Transcriptome-Based Dissection of Intracranial Aneurysms Unveils an “Immuno-Thermal” Microenvironment and Defines a Pathological Feature-Derived Gene Signature for Risk Estimation

Abstract

Immune inflammation plays an essential role in the formation and rupture of intracranial aneurysm (IA). However, the current limited knowledge of alterations in the immune microenvironment of IA has hampered the mastery of pathological mechanisms and technological advances, such as molecular diagnostic and coated stent-based molecular therapy. In this study, seven IA datasets were enrolled from the GEO database to decode the immune microenvironment and relevant biometric alterations. The ssGSEA algorithm was employed for immune infiltration assessment. IAs displayed abundant immune cell infiltration, activated immune-related pathways, and high expression of immune-related genes. Several immunosuppression cells and genes were also coordinately upregulated in IAs. Five immune-related hub genes, including CXCL10, IL6, IL10, STAT1, and VEGFA, were identified from the protein-protein interaction network and further detected at the protein level. CeRNA networks and latent drugs targeting the hub genes were predicted for targeted therapy reference. Two gene modules recognized via WCGNA were functionally associated with contractile smooth muscle loss and extracellular matrix metabolism, respectively. In blood datasets, a pathological feature-derived gene signature (PFDGS) for IA diagnosis and rupture risk prediction was established using machine learning. Patients with high PFDGS scores may possess adverse biological alterations and present with a high risk of morbidity or IA rupture, requiring more vigilance or prompt intervention. Overall, we systematically unveiled an “immuno-thermal” microenvironment characterized by co-enhanced immune activation and immunosuppression in IA, which provides a novel insight into molecular pathology. The PFDGS is a promising signature for optimizing risk surveillance and clinical decision-making in IA patients.

An immunogenic cell death-related regulators classification patterns and immune microenvironment infiltration characterization in intracranial aneurysm based on machine learning

“…used WGCNA and ssGSEA methods to analyze IA and normal samples and identified immune-related genes that mediate IA. The final results showed that inflammation and immune responses are involved in IA pathogenesis ( 23 ).…”

Transcriptomic Studies on Intracranial Aneurysms

“…Along with the development of bioinformatic tools appeared a new type of study presenting re-analyzed data from available datasets, including expression data from the Gene Expression Omnibus (GEO). Approximately one third of these published secondary analyses utilized a single dataset [ 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 ] and two thirds leveraged data from two to eight datasets [ 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 ]. These studies did not provide any new additional clinical data but rather aimed to deepen the insight into molecular mechanisms of the IA pathophysiology by revealing key regulatory networks and interactions between investigated molecules.…”

“…Although differential expression and functional annotation were examined, further analyses of co-expression networks with identification of hub RNA molecules, competing endogenous RNA (ceRNA) networks, or protein–protein interaction (PPI) networks became a standard approach. In some of these studies, specific areas of interest were predefined, such as: epithelial–mesenchymal transition [ 78 ], endoplasmic reticulum stress [ 81 ], immune environment [ 79 , 83 ], or ferroptosis [ 84 , 85 ]. In three studies, an attempt was made to identify potential therapeutic targets [ 71 , 82 , 83 ].…”

“…In some of these studies, specific areas of interest were predefined, such as: epithelial–mesenchymal transition [ 78 ], endoplasmic reticulum stress [ 81 ], immune environment [ 79 , 83 ], or ferroptosis [ 84 , 85 ]. In three studies, an attempt was made to identify potential therapeutic targets [ 71 , 82 , 83 ]. Sun et al investigated expression profiles and networks in various aneurysms, including thoracic and abdominal aorta aneurysms [ 77 ].…”

Six macrophage-associated genes in synovium constitute a novel diagnostic signature for osteoarthritis

“…The gene set for marking 28 immune cell types was enrolled from a previously published article (19) and illustrated in Supplementary Table S2. Then, the relative infiltration abundance of immune cells in OA and normal synovium was estimated by the ssGSEA algorithm implemented in the GSVA R package, which is broadly utilized in immune infiltration-related bioinformatics studies (20)(21)(22)(23).…”