Decreased syntaxin17 expression contributes to the pathogenesis of acute pancreatitis in murine models by impairing autophagic degradation.

Abstract

Acute pancreatitis (AP) is an inflammatory disease of the exocrine pancreas. Disruptions in organelle homeostasis, including macroautophagy/autophagy dysfunction and endoplasmic reticulum (ER) stress, have been implicated in human and rodent pancreatitis. Syntaxin 17 (STX17) belongs to the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) subfamily. The Qa-SNARE STX17 is an autophagosomal SNARE protein that interacts with SNAP29 (Qbc-SNARE) and the lysosomal SNARE VAMP8 (R-SNARE) to drive autophagosome-lysosome fusion. In this study, we investigated the role of STX17 in the pathogenesis of AP in male mice or rats induced by repeated intraperitoneal injections of cerulein. We showed that cerulein hyperstimulation induced AP in mouse and rat models, which was characterized by increased serum amylase and lipase activities, pancreatic edema, necrotic cell death and the infiltration of inflammatory cells, as well as markedly decreased pancreatic STX17 expression. A similar reduction in STX17 levels was observed in primary and AR42J pancreatic acinar cells treated with CCK (100 nM) in vitro. By analyzing autophagic flux, we found that the decrease in STX17 blocked autophagosome-lysosome fusion and autophagic degradation, as well as the activation of ER stress. Pancreas-specific STX17 knockdown using adenovirus-shSTX17 further exacerbated pancreatic edema, inflammatory cell infiltration and necrotic cell death after cerulein injection. These data demonstrate a critical role of STX17 in maintaining pancreatic homeostasis and provide new evidence that autophagy serves as a protective mechanism against AP.

• Authors: Tian-Tian Wang, Li-Chun Zhang, Zhen Qin, Shu-Jun Chen, Jing-Min Zeng, Jing-Yan Li, Lin An, Cai-Yan Wang, Yong Gao, Li-Ming Wang, Zhong-Xiang Zhao, Zhong-Qiu Liu, Shao-Gui Wang
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 44 Issue 12 Pg. 2445-2454 (Dec 2023) ISSN: 1745-7254 [Electronic] United States
• PMID: 37580492 (Publication Type: Journal Article)
• Copyright: © 2023. The Author(s), under exclusive licence to Shanghai Institute of Materia Medica, Chinese Academy of Sciences and Chinese Pharmacological Society.

Chemical References

• Ceruletide
• SNARE Proteins

Topics

• Male
• Mice
• Animals
• Rats
• Humans
• Acute Disease
• Ceruletide (toxicity)
• Disease Models, Animal
• Pancreatitis (chemically induced)
• Autophagy (physiology)
• SNARE Proteins (metabolism)
• Edema