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

Acta Pharmacologica Sinica volume 44, pages 2445–2454 (2023)Cite this article

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.

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Fig. 1: Cerulein induces acute pancreatitis in mice and rats.
Fig. 2: Cerulein blocks autophagic degradation.
Fig. 3: Cerulein decreases pancreatic STX17 expression.
Fig. 4: The decrease in STX17 blocks autophagosome-lysosome fusion.
Fig. 5: The decrease in STX17 is accompanied by ER stress in cerulein-induced pancreatitis.
Fig. 6: Knockdown of STX17 exacerbates cerulein-induced pancreatitis.
Fig. 7: STX17 knockdown worsens cerulein-induced ER stress.
Fig. 8: A schematic summary of STX17 in cerulein-induced impaired autophagy and pancreatitis.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (82000612, 81720108033 and 81930114), National Key Research and Development Program of China (2017YFE0119900). Some figures were drawn by Figdraw.

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  1. These authors contributed equally: Tian-tian Wang, Li-chun Zhang

Authors and Affiliations

  1. International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Tian-tian Wang, Li-chun Zhang, Zhen Qin, Shu-jun Chen, Jing-min Zeng, Jing-yan Li, Lin An, Cai-yan Wang, Zhong-xiang Zhao, Zhong-qiu Liu & Shao-gui Wang

  2. Guangdong Provincial Key Laboratory of Translational Cancer Research of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Tian-tian Wang, Li-chun Zhang, Zhen Qin, Shu-jun Chen, Jing-min Zeng, Jing-yan Li, Lin An, Cai-yan Wang, Zhong-xiang Zhao, Zhong-qiu Liu & Shao-gui Wang

  3. Joint International Research Laboratory of Translational Cancer Research of Chinese Medicines, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Tian-tian Wang, Li-chun Zhang, Zhen Qin, Shu-jun Chen, Jing-min Zeng, Jing-yan Li, Lin An, Cai-yan Wang, Zhong-xiang Zhao, Zhong-qiu Liu & Shao-gui Wang

  4. Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Yong Gao

  5. School of Biomedical Science, Hunan University, Changsha, 410082, China

    Li-ming Wang

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Contributions

SGW, ZQL and ZXZ conceived and designed the study, TTW, LCZ, ZQ, SJC, JMZ, JYL, LA conducted the experiments and analyzed the data, CYW, YG. LMW provided reagents, SGW analyzed data and wrote the manuscript.

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Correspondence to Zhong-xiang Zhao, Zhong-qiu Liu or Shao-gui Wang.

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Wang, Tt., Zhang, Lc., Qin, Z. et al. Decreased syntaxin17 expression contributes to the pathogenesis of acute pancreatitis in murine models by impairing autophagic degradation. Acta Pharmacol Sin 44, 2445–2454 (2023). https://doi.org/10.1038/s41401-023-01139-x

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