AUTHOR=Shan Dezhi , Guo Xing , Yang Guozheng , He Zheng , Zhao Rongrong , Xue Hao , Li Gang 

TITLE=Integrated Transcriptional Profiling Analysis and Immune-Related Risk Model Construction for Intracranial Aneurysm Rupture

JOURNAL=Frontiers in Neuroscience

VOLUME=Volume 15 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2021.613329

DOI=10.3389/fnins.2021.613329

ISSN=1662-453X

ABSTRACT=17	Intracranial aneurysms (IAs) may cause lethal subarachnoid hemorrhage upon rupture, but the 
18	molecular mechanisms are poorly understood. The aims of this study were to analyze the 
19	transcriptional profiles to explore the functions and regulatory networks of differentially expressed 
20	genes (DEGs) in IA rupture by bioinformatics methods and to identify the underlying mechanisms.  
21	In this study, 1471 DEGs were obtained, of which 619 were upregulated and 852 were downregulated. 
22	Gene enrichment analysis showed that the DEGs were mainly enriched in the inflammatory response, 
23	immune response, neutrophil chemotaxis and macrophage differentiation. Related pathways include 
24	the regulation of actin cytoskeleton, leukocyte transendothelial migration, nuclear factor-kappaB (NF-
25	κB) signaling pathway, Toll-like receptor signaling pathway, tumor necrosis factor (TNF) signaling 
26	pathway and chemokine signaling pathway. The enrichment analysis of 20 hub genes, subnetworks
27	and significant enrichment modules of weighted gene coexpression network analysis (WGCNA) 
28	showed that the inflammatory response and immune response had a causal relationship with the 
29	rupture of unruptured intracranial aneurysms (UIAs). Next, the CIBERSORT method was used to 
30	analyze immune cell infiltration into ruptured intracranial aneurysms (RIAs) and UIAs. Macrophage 
31	infiltration into RIAs increased significantly compared with that into UIAs. The result of Principal 
32	component analysis (PCA) revealed that there was difference between RIAs and UIAs in immune cell 
33	infiltration. A 4-gene immune-related risk model for IA rupture (IRMIR), containing CXCR4, CXCL3, 
34	CX3CL1 and CXCL16, was established using the glmnet package in R software. The receiver 
35	operating characteristic (ROC) value revealed that the model represented an excellent clinical situation 
36	for potential application. Enzyme-linked immunosorbent assay (ELISA) was performed and showed 
37	that the concentrations of CXCR4 and CXCL3 in serum from RIA patients were significantly higher 
38	than those in serum from UIA patients. Finally, a competing endogenous RNA (ceRNA) network was 
39	constructed to provide a potential explanation for the mechanism of immune cell infiltration into IAs. 
40	Our findings highlighted the importance of immune cell infiltration into RIAs, providing a direction 
41	for further research.