Legumain is activated in macrophages during pancreatitis

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

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Pancre-atitis 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 caeruleintreated 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.

Original languageEnglish (US)
Pages (from-to)G548-G560
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume311
Issue number3
DOIs
StatePublished - 2016

Fingerprint

asparaginylendopeptidase
Pancreatitis
Macrophages
Pancreatic Neoplasms
Pancreas
Peptide Hydrolases
Ceruletide
Cysteine Proteases
Acinar Cells
Chronic Pancreatitis
Metaplasia

Keywords

  • Activity-based probe
  • Biomarker
  • Cysteine cathepsin
  • Inflammation
  • Legumain
  • Macrophage
  • Pancreas
  • Pancreatic cancer
  • Pancreatitis

ASJC Scopus subject areas

  • Physiology
  • Medicine(all)
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

Edgington-Mitchell, L. E., Wartmann, T., Fleming, A. K., Gocheva, V., Van Der Linden, W. A., Withana, N. P., ... Bunnett, N. W. (2016). Legumain is activated in macrophages during pancreatitis. American Journal of Physiology - Gastrointestinal and Liver Physiology, 311(3), G548-G560. https://doi.org/10.1152/ajpgi.00047.2016

Legumain is activated in macrophages during pancreatitis. / Edgington-Mitchell, Laura E.; Wartmann, Thomas; Fleming, Alicia K.; Gocheva, Vasilena; Van Der Linden, Wouter A.; Withana, Nimali P.; Verdoes, Martijn; Aurelio, Luigi; Edgington-Mitchell, Daniel; Lieu, Tinamarie; Parker, Belinda S.; Graham, Bim; Reinheckel, Thomas; Furness, John B.; Joyce, Johanna A.; Storz, Peter; Halangk, Walter; Bogyo, Matthew; Bunnett, Nigel W.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 311, No. 3, 2016, p. G548-G560.

Research output: Contribution to journalArticle

Edgington-Mitchell, LE, Wartmann, T, Fleming, AK, Gocheva, V, Van Der Linden, WA, Withana, NP, Verdoes, M, Aurelio, L, Edgington-Mitchell, D, Lieu, T, Parker, BS, Graham, B, Reinheckel, T, Furness, JB, Joyce, JA, Storz, P, Halangk, W, Bogyo, M & Bunnett, NW 2016, 'Legumain is activated in macrophages during pancreatitis', American Journal of Physiology - Gastrointestinal and Liver Physiology, vol. 311, no. 3, pp. G548-G560. https://doi.org/10.1152/ajpgi.00047.2016
Edgington-Mitchell LE, Wartmann T, Fleming AK, Gocheva V, Van Der Linden WA, Withana NP et al. Legumain is activated in macrophages during pancreatitis. American Journal of Physiology - Gastrointestinal and Liver Physiology. 2016;311(3):G548-G560. https://doi.org/10.1152/ajpgi.00047.2016
Edgington-Mitchell, Laura E. ; Wartmann, Thomas ; Fleming, Alicia K. ; Gocheva, Vasilena ; Van Der Linden, Wouter A. ; Withana, Nimali P. ; Verdoes, Martijn ; Aurelio, Luigi ; Edgington-Mitchell, Daniel ; Lieu, Tinamarie ; Parker, Belinda S. ; Graham, Bim ; Reinheckel, Thomas ; Furness, John B. ; Joyce, Johanna A. ; Storz, Peter ; Halangk, Walter ; Bogyo, Matthew ; Bunnett, Nigel W. / Legumain is activated in macrophages during pancreatitis. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2016 ; Vol. 311, No. 3. pp. G548-G560.
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AU - Fleming, Alicia K.

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AU - Van Der Linden, Wouter A.

AU - Withana, Nimali P.

AU - Verdoes, Martijn

AU - Aurelio, Luigi

AU - Edgington-Mitchell, Daniel

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AU - Parker, Belinda S.

AU - Graham, Bim

AU - Reinheckel, Thomas

AU - Furness, John B.

AU - Joyce, Johanna A.

AU - Storz, Peter

AU - Halangk, Walter

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AU - Bunnett, Nigel W.

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