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

Abstract

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.

Identification of the key immune-related genes in aneurysmal subarachnoid hemorrhage

“…TNFSF13B is also known as a marked gene of neutrophil activation (Besteman et al, 2020 ). CXCL16 was reported to have great value for predicting UIA rupture, and is significantly associated with poor outcome in patients with aSAH (Shan et al, 2021 ; Xu et al, 2021 ). It is possible that SRPK1 promotes SAH progression by interacting with these immunomodulators, for example by affecting the maturation of mRNAs transcribed by target genes.…”

Common mechanisms of physiological and pathological rupture events in biology: novel insights into mammalian ovulation and beyond

“…Immune-related pathways may include the infiltration of external immune cells into the rupture system. Ruptured ICAs have larger populations of neutrophils, monocytes, M0 macrophages, and M2 macrophages ( Shan et al ., 2021 ). Most leukocytes that infiltrate aneurysmal walls are macrophages, and mice with depleted macrophages had a lower incidence of aneurysms ( Kanematsu et al ., 2011 ).…”

Peripheral macrophages in the development and progression of structural cerebrovascular pathologies

“…14,23 M1 and M2-polarized macrophages are present in relatively equal proportions in unruptured IAs, however, M1 macrophage expression is significantly elevated in IAs at the time of rupture. 23,144 It is possible that periods of rapid growth leading to rupture are catalyzed by macrophage polarity imbalance (Figure 5). This concept is supported by the observation that reduced M2 macrophage levels correlate with impaired IA structural integrity.…”