High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca2+/PAD4 pathway to exacerbate acute pancreatitis
BackgroundExcessive neutrophil extracellular traps (NETs) is involved in the progression of acute pancreatitis (AP) but the mechanisms controlling NETs formation in AP are not fully understood. Therefore, our study sought to investigate the mechanism of the highly expressed P-selectin stimulating th...
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| Format: | Article |
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Frontiers Media S.A.
2023-09-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1265344/full |
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| author | Qi Xu Ming Shi Lu Ding Yu Xia Liang Luo Xiaofang Lu Xiaoying Zhang David Y. B. Deng David Y. B. Deng |
| author_facet | Qi Xu Ming Shi Lu Ding Yu Xia Liang Luo Xiaofang Lu Xiaoying Zhang David Y. B. Deng David Y. B. Deng |
| author_sort | Qi Xu |
| collection | DOAJ |
| description | BackgroundExcessive neutrophil extracellular traps (NETs) is involved in the progression of acute pancreatitis (AP) but the mechanisms controlling NETs formation in AP are not fully understood. Therefore, our study sought to investigate the mechanism of the highly expressed P-selectin stimulating the formation of NETs in AP.MethodsNETs formation was detected by flow cytometry, immunofluorescence staining, and cf-DNA and MPO-DNA complexes were measured as biomarkers of NETs formation. Neutrophils treated with P-selectin and pharmacological inhibitors were examined by western blot, immunofluorescence staining and flow cytometry. Mouse model of AP was established by caerulein and the effect of inhibiting P-selectin by PSI-697 on the level of NETs and PAD4 in pancreatic tissue was observed. The severity of AP was evaluated by histopathological score and the detection of serum amylase and lipase.ResultsPatients with AP had elevated levels of NETs and P-selectin compared with healthy volunteers. Stimulation of P-selectin up-regulated the expression of PSGL-1, increased the phosphorylation of Syk, mediated intracellular calcium signal and led to the activation and expression of PAD4, which modulated NETs formation in neutrophils. Pretreament with PSI-697 blunted NETs formation and PAD4 expression in the pancreatic tissue, and ameliorated the severity of AP in mice.ConclusionTaken together, these results suggest that P-selectin induces NETs through PSGL-1 and its downstream Syk/Ca2+/PAD4 signaling pathway, and that targeting this pathway might be a promising strategy for the treatment of AP. |
| first_indexed | 2024-03-11T21:15:38Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T21:15:38Z |
| publishDate | 2023-09-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Immunology |
| spelling | doaj.art-185226daf3cd4447aeffbe254b10a4e72023-09-29T03:59:05ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-09-011410.3389/fimmu.2023.12653441265344High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca2+/PAD4 pathway to exacerbate acute pancreatitisQi Xu0Ming Shi1Lu Ding2Yu Xia3Liang Luo4Xiaofang Lu5Xiaoying Zhang6David Y. B. Deng7David Y. B. Deng8Department of Scientific Research Center, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, ChinaDepartment of Scientific Research Center, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, ChinaDepartment of Scientific Research Center, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, ChinaDepartment of Scientific Research Center, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, ChinaDepartment of Critical Care Medicine, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, ChinaDepartment of Pathology, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, ChinaDepartment of Health Management Center, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, ChinaDepartment of Scientific Research Center, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, ChinaDepartment of Critical Care Medicine, Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen, ChinaBackgroundExcessive neutrophil extracellular traps (NETs) is involved in the progression of acute pancreatitis (AP) but the mechanisms controlling NETs formation in AP are not fully understood. Therefore, our study sought to investigate the mechanism of the highly expressed P-selectin stimulating the formation of NETs in AP.MethodsNETs formation was detected by flow cytometry, immunofluorescence staining, and cf-DNA and MPO-DNA complexes were measured as biomarkers of NETs formation. Neutrophils treated with P-selectin and pharmacological inhibitors were examined by western blot, immunofluorescence staining and flow cytometry. Mouse model of AP was established by caerulein and the effect of inhibiting P-selectin by PSI-697 on the level of NETs and PAD4 in pancreatic tissue was observed. The severity of AP was evaluated by histopathological score and the detection of serum amylase and lipase.ResultsPatients with AP had elevated levels of NETs and P-selectin compared with healthy volunteers. Stimulation of P-selectin up-regulated the expression of PSGL-1, increased the phosphorylation of Syk, mediated intracellular calcium signal and led to the activation and expression of PAD4, which modulated NETs formation in neutrophils. Pretreament with PSI-697 blunted NETs formation and PAD4 expression in the pancreatic tissue, and ameliorated the severity of AP in mice.ConclusionTaken together, these results suggest that P-selectin induces NETs through PSGL-1 and its downstream Syk/Ca2+/PAD4 signaling pathway, and that targeting this pathway might be a promising strategy for the treatment of AP.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1265344/fullacute pancreatitisneutrophil extracellular trapsP-selectinP-selectin glycoprotein ligand-1peptidylarginine deiminase 4 |
| spellingShingle | Qi Xu Ming Shi Lu Ding Yu Xia Liang Luo Xiaofang Lu Xiaoying Zhang David Y. B. Deng David Y. B. Deng High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca2+/PAD4 pathway to exacerbate acute pancreatitis Frontiers in Immunology acute pancreatitis neutrophil extracellular traps P-selectin P-selectin glycoprotein ligand-1 peptidylarginine deiminase 4 |
| title | High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca2+/PAD4 pathway to exacerbate acute pancreatitis |
| title_full | High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca2+/PAD4 pathway to exacerbate acute pancreatitis |
| title_fullStr | High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca2+/PAD4 pathway to exacerbate acute pancreatitis |
| title_full_unstemmed | High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca2+/PAD4 pathway to exacerbate acute pancreatitis |
| title_short | High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca2+/PAD4 pathway to exacerbate acute pancreatitis |
| title_sort | high expression of p selectin induces neutrophil extracellular traps via the psgl 1 syk ca2 pad4 pathway to exacerbate acute pancreatitis |
| topic | acute pancreatitis neutrophil extracellular traps P-selectin P-selectin glycoprotein ligand-1 peptidylarginine deiminase 4 |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1265344/full |
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