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

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Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brice Korkmaz has been paid for the time spent as a committee member for advisory boards (Brensocatib Advisory Board (BRAB), INSMED, USA), other forms of consulting (Boehringer Ingelheim (Germany), Neuprozyme Therapeutics Aps (Denmark), Santhera Pharmaceuticals (Switzerland), Chiesi (Italy), Gerson Lehrman Group (GLG) (USA), Slingshot Insights expert network (USA)), symposium organisation (INSMED, Boehringer Ingelheim, Chiesi) and travel support, lectures or presentations, outside the submitted work. Other authors declare no competing financial interests.