NLRC4-mediated pyroptosis was involved in coagulation disorders of acute pancreatitis

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Journal of Gene Medicine Pub Date : 2024-04-04 DOI:10.1002/jgm.3683

Sunkuan Hu, Tiesu Lin, Yufeng Chen, Yimo Guo, Xuecheng Sun, Lingyan Shi, Jingye Pan

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Abstract

Background

Acute pancreatitis (AP) is a potentially lethal acute disease highly involved in coagulation disorders. Pyroptosis has been reported to exacerbate coagulation disorders, yet this implication has not been illustrated completely in AP.

Methods

RNA sequencing data of peripheral blood of AP patients were downloaded from the Gene Expression Omnibus database. Gene set variation analysis and single sample gene set enrichment analysis were used to calculate the enrichment score of coagulation-related signatures and pyroptosis. Spearman and Pearson correlation analysis was used for correlation analysis. Peripheral blood samples and related clinical parameters were collected from patients with AP and healthy individuals. A severe AP (SAP) model of mice was established using caerulein and lipopolysaccharide. Enzyme-linked immunosorbent assay, chemiluminescence immunoassay and immunohistochemical analysis were employed to detect the level of coagulation indicators and pyroptosis markers in serum and pancreas tissues. Additionally, we evaluated the effect of pyroptosis inhibition and NLRC4 silence on the function of human umbilical vein endothelial cells (HUVECs).

Results

Coagulation disorders were significantly positively correlated to the severity of AP, and they could be a predictor for AP severity. Further analyses indicated that six genes—DOCK9, GATA3, FCER1G, NLRC4, C1QB and C1QC—may be involved in coagulation disorders of AP. Among them, NLRC4 was positively related to pyroptosis that had a positive association with most coagulation-related signatures. Data from patients showed that NLRC4 and other pyroptosis markers, including IL-1β, IL-18, caspase1 and GSDMD, were significant correlation to AP severity. In addition, NLRC4 was positively associated with coagulation indicators in AP patients. Data from mice showed that NLRC4 was increased in the pancreas tissues of SAP mice. Treatment with a pyroptosis inhibitor effectively alleviated SAP and coagulation disorders in mice. Finally, inhibiting pyroptosis or silencing NLRC4 could relieve endothelial dysfunction in HUVECs.

Conclusions

NLRC4-mediated pyroptosis damages the function of endothelial cells and thereby exacerbates coagulation disorders of AP. Inhibiting pyroptosis could improve coagulation function and alleviate AP.

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NLRC4 介导的热蛋白沉积参与了急性胰腺炎的凝血障碍

背景急性胰腺炎（AP）是一种可能致命的急性疾病，与凝血功能障碍有很大关系。有报道称热蛋白沉积会加重凝血功能障碍，但这一影响在急性胰腺炎中尚未得到充分说明。方法从基因表达总库（Gene Expression Omnibus）数据库下载 AP 患者外周血的 RNA 序列数据。采用基因组变异分析和单样本基因组富集分析计算凝血相关特征和热病的富集得分。相关性分析采用了 Spearman 和 Pearson 相关性分析。采集了 AP 患者和健康人的外周血样本和相关临床参数。使用茶碱和脂多糖建立了严重 AP（SAP）小鼠模型。采用酶联免疫吸附试验、化学发光免疫测定和免疫组化分析法检测血清和胰腺组织中的凝血指标和热蛋白沉积标志物水平。此外，我们还评估了热蛋白沉积抑制和 NLRC4 沉默对人脐静脉内皮细胞（HUVECs）功能的影响。结果凝血功能障碍与 AP 的严重程度呈显著正相关，可预测 AP 的严重程度。进一步的分析表明，有六个基因-DOCK9、GATA3、FCER1G、NLRC4、C1QB 和 C1QC 可能与 AP 的凝血障碍有关。其中，NLRC4 与大多数凝血相关特征呈正相关的脓毒症呈正相关。来自患者的数据显示，NLRC4和其他裂解标志物（包括IL-1β、IL-18、caspase1和GSDMD）与AP的严重程度显著相关。此外，NLRC4 与 AP 患者的凝血指标呈正相关。小鼠数据显示，SAP 小鼠胰腺组织中的 NLRC4 增加。使用热蛋白沉积抑制剂能有效缓解小鼠的 SAP 和凝血功能障碍。最后，抑制化脓过程或沉默 NLRC4 可缓解 HUVECs 内皮功能障碍。结论 NLRC4 介导的热蛋白沉积会损害内皮细胞的功能，从而加剧 AP 的凝血功能障碍。抑制裂解酶可改善凝血功能并缓解 AP。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Gene Medicine 医学-生物工程与应用微生物

CiteScore

6.40

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： The aims and scope of The Journal of Gene Medicine include cutting-edge science of gene transfer and its applications in gene and cell therapy, genome editing with precision nucleases, epigenetic modifications of host genome by small molecules, siRNA, microRNA and other noncoding RNAs as therapeutic gene-modulating agents or targets, biomarkers for precision medicine, and gene-based prognostic/diagnostic studies. Key areas of interest are the design of novel synthetic and viral vectors, novel therapeutic nucleic acids such as mRNA, modified microRNAs and siRNAs, antagomirs, aptamers, antisense and exon-skipping agents, refined genome editing tools using nucleic acid /protein combinations, physically or biologically targeted delivery and gene modulation, ex vivo or in vivo pharmacological studies including animal models, and human clinical trials. Papers presenting research into the mechanisms underlying transfer and action of gene medicines, the application of the new technologies for stem cell modification or nucleic acid based vaccines, the identification of new genetic or epigenetic variations as biomarkers to direct precision medicine, and the preclinical/clinical development of gene/expression signatures indicative of diagnosis or predictive of prognosis are also encouraged.