S1P/S1PR2 通过调控自噬和 NLRP3 炎性小体促进慢性胰腺炎中胰腺星状细胞的激活和胰腺纤维化。
S1P/S1PR2 promote pancreatic stellate cell activation and pancreatic fibrosis in chronic pancreatitis by regulating autophagy and the NLRP3 inflammasome.
机构信息
Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Nankai Clinical College, Tianjin Medical University, Tianjin, 300100, China.
Tianjin Key Laboratory of Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Institute of Acute Abdominal Diseases of Integrated Traditional Chinese and Western Medicine, Tianjin Nankai Hospital, Nankai Clinical College, Tianjin Medical University, Tianjin, 300100, China.
出版信息
Chem Biol Interact. 2023 Aug 1;380:110541. doi: 10.1016/j.cbi.2023.110541. Epub 2023 May 9.
Sphingosine-1-phosphate (S1P) is a bioactive lipid molecule that governs various functions by embedding its receptor, S1PR, in different cells. Chronic pancreatitis (CP) is characterized by pancreatic fibrosis via activation of pancreatic stellate cells (PSCs). However, the effect of S1P on CP and PSC activation is still unknown. Here, we conducted a series of experiments to explore the effect of S1P on a CP rat model and primary cultured PSCs. In vivo, CP was induced by intravenous injection of dibutyltin dichloride. S1P was administered at a dosage of 200 μg/kg body weight per day by intraperitoneal injection. After 4 weeks, serum, plasma and pancreas samples were collected for molecular analysis and histological detection. In vitro, PSCs were isolated and cultured for treatment with different doses of S1P. 3MA and MCC950 were used to determine the effect of S1P on PSC activation by regulating autophagy and the NLRP3 inflammasome. JTE013 and Si-S1PR2 were applied to verify that the functions of S1P were realized by combining with S1PR2. Cells were collected for RT‒PCR, western blotting and immunofluorescence. The results showed that S1P was increased in the plasma and pancreatic tissue of CP rats. When S1P was administered to CP rats, the function and histomorphology of the pancreas were severely impaired. In addition, S1P promoted PSC activation, heightened autophagy and enhanced the NLRP3 inflammasome in vivo and in vitro. Moreover, S1PR2 mediated the effect of S1P on PSC activation by regulating autophagy and the NLRP3 inflammasome sequentially. In conclusion, S1P binding to S1PR2 promoted PSC activation and pancreatic fibrosis in CP by regulating autophagy and the NLRP3 inflammasome. These findings provide a theoretical basis for targeting S1P/S1PR2 to treat pancreatic fibrosis and further suggest that considering the role of autophagy and the NLRP3 inflammasome may help with the treatment pancreatic fibrosis.
鞘氨醇-1-磷酸（S1P）是一种生物活性脂质分子，通过将其受体 S1PR 嵌入不同的细胞中来调节各种功能。慢性胰腺炎（CP）的特征是通过激活胰腺星状细胞（PSCs）导致胰腺纤维化。然而，S1P 对 CP 和 PSC 激活的影响尚不清楚。在这里，我们进行了一系列实验来探索 S1P 对 CP 大鼠模型和原代培养的 PSCs 的影响。在体内，通过静脉注射二丁基锡二氯化物诱导 CP。通过腹腔注射每天给予 200μg/kg 体重的 S1P。4 周后，收集血清、血浆和胰腺样本进行分子分析和组织学检测。在体外，分离和培养 PSCs，并给予不同剂量的 S1P 进行处理。使用 3MA 和 MCC950 来确定 S1P 通过调节自噬和 NLRP3 炎性小体对 PSC 激活的影响。应用 JTE013 和 Si-S1PR2 来验证 S1P 通过与 S1PR2 结合来实现其功能。收集细胞进行 RT-PCR、western blot 和免疫荧光。结果表明，CP 大鼠血浆和胰腺组织中 S1P 增加。当 S1P 给予 CP 大鼠时，胰腺的功能和组织形态学严重受损。此外，S1P 在体内和体外促进 PSC 激活、增加自噬并增强 NLRP3 炎性小体。此外，S1PR2 通过顺序调节自噬和 NLRP3 炎性小体来介导 S1P 对 PSC 激活的作用。总之，S1P 与 S1PR2 结合通过调节自噬和 NLRP3 炎性小体促进 CP 中的 PSC 激活和胰腺纤维化。这些发现为靶向 S1P/S1PR2 治疗胰腺纤维化提供了理论依据，并进一步表明考虑自噬和 NLRP3 炎性小体的作用可能有助于治疗胰腺纤维化。
Zotero 插件