Shan Dezhi, Guo Xing, Yang Guozheng, He Zheng, Zhao Rongrong, Xue Hao, Li Gang
Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, China.
Shandong Key Laboratory of Brain Function Remodeling, Jinan, China.
Front Neurosci. 2021 Apr 1;15:613329. doi: 10.3389/fnins.2021.613329. eCollection 2021.
Intracranial aneurysms (IAs) may cause lethal subarachnoid hemorrhage upon rupture, but the molecular mechanisms are poorly understood. The aims of this study were to analyze the transcriptional profiles to explore the functions and regulatory networks of differentially expressed genes (DEGs) in IA rupture by bioinformatics methods and to identify the underlying mechanisms. In this study, 1,471 DEGs were obtained, of which 619 were upregulated and 852 were downregulated. Gene enrichment analysis showed that the DEGs were mainly enriched in the inflammatory response, immune response, neutrophil chemotaxis, and macrophage differentiation. Related pathways include the regulation of actin cytoskeleton, leukocyte transendothelial migration, nuclear factor κB signaling pathway, Toll-like receptor signaling pathway, tumor necrosis factor signaling pathway, and chemokine signaling pathway. The enrichment analysis of 20 hub genes, subnetworks, and significant enrichment modules of weighted gene coexpression network analysis showed that the inflammatory response and immune response had a causal relationship with the rupture of unruptured IAs (UIAs). Next, the CIBERSORT method was used to analyze immune cell infiltration into ruptured IAs (RIAs) and UIAs. Macrophage infiltration into RIAs increased significantly compared with that into UIAs. The result of principal component analysis revealed that there was a difference between RIAs and UIAs in immune cell infiltration. A 4-gene immune-related risk model for IA rupture (IRMIR), containing CXCR4, CXCL3, CX3CL1, and CXCL16, was established using the glmnet package in R software. The receiver operating characteristic value revealed that the model represented an excellent clinical situation for potential application. Enzyme-linked immunosorbent assay was performed and showed that the concentrations of CXCR4 and CXCL3 in serum from RIA patients were significantly higher than those in serum from UIA patients. Finally, a competing endogenous RNA network was constructed to provide a potential explanation for the mechanism of immune cell infiltration into IAs. Our findings highlighted the importance of immune cell infiltration into RIAs, providing a direction for further research.
颅内动脉瘤（IAs）破裂时可能导致致命的蛛网膜下腔出血，但其分子机制尚不清楚。本研究旨在通过生物信息学方法分析转录谱，以探索IA破裂中差异表达基因（DEGs）的功能和调控网络，并确定潜在机制。在本研究中，共获得1471个DEGs，其中619个上调，852个下调。基因富集分析表明，DEGs主要富集于炎症反应、免疫反应、中性粒细胞趋化和巨噬细胞分化。相关通路包括肌动蛋白细胞骨架调控、白细胞跨内皮迁移、核因子κB信号通路、Toll样受体信号通路、肿瘤坏死因子信号通路和趋化因子信号通路。对20个枢纽基因、子网和加权基因共表达网络分析的显著富集模块进行富集分析，结果表明炎症反应和免疫反应与未破裂IA（UIAs）的破裂存在因果关系。接下来，使用CIBERSORT方法分析免疫细胞向破裂IA（RIAs）和UIAs的浸润情况。与UIAs相比，RIAs中巨噬细胞浸润显著增加。主成分分析结果显示，RIAs和UIAs在免疫细胞浸润方面存在差异。使用R软件中的glmnet包建立了一个包含CXCR4、CXCL3、CX3CL1和CXCL16的IA破裂4基因免疫相关风险模型（IRMIR）。受试者工作特征值表明该模型在潜在应用中具有良好的临床情况。进行酶联免疫吸附测定，结果显示RIA患者血清中CXCR4和CXCL3的浓度显著高于UIA患者血清中的浓度。最后，构建了一个竞争性内源性RNA网络，为免疫细胞浸润IA的机制提供了潜在解释。我们的研究结果突出了免疫细胞浸润RIAs的重要性，为进一步研究提供了方向。
