Inhibition of Notch activity suppresses hyperglycemia-augmented polarization of macrophages to the M1 phenotype and alleviates acute pancreatitis.
Inhibition of Notch activity suppresses hyperglycemia-augmented polarization of macrophages to the M1 phenotype and alleviates acute pancreatitis.
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DOI：
10.1042/cs20211031
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发表时间：
2022-04-14
期刊：
影响因子：
--
通讯作者：
Shi Q
中科院分区：
文献类型：
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作者：
Hu N;Zhang X;Zhang X;Guan Y;He R;Xue E;Zhang X;Deng W;Yu J;Wang W;Shi Q
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。多种因素导致AP后高血糖。巨噬细胞极化参与组织损伤和修复，并且在某些炎性疾病期间由Notch信号传导调节。本研究旨在探讨AP时高血糖、巨噬细胞极化和Notch信号之间的关系及其相关机制。建立蛙皮素诱导的FVB/N小鼠AP模型，用50%葡萄糖诱导AP伴高血糖。在胰腺组织中评估组织损伤、Notch活性和巨噬细胞极化。通过共培养原代巨噬细胞和胰腺腺泡细胞，并在RAW264.7细胞中建立脂多糖（LPS）诱导的炎症模型，还在体外评估了AP期间Notch信号传导在巨噬细胞极化中的作用。AP时胰腺腺泡细胞受损，胰腺组织中促炎因子水平升高。高血糖状态加重胰腺损伤，增加巨噬细胞浸润，促进巨噬细胞向M1表型极化，并导致Notch活性过度上调。通过DAPT或Notch 1敲低抑制Notch信号传导降低了M1巨噬细胞的比例，并减少了促炎因子的产生，从而减轻了胰腺损伤。这些发现表明，高血糖诱导AP后过度Notch信号传导，并通过促进胰腺巨噬细胞向M1表型极化而进一步加重AP。Notch信号通路是预防和治疗AP的潜在靶点。
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.