Neutrophilic Cathepsin C Is Maturated by a Multistep Proteolytic Process and Secreted by Activated Cells during Inflammatory Lung Diseases

Yveline Hamon, Monika Legowska, Virginie Hervé, Sandrine Dallet-Choisy, Sylvain Marchand-Adam, Lise Vanderlynden, Michèle Demonte, Rich Williams, Christopher J Scott, Mustapha Si-Tahar, Nathalie Heuzé-Vourc'h, Gilles Lalmanach, Dieter E Jenne, Adam Lesner, Francis Gauthier, Brice Korkmaz

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

The cysteine protease cathepsin C (CatC) activates granule-associated proinflammatory serine proteases in hematopoietic precursor cells. Its early inhibition in the bone marrow is regarded as a new therapeutic strategy for treating proteolysis-driven chronic inflammatory diseases, but its complete inhibition is elusive in vivo Controlling the activity of CatC may be achieved by directly inhibiting its activity with a specific inhibitor or/and by preventing its maturation. We have investigated immunochemically and kinetically the occurrence of CatC and its proform in human hematopoietic precursor cells and in differentiated mature immune cells in lung secretions. The maturation of proCatC obeys a multistep mechanism that can be entirely managed by CatS in neutrophilic precursor cells. CatS inhibition by a cell-permeable inhibitor abrogated the release of the heavy and light chains from proCatC and blocked ∼80% of CatC activity. Under these conditions the activity of neutrophil serine proteases, however, was not abolished in precursor cell cultures. In patients with neutrophilic lung inflammation, mature CatC is found in large amounts in sputa. It is secreted by activated neutrophils as confirmed through lipopolysaccharide administration in a nonhuman primate model. CatS inhibitors currently in clinical trials are expected to decrease the activity of neutrophilic CatC without affecting those of elastase-like serine proteases.

Original languageEnglish
Pages (from-to)8486-99
Number of pages14
JournalThe Journal of biological chemistry
Volume291
Issue number16
Early online date16 Feb 2016
DOIs
Publication statusPublished - 15 Apr 2016

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