Legumain is activated in macrophages during pancreatitis.

Abstract

Pancreatitis is an inflammatory disease of the pancreas characterized by dysregulated activity of digestive enzymes, necrosis, immune infiltration, and pain. Repeated incidence of pancreatitis is an important risk factor for pancreatic cancer. Legumain, a lysosomal cysteine protease, has been linked to inflammatory diseases such as atherosclerosis, stroke, and cancer. Until now, legumain activation has not been studied during pancreatitis. We used a fluorescently quenched activity-based probe to assess legumain activation during caerulein-induced pancreatitis in mice. We detected activated legumain by ex vivo imaging, confocal microscopy, and gel electrophoresis. Compared with healthy controls, legumain activity in the pancreas of caerulein-treated mice was increased in a time-dependent manner. Legumain was localized to CD68(+) macrophages and was not active in pancreatic acinar cells. Using a small-molecule inhibitor of legumain, we found that this protease is not essential for the initiation of pancreatitis. However, it may serve as a biomarker of disease, since patients with chronic pancreatitis show strongly increased legumain expression in macrophages. Moreover, the occurrence of legumain-expressing macrophages in regions of acinar-to-ductal metaplasia suggests that this protease may influence reprogramming events that lead to inflammation-induced pancreatic cancer.

• Authors: Laura E Edgington-Mitchell, Thomas Wartmann, Alicia K Fleming, Vasilena Gocheva, Wouter A van der Linden, Nimali P Withana, Martijn Verdoes, Luigi Aurelio, Daniel Edgington-Mitchell, TinaMarie Lieu, Belinda S Parker, Bim Graham, Thomas Reinheckel, John B Furness, Johanna A Joyce, Peter Storz, Walter Halangk, Matthew Bogyo, Nigel W Bunnett
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 311 Issue 3 Pg. G548-60 (09 01 2016) ISSN: 1522-1547 [Electronic] United States
• PMID: 27514475 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2016 the American Physiological Society.

Chemical References

• Enzyme Inhibitors
• Ceruletide
• Cysteine Endopeptidases
• asparaginylendopeptidase

Topics

• Animals
• Ceruletide (toxicity)
• Cysteine Endopeptidases (genetics, metabolism)
• Enzyme Inhibitors (pharmacology)
• Female
• Gene Expression Regulation, Enzymologic
• Macrophages (enzymology, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Pancreatitis (chemically induced, enzymology)