au service de la santé (FR), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), Clinical Investigation Center Plurithematic Tours (FR), Immunologie et Neurogénétique Expérimentales et Moléculaires (FR), Insmed (United States) (US), Charité - Universitätsmedizin Berlin (DE)
GlaxoSmithKline, Institut National de la Santé et de la Recherche Médicale, Studium Loire Valley-Institute for Advanced Studies
Openalex Percentile: Top 39%
Protease and Inhibitor Mechanisms
0.29
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