颅内动脉瘤的相关信号通路基因集富集及免疫浸润分析

Analysis on Gene Set Enrichment of Related Signaling Pathways and Immune Infiltration in Intracranial Aneurysm

目的:基于基因芯片技术,对颅内动脉瘤(IA)mRNA表达谱芯片数据进行基因集富集分析(GSEA)和免疫浸润分析,为深入了解IA的形成机制提供理论依据。方法:从基因表达数据库(GEO)中获取GSE75436芯片数据,利用R软件对基因表达谱进行基因本体论(GO)中生物学过程(BP)和京都基因与基因组百科全书(KEGG)信号通路的GSEA;采用CIBERSORT反卷积方法对表达谱中22种免疫细胞浸润比例进行分析;应用COREMINE数据库对显著富集过程进行中药预测。结果:GSEA结果显示,IA样本的基因表达改变主要涉及细胞因子的调节、白细胞激活及分化、炎症免疫应答等过程。对免疫细胞的浸润矩阵分析结果表明,静息肥大细胞和中性粒细胞在IA样本中显著减少。配对样本的分析结果显示,同一个体的IA样本中肥大细胞和自然杀伤细胞(NK细胞)呈明显活化趋势,而中性粒细胞和初始CD4+T细胞明显减少。通过COREMINE预测发现,防己与粒细胞激活相关,黄连木、无患子与中性粒细胞激活相关,瓜蒌子、白芍和女贞子与NK细胞介导的细胞毒性相关。结论:肥大细胞活化和NK细胞活化与IA发生发展密切相关,筛选出的核苷酸结合寡聚化结构域(NOD)样受体(NLR)信号通路以及NK细胞介导的细胞毒性等炎症免疫相关通路可能作为IA形成机制中的重要影响因素,而防己等中药可能作为其潜在的分子药物来源。

Objective:Based on gene array technology,gene set enrichment analysis(GSEA)and immune infiltration analysis were performed on chip data of intracranial aneurysm(IA)mRNA expression profile,in order to provide theoretical basis for understanding the formation mechanism of IA.Method:The GSE75436 raw data were obtained from the gene expression omnibus(GEO).GSEA of biological process(BP)in gene ontology(GO)and Kyoto gene and genome encyclopedia(KEGG)signaling pathways were analyzed for gene expression profile by R software.The CIBERSORT deconvolution method was used to analyze the infiltration ratio of22 types of immune cells in the expression profile.And COREMINE database was used to predict traditional Chinese medicines(TCMs),which were significant correlation with the enrichment result.Result:The GSEA results showed that the changes in gene expression of IA samples mainly involved in the regulation of cytokines,activation and differentiation of leukocyte,inflammatory immune response and other processes.The infiltration matrix analysis of immune cells showed that mast cells resting and neutrophils were significantly reduced in IA samples.The comparison of paired samples showed that mast cells and natural killer cells(NK cells)were significantly activated in the IA samples of the same individual,while neutrophils and T cells CD4 naive were significantly reduced.Through COREMINE prediction,it was found that Stephaniae Tetrandrae Radix was correlated with the activation of granulocytes,Sapindi Mukorossi Semen and Pistaciae Chinensis Cortex were correlated with the activation of neutrophils,Trichosanthis Semen,Paeoniae Radix Alba and Ligustri Lucidi Fructus were correlated with the cytotoxicity mediated by NK cells.Conclusion:Activation of mast cells and NK cells are closely associated with the occurrence and development of IA.The inflammatory immune processes and pathways such as nucleotide-binding oligomerization domain(NOD)-like receptor(NLR)signaling pathway and cytotoxicity mediated by NK cells may be important factors in the pathogenesis of IA,and TCMs such as Stephaniae Tetrandrae Radix may be the potential molecular drug sources.