Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Critical Care Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China.
Clin Sci (Lond). 2022 Apr 14;136(7):455-471. doi: 10.1042/CS20211031.
Acute pancreatitis (AP) is an acute inflammatory disorder characterized by acinar cell death and inflammation. Multiple factors cause hyperglycemia after AP. Macrophage polarization is involved in tissue injury and repair, and is regulated by Notch signaling during certain inflammatory diseases. The present study explores the relationship among hyperglycemia, macrophage polarization, and Notch signaling during AP and the related mechanisms. A cerulein-induced AP model was established in FVB/N mice, and AP with hyperglycemia was initiated by injection of 50% concentration glucose. Tissue damage, Notch activity, and macrophage polarization were assessed in pancreatic tissues. The role of Notch signaling in macrophage polarization during AP was also assessed in vitro by co-culturing primary macrophages and pancreatic acinar cells, and establishing a lipopolysaccharide (LPS)-induced inflammatory model in RAW264.7 cells. Pancreatic acinar cells were damaged and proinflammatory factor levels were increased in pancreatic tissues during AP. The hyperglycemic conditions aggravated pancreatic injury, increased macrophage infiltration, promoted macrophage polarization towards an M1 phenotype, and led to excessive up-regulation of Notch activity. Inhibition of Notch signaling by DAPT or Notch1 knockdown decreased the proportion of M1 macrophages and reduced the production of proinflammatory factors, thus mitigating pancreatic injury. These findings suggest that hyperglycemia induces excessive Notch signaling after AP and further aggravates AP by promoting pancreatic macrophage polarization towards the M1 phenotype. The Notch signaling pathway is a potential target for the prevention and treatment of AP.
急性胰腺炎（AP）是一种以腺泡细胞死亡和炎症为特征的急性炎症性疾病。多种因素可导致 AP 后发生高血糖。巨噬细胞极化参与组织损伤和修复，在某些炎症性疾病中受 Notch 信号通路调节。本研究探讨了 AP 时高血糖、巨噬细胞极化和 Notch 信号通路之间的关系及其相关机制。采用 FVB/N 小鼠建立了雨蛙肽诱导的 AP 模型，并通过注射 50%浓度葡萄糖启动伴有高血糖的 AP。评估胰腺组织中的组织损伤、Notch 活性和巨噬细胞极化。还通过原代巨噬细胞和胰腺腺泡细胞共培养，并在 RAW264.7 细胞中建立脂多糖（LPS）诱导的炎症模型，在体外评估了 Notch 信号通路在 AP 中对巨噬细胞极化的作用。AP 时胰腺腺泡细胞受损，胰腺组织中促炎因子水平升高。高血糖条件加重了胰腺损伤，增加了巨噬细胞浸润，促进了巨噬细胞向 M1 表型极化，并导致 Notch 活性过度上调。用 DAPT 或 Notch1 敲低抑制 Notch 信号通路可降低 M1 巨噬细胞的比例，并减少促炎因子的产生，从而减轻胰腺损伤。这些发现表明，AP 后高血糖诱导 Notch 信号通路过度激活，并通过促进胰腺巨噬细胞向 M1 表型极化进一步加重 AP。Notch 信号通路是预防和治疗 AP 的潜在靶点。
