Deficiency of cathepsin C ameliorates severity of acute pancreatitis by reduction of neutrophil elastase activation and cleavage of E-cadherin.

Abstract

Acute pancreatitis is characterized by premature intracellular protease activation and infiltration of inflammatory cells, mainly neutrophil granulocytes and macrophages, into the organ. The lysosomal proteases cathepsin B, D, and L have been identified as regulators of early zymogen activation and thus modulators of the severity of pancreatitis. Cathepsin C (CTSC, syn. dipeptidly-peptidase I) is a widely expressed, exo-cystein-protease involved in the proteolytic processing of various other lysosomal enzymes. We have studied its role in pancreatitis. We used CTSC-deleted mice and their WT littermates in two experimental models of pancreatitis. The mild model involved eight hourly caerulein injections and the severe model partial duct ligation. Isolated pancreatic acini and spleen-derived leukocytes were used for ex vivo experiments. CTSC is expressed in the pancreas and in inflammatory cells. CTSC deletion reduced the severity of pancreatitis (more prominently in the milder model) without directly affecting intra-acinar cell trypsin activation in vitro The absence of CTSC reduced infiltration of neutrophil granulocytes impaired their capacity for cleaving E-cadherin in adherens junctions between acinar cells and reduced the activity of neutrophil serine proteases polymorphonuclear (neutrophil) elastase, cathepsin G, and proteinase 3, but not neutrophil motility. Macrophage invasion was not dependent on the presence of CTSC. CTSC is a regulator and activator of various lysosomal enzymes such as cathepsin B, D, and L. Its loss mitigates the severity of pancreatitis not by reducing intra-acinar cell zymogen activation but by reducing infiltration of neutrophil granulocytes into the pancreas. In this context one of its key roles is that of an activator of neutrophil elastase.

• Authors: Daniel S John, Julia Aschenbach, Burkhard Krüger, Matthias Sendler, F Ulrich Weiss, Julia Mayerle, Markus M Lerch, Ali A Aghdassi
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 294 Issue 2 Pg. 697-707 (01 11 2019) ISSN: 1083-351X [Electronic] United States
• PMID: 30455353 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 John et al.

Chemical References

• Cadherins
• Cathepsin C
• Leukocyte Elastase

Topics

• Acinar Cells (metabolism, pathology)
• Acute Disease
• Animals
• Cadherins (metabolism)
• Cathepsin C (genetics, metabolism)
• Cells, Cultured
• Enzyme Activation
• Gene Deletion
• Leukocyte Elastase (metabolism)
• Mice
• Pancreatitis (genetics, metabolism, pathology)