IL-37抑制NLRP3炎症小体活化保护重症急性胰腺炎的作用及机制研究

Pancreatic acinar cell necrosis and macrophage activation are two key factors affecting the severity of severe acute pancreatitis (SAP). Interleukin 37 (IL-37) is a new anti-inflammatory cytokine, which can inhibit the activation of NLRP3 inflammasome. Our preliminary findings showed that: ① the serum IL-37 levels were significantly lower in patients with SAP; ② the expression of NLRP3 increased in pancreatic acinar cells in SAP mice, and specific knockout of NLRP3 in pancreatic acinar cells reduced the acinar cells necrosis in SAP mice; ③ compared with wild type mice, the severity of SAP in IL-37 transgenic mice was decreased with lower reactive oxygen species (ROS) production in pancreas. We suggested that IL-37 could protect mice from SAP by reducing ROS production and inhibiting NLRP3 activation. This study aims to: ① clarify the protective (theraphy) effect of IL-37 on SAP by IL-37 recombinant protein; ② assess the target cell in protective effect of IL-37 on SAP mice using acinar cell/macrophage NLRP3 specific knock-out mice; ③ investigate the underlying molecular mechanism of IL-37 on NLRP3 inflammasome activation. The results will further enrich the pathogenesis of SAP and provide potential therapeutic targets for SAP, which has a good value in translational medicine.

腺泡细胞坏死和巨噬细胞活化是导致重症急性胰腺炎(SAP)的两大关键因素。IL-37是一种新型抗炎因子，具有抑制NLRP3炎症小体活化的作用。我们前期发现：①SAP患者血清IL-37水平降低；②SAP小鼠腺泡细胞NLRP3表达增加，腺泡细胞特异性敲除NLRP3降低SAP小鼠腺泡细胞坏死；③与野生型小鼠相比，IL-37转基因小鼠SAP严重程度减轻，胰腺组织活性氧(ROS)生成减少。我们推测IL-37通过减少ROS生成，抑制NLRP3炎症小体活化保护小鼠SAP。本课题拟：①通过外源性补充IL-37重组蛋白进一步明确IL-37对SAP的保护(治疗)作用；②应用腺泡细胞和巨噬细胞NLRP3特异性敲除小鼠等动物模型，分析IL-37保护SAP的作用靶细胞；③探索 IL-37抑制NLRP3炎症小体活化的分子机制。研究结果将丰富SAP发病机制，提供新的治疗靶点，具有较好的转化医学价值。

IL-37是一种新型抗炎因子，具有抑制NLRP3炎症小体的生物学活性。本项目发现:（1）腺泡细胞焦亡而非巨噬细胞焦亡对AP胰腺坏死具有关键作用；（2）AP患者血清IL-37水平显著降低，血清IL-37水平降低是AP胰腺坏死（PN）的重要危险因素;（3）IL-37转基因小鼠可减轻小鼠AP模型的胰腺炎症程度；（4）补充IL-37重组蛋白可缓解小鼠AP腺泡细胞损伤/死亡；（5）骨髓来源的IL-37在保护AP过程中有一定的作用；（6）IL-37通过抑制GSDMD介导的焦亡通路而靶向保护腺泡细胞损伤。研究结果将丰富AP发病机制，提供新的治疗靶点，具有较好的转化医学价值。项目培养研究生4名，其中2名已经毕业并取得硕士（博士）学位，2名在读。项目累计发表期刊论文18篇，其中SCI论文14篇。项目的第一个主旨研究内容（腺泡细胞焦亡而非巨噬细胞焦亡对AP胰腺坏死具有关键作用）已发表于BJP（Br J Pharmacol. 2021.178 (17):3533-3552. 中科院TOP杂志，药理学一区，主持人为共同通讯作者倒数2/2）；第二个主旨研究内容（IL-37对AP的保护作用）已撰写完毕，已投Redox biology。