2. Academic Validation
  3. Cathepsin C inhibition reduces neutrophil serine protease activity and improves activated neutrophil-mediated disorders

Cathepsin C inhibition reduces neutrophil serine protease activity and improves activated neutrophil-mediated disorders

  • Nat Commun. 2024 Aug 22;15(1):6519. doi: 10.1038/s41467-024-50747-6.
Yuka Nishibata 1,  Suishin Arai 1,  Mai Taniguchi 1,  Issei Nakade 1,  Hodaka Ogawa 1,  Shota Kitano 1,  Yumeka Hosoi 1,  Ayano Shindo 1,  Ryo Nishiyama 1,  Sakiko Masuda 1,  Daigo Nakazawa 2,  Utano Tomaru 3,  Takafumi Shimizu 4,  William Sinko 4,  Tadashi Nagakura 4,  Yoh Terada 4,  Akihiro Ishizu 5
Affiliations

Affiliations

  • 1 Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan.
  • 2 Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
  • 3 Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.
  • 4 Alivexis, Inc., Tokyo, Japan.
  • 5 Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University, Sapporo, Japan. [email protected].
PMID: 39174512 DOI: 10.1038/s41467-024-50747-6
Abstract

Cathepsin C (CatC) is an enzyme which regulates the maturation of neutrophil serine proteases (NSPs) essential for neutrophil activation. Activated neutrophils are key players in the innate immune system, and are also implicated in the etiology of various inflammatory diseases. This study aims to demonstrate a therapeutic potential for CatC inhibitors against disorders in which activated neutrophil-derived neutrophil extracellular traps (NETs) play a significant role. We demonstrate that a CatC inhibitor, MOD06051, dose-dependently suppresses the cellular activity of NSPs, including neutrophil Elastase (NE), in vitro. Neutrophils derived from MOD06051-administered rats exhibit significantly lower NE activity and NET-forming ability than controls. Furthermore, MOD06051 dose-dependently ameliorates vasculitis and significantly decreases NETs when administered to a rat model of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody-associated vasculitis (AAV). These findings suggest that CatC inhibition is a promising strategy to reduce neutrophil activation and improve activated neutrophil-mediated diseases such as MPO-AAV.

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