Exosomes Derived From Cerulein-Stimulated Pancreatic Acinar Cells Mediate Peritoneal Macrophage M1 Polarization and Pyroptosis via an miR-24-3p/MARCH3/NLRP3 Axis in Acute Pancreatitis.
Xiao-Ju Su, Yan Chen, Qi-Chen Zhang, Xiao-Bo Peng, Ya-Ping Liu, Lei Wang, Yi-Qi Du
{"title":"Exosomes Derived From Cerulein-Stimulated Pancreatic Acinar Cells Mediate Peritoneal Macrophage M1 Polarization and Pyroptosis via an miR-24-3p/MARCH3/NLRP3 Axis in Acute Pancreatitis.","authors":"Xiao-Ju Su, Yan Chen, Qi-Chen Zhang, Xiao-Bo Peng, Ya-Ping Liu, Lei Wang, Yi-Qi Du","doi":"10.1097/MPA.0000000000002351","DOIUrl":null,"url":null,"abstract":"<p><strong>Objectives: </strong>Acute pancreatitis (AP) has a high incidence of hospitalizations, morbidity, and mortality worldwide. A growing number of studies on AP pathogenesis are based on cerulein-induced experimental model, which simulates human AP in vivo. It has been demonstrated that both pancreatic acinar cells and peritoneal macrophages are involved in pancreatic inflammation and damage. However, their connection has not been well understood.</p><p><strong>Methods: </strong>A cerulein-induced AP model was established on the pancreatic acinar cell line AR42J. Rat macrophages were isolated from the peritoneal cavity. The effects of cerulein-induced pancreatic exosomes on the peritoneal macrophage and pancreas in vivo and in vitro were examined. The underlying molecular mechanism was investigated by exploring the regulatory role of downstream molecules.</p><p><strong>Results: </strong>We found that exosomes derived from cerulein-treated AR42J cells induced rat peritoneal macrophage M1 polarization and pyroptosis. miR-24-3p was upregulated in cerulein-stimulated exosomes, whereas the miR-24-3p inhibitor counteracted the effect of pancreatic exosomes on peritoneal macrophage M1 polarization and pyroptosis. Furthermore, miR-24-3p inhibited March3 expression, whereas MARCH3 mediated NLRP3 ubiquitination in rat peritoneal macrophages, which, in turn, contributed to the apoptosis, reactive oxygen species production, and inflammation in AR42J cells.</p><p><strong>Conclusions: </strong>Exosomes derived from cerulein-stimulated pancreatic acinar cells mediate peritoneal macrophage M1 polarization and pyroptosis via an miR-24-3p/MARCH3/NLRP3 axis in AP.</p>","PeriodicalId":19733,"journal":{"name":"Pancreas","volume":" ","pages":"e641-e651"},"PeriodicalIF":1.7000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pancreas","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/MPA.0000000000002351","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/3/27 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Objectives: Acute pancreatitis (AP) has a high incidence of hospitalizations, morbidity, and mortality worldwide. A growing number of studies on AP pathogenesis are based on cerulein-induced experimental model, which simulates human AP in vivo. It has been demonstrated that both pancreatic acinar cells and peritoneal macrophages are involved in pancreatic inflammation and damage. However, their connection has not been well understood.
Methods: A cerulein-induced AP model was established on the pancreatic acinar cell line AR42J. Rat macrophages were isolated from the peritoneal cavity. The effects of cerulein-induced pancreatic exosomes on the peritoneal macrophage and pancreas in vivo and in vitro were examined. The underlying molecular mechanism was investigated by exploring the regulatory role of downstream molecules.
Results: We found that exosomes derived from cerulein-treated AR42J cells induced rat peritoneal macrophage M1 polarization and pyroptosis. miR-24-3p was upregulated in cerulein-stimulated exosomes, whereas the miR-24-3p inhibitor counteracted the effect of pancreatic exosomes on peritoneal macrophage M1 polarization and pyroptosis. Furthermore, miR-24-3p inhibited March3 expression, whereas MARCH3 mediated NLRP3 ubiquitination in rat peritoneal macrophages, which, in turn, contributed to the apoptosis, reactive oxygen species production, and inflammation in AR42J cells.
Conclusions: Exosomes derived from cerulein-stimulated pancreatic acinar cells mediate peritoneal macrophage M1 polarization and pyroptosis via an miR-24-3p/MARCH3/NLRP3 axis in AP.
目的:急性胰腺炎(AP)在全世界的住院率、发病率和死亡率都很高。越来越多关于急性胰腺炎发病机制的研究都是基于胰岛素诱导的实验模型,该模型模拟了人体急性胰腺炎。研究表明,胰腺尖叶细胞和腹腔巨噬细胞都参与了胰腺炎症和损伤。然而,人们对它们之间的联系还不甚了解:方法:在胰腺尖细胞株 AR42J 上建立了由开塞露素诱导的 AP 模型。从腹腔中分离出大鼠巨噬细胞。研究了caerulein诱导的胰腺外泌体在体内和体外对腹腔巨噬细胞和胰腺的影响。通过探索下游分子的调控作用,研究了其潜在的分子机制:结果:我们发现,来自经caerulein处理的AR42J细胞的外泌体可诱导大鼠腹腔巨噬细胞M1极化和嗜热。此外,miR-24-3p抑制了March3的表达,而MARCH3介导了大鼠腹腔巨噬细胞中NLRP3的泛素化,这反过来又促进了AR42J细胞的凋亡、活性氧的产生和炎症:结论:在AP中,来自caerulein刺激的胰腺尖腺细胞的外泌体通过miR-24-3p/MARCH3/NLRP3轴介导腹腔巨噬细胞M1极化和热凋亡。
期刊介绍:
Pancreas provides a central forum for communication of original works involving both basic and clinical research on the exocrine and endocrine pancreas and their interrelationships and consequences in disease states. This multidisciplinary, international journal covers the whole spectrum of basic sciences, etiology, prevention, pathophysiology, diagnosis, and surgical and medical management of pancreatic diseases, including cancer.