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

Author

Listed:
  • Yuka Nishibata

    (Hokkaido University)

  • Suishin Arai

    (Hokkaido University)

  • Mai Taniguchi

    (Hokkaido University)

  • Issei Nakade

    (Hokkaido University)

  • Hodaka Ogawa

    (Hokkaido University)

  • Shota Kitano

    (Hokkaido University)

  • Yumeka Hosoi

    (Hokkaido University)

  • Ayano Shindo

    (Hokkaido University)

  • Ryo Nishiyama

    (Hokkaido University)

  • Sakiko Masuda

    (Hokkaido University)

  • Daigo Nakazawa

    (Hokkaido University)

  • Utano Tomaru

    (Hokkaido University Hospital)

  • Takafumi Shimizu

    (Inc.)

  • William Sinko

    (Inc.)

  • Tadashi Nagakura

    (Inc.)

  • Yoh Terada

    (Inc.)

  • Akihiro Ishizu

    (Hokkaido University)

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.

Suggested Citation

  • Yuka Nishibata & Suishin Arai & Mai Taniguchi & Issei Nakade & Hodaka Ogawa & Shota Kitano & Yumeka Hosoi & Ayano Shindo & Ryo Nishiyama & Sakiko Masuda & Daigo Nakazawa & Utano Tomaru & Takafumi Shim, 2024. "Cathepsin C inhibition reduces neutrophil serine protease activity and improves activated neutrophil-mediated disorders," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50747-6
    DOI: 10.1038/s41467-024-50747-6
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    References listed on IDEAS

    as
    1. Elsa Neubert & Daniel Meyer & Francesco Rocca & Gökhan Günay & Anja Kwaczala-Tessmann & Julia Grandke & Susanne Senger-Sander & Claudia Geisler & Alexander Egner & Michael P. Schön & Luise Erpenbeck &, 2018. "Chromatin swelling drives neutrophil extracellular trap release," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
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