2. Academic Validation
  3. S1P/S1PR2 promote pancreatic stellate cell activation and pancreatic fibrosis in chronic pancreatitis by regulating autophagy and the NLRP3 inflammasome

S1P/S1PR2 promote pancreatic stellate cell activation and pancreatic fibrosis in chronic pancreatitis by regulating autophagy and the NLRP3 inflammasome

  • Chem Biol Interact. 2023 May 9;110541. doi: 10.1016/j.cbi.2023.110541.
Lihua Cui 1,  Caixia Li 2,  Guixian Zhang 3,  Lanqiu Zhang 2,  Guowang Yao 4,  Yuzhen Zhuo 2,  Naiqiang Cui 5,  Shukun Zhang 6
Affiliations

Affiliations

  • 1 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. Electronic address: [email protected].
  • 2 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.
  • 3 Department of Cancer Pharmacology, Tianjin Institute of Medical and Pharmaceutical Sciences, Tianjin Medicine and Health Research Center, Duolun Road, Tianjin, 300020, China.
  • 4 Department of Gastrointestinal Surgery, Tianjin Nankai Hospital, Tianjin, 300100, China.
  • 5 Department of Hepatobiliary and Pancreatic Surgery, Tianjin Nankai Hospital, Tianjin, 300100, China.
  • 6 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. Electronic address: [email protected].
PMID: 37169277 DOI: 10.1016/j.cbi.2023.110541
Abstract

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. 3 MA 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.

Keywords

Autophagy; Chronic pancreatitis; NLRP3 inflammasome; Pancreatic stellate cell; S1P; S1PR2.

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