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High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca(2+)/PAD4 pathway to exacerbate acute pancreatitis

BACKGROUND: Excessive 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...

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Autores principales: Xu, Qi, Shi, Ming, Ding, Lu, Xia, Yu, Luo, Liang, Lu, Xiaofang, Zhang, Xiaoying, Deng, David Y. B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568494/
https://www.ncbi.nlm.nih.gov/pubmed/37841279
http://dx.doi.org/10.3389/fimmu.2023.1265344
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author Xu, Qi
Shi, Ming
Ding, Lu
Xia, Yu
Luo, Liang
Lu, Xiaofang
Zhang, Xiaoying
Deng, David Y. B.
author_facet Xu, Qi
Shi, Ming
Ding, Lu
Xia, Yu
Luo, Liang
Lu, Xiaofang
Zhang, Xiaoying
Deng, David Y. B.
author_sort Xu, Qi
collection PubMed
description BACKGROUND: Excessive 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. METHODS: NETs 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. RESULTS: Patients 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. CONCLUSION: Taken together, these results suggest that P-selectin induces NETs through PSGL-1 and its downstream Syk/Ca(2+)/PAD4 signaling pathway, and that targeting this pathway might be a promising strategy for the treatment of AP.
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spelling pubmed-105684942023-10-13 High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca(2+)/PAD4 pathway to exacerbate acute pancreatitis Xu, Qi Shi, Ming Ding, Lu Xia, Yu Luo, Liang Lu, Xiaofang Zhang, Xiaoying Deng, David Y. B. Front Immunol Immunology BACKGROUND: Excessive 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. METHODS: NETs 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. RESULTS: Patients 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. CONCLUSION: Taken together, these results suggest that P-selectin induces NETs through PSGL-1 and its downstream Syk/Ca(2+)/PAD4 signaling pathway, and that targeting this pathway might be a promising strategy for the treatment of AP. Frontiers Media S.A. 2023-09-28 /pmc/articles/PMC10568494/ /pubmed/37841279 http://dx.doi.org/10.3389/fimmu.2023.1265344 Text en Copyright © 2023 Xu, Shi, Ding, Xia, Luo, Lu, Zhang and Deng https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Xu, Qi
Shi, Ming
Ding, Lu
Xia, Yu
Luo, Liang
Lu, Xiaofang
Zhang, Xiaoying
Deng, David Y. B.
High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca(2+)/PAD4 pathway to exacerbate acute pancreatitis
title High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca(2+)/PAD4 pathway to exacerbate acute pancreatitis
title_full High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca(2+)/PAD4 pathway to exacerbate acute pancreatitis
title_fullStr High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca(2+)/PAD4 pathway to exacerbate acute pancreatitis
title_full_unstemmed High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca(2+)/PAD4 pathway to exacerbate acute pancreatitis
title_short High expression of P-selectin induces neutrophil extracellular traps via the PSGL-1/Syk/Ca(2+)/PAD4 pathway to exacerbate acute pancreatitis
title_sort high expression of p-selectin induces neutrophil extracellular traps via the psgl-1/syk/ca(2+)/pad4 pathway to exacerbate acute pancreatitis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10568494/
https://www.ncbi.nlm.nih.gov/pubmed/37841279
http://dx.doi.org/10.3389/fimmu.2023.1265344
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