From the Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China.
Department of Oncology, Changhai Hospital, Naval Medical University, Shanghai, China.
Pancreas. 2024 Sep 1;53(8):e641-e651. doi: 10.1097/MPA.0000000000002351. Epub 2024 Mar 27.
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.
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.
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.
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.
急性胰腺炎（AP）在全球范围内具有较高的住院率、发病率和死亡率。越来越多的关于 AP 发病机制的研究基于胆胰酶诱导的实验模型，该模型模拟了人类体内的 AP。已经证明，胰腺腺泡细胞和腹膜巨噬细胞都参与了胰腺炎症和损伤。然而，它们之间的联系尚未得到很好的理解。
在胰腺腺泡细胞系 AR42J 上建立了胆胰酶诱导的 AP 模型。从腹腔中分离大鼠巨噬细胞。检测了胆胰酶诱导的胰腺外泌体对体内和体外腹膜巨噬细胞和胰腺的影响。通过探索下游分子的调节作用，研究了潜在的分子机制。
我们发现，胆胰酶处理的 AR42J 细胞衍生的外泌体诱导大鼠腹膜巨噬细胞 M1 极化和细胞焦亡。miR-24-3p 在胆胰酶刺激的外泌体中上调，而 miR-24-3p 抑制剂则抵消了胰腺外泌体对腹膜巨噬细胞 M1 极化和细胞焦亡的作用。此外，miR-24-3p 抑制了 March3 的表达，而 MARCH3 介导了大鼠腹膜巨噬细胞中 NLRP3 的泛素化，进而导致了 AR42J 细胞的凋亡、活性氧的产生和炎症。
胆胰酶刺激的胰腺腺泡细胞衍生的外泌体通过 miR-24-3p/MARCH3/NLRP3 轴介导 AP 中腹膜巨噬细胞 M1 极化和细胞焦亡。
