Systemic response to rupture of intracranial aneurysms involves expression of specific gene isoforms

Abstract

Background Rupture of an intracranial aneurysm (IA) causes a systemic response that involves an immune/inflammatory reaction. Our previous study revealed a downregulation of genes related to T lymphocytes and an upregulation of genes related to monocytes and neutrophils after IA rupture. It remains unknown whether that resulted from alterations in transcription or cell count. We sought to characterize the systemic response to IA rupture through analysis of transcript expression profiles in peripheral blood cells. We also investigated effects of IA rupture on the composition of mononuclear cells in peripheral blood. Methods We included 19 patients in the acute phase of IA rupture (RAA, first 72 h), 20 patients in the chronic phase (RAC, 3–15 months), and 20 controls. Using deep transcriptome sequencing, we analyzed the expression of protein-coding and noncoding RNAs. Expression levels, transcript biotypes, alternative splicing and other features of the regulated transcripts were studied. A functional analysis was performed to determine overrepresented ontological groups among gene expression profiles. Flow cytometry was used to analyze alterations in the level of mononuclear leukocyte subpopulations. Results Comparing RAA and controls, we identified 491 differentially expressed transcripts (303 were downregulated, and 188 were upregulated in RAA). The results indicate that the molecular changes in response to IA rupture occur at the level of individual transcripts. Functional analysis revealed that the most impacted biological processes are related to regulation of lymphocyte activation and toll-like receptor signaling pathway. Differences between RAC and controls were less prominent. Analysis of leukocyte subsets revealed a significantly decreased number of CD4+ lymphocytes and increase of classical and intermediate monocytes in RAA patients compared to controls. Conclusions IA rupture in the acute phase strongly influences the transcription profiles of peripheral blood cells as well as the composition of mononuclear cells. A specific pattern of gene expression alteration was found, suggesting a depression of lymphocyte response and enhancement of monocyte activity. Electronic supplementary material The online version of this article (10.1186/s12967-019-1891-6) contains supplementary material, which is available to authorized users.

Inflammatory Responses Induced by the Rupture of Intracranial Aneurysms Are Modulated by miRNAs

“…2 Alterations in the transcript expression of the predicted target genes for the identified miRNAs. The differences in gene expression between the samples from subjects in the acute phase of IA rupture (RAA), the chronic phase of IA rupture (RAC) and healthy controls (C) were analyzed by using total RNA sequencing [8]. The mRNA abundance levels of the target genes HMGB1, CXCL5, CSF1 and FASLG were analyzed in peripheral blood cells from patients after IA rupture.…”

“…Patients with ruptured IAs were prospectively recruited from patients at the Department of Neurology or Neurosurgery and Neurotraumatology, University Hospital, Krakow, as previously described [8]. Briefly, two independent SAH patient groups were analyzed: acute (first 72 h after IA rupture) and chronic (3-15 months after SAH).…”

“…To determine the possible miRNA-mRNA interactions, the list of gene targets was compared with the list of differentially expressed miRNA genes. The results of the gene expression profiling were obtained from RNAseq of the total transcriptome from the same patients [8].…”

“…The study included 19 patients in the acute phase of IA rupture (RAA, first 72 h), 20 patients in the chronic phase of SAH (RAC, 3-15 months), and 20 controls. Their clinical characteristics were previously described [8] and are briefly summarized in Table 1. Ruptured IA were located in the anterior circulation in 17 RAA patients and 16 RAC patients.…”

“…Previously, we demonstrated that IA rupture induces a systemic response associated with changes in the mRNA profiles in peripheral blood cells and the composition of mononuclear cells, in an inhibition of lymphocyte responses and a concomitant enhancement of monocyte activity [8]. Here, we sought to investigate the effects of IA rupture on the expression of small ncRNAs in peripheral blood cells using deep transcriptome sequencing.…”