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Intracerebral Hemorrhage Induces Inflammatory Gene Expression in Peripheral Blood: Global Transcriptional Profiling in Intracerebral Hemorrhage Patients.

ABSTRACT: To perform global transcriptome profiling using RNA-seq in the peripheral blood of intracerebral hemorrhage (ICH) patients. In 11 patients with ICH, peripheral blood was collected within 24?h of symptom onset or last known well, and a second blood draw occurred 72?h (±6) after the first. RNA-seq identified differentially expressed genes (DEGs) between the first and second samples. Biological pathway enrichment analysis was performed with Ingenuity® Pathway Analysis (IPA). A total of 16,640 genes were identified and 218 were significant DEGs after ICH (false discovery rate <0.1). IPA identified 97 disease and functional categories that were significantly upregulated (z-score >2) post-ICH; 46 categories were specifically related to immune cell activation, 22 to general cellular activation processes, and 4 to other inflammation-related responses. In the canonical pathway and network analysis, inflammatory mediators of particular importance included interleukin-8, NF-?B, ERK1/2, and members of the integrin class. ICH induced peripheral blood gene expression at 72 to 96?h compared with 0 to 24?h from symptom onset. DEGs that were highly expressed included those related to inflammation and activation of the immune response. Further research is needed to determine whether these changes affect outcomes and may represent new therapeutic targets.

SUBMITTER: Walsh KB

PROVIDER: S-EPMC6909779 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Intracerebral Hemorrhage Induces Inflammatory Gene Expression in Peripheral Blood: Global Transcriptional Profiling in Intracerebral Hemorrhage Patients.

Walsh Kyle B KB Zhang Xiang X Zhu Xiaoting X Wohleb Eric E Woo Daniel D Lu Long L Adeoye Opeolu O

DNA and cell biology 20190522 7

To perform global transcriptome profiling using RNA-seq in the peripheral blood of intracerebral hemorrhage (ICH) patients. In 11 patients with ICH, peripheral blood was collected within 24 h of symptom onset or last known well, and a second blood draw occurred 72 h (±6) after the first. RNA-seq identified differentially expressed genes (DEGs) between the first and second samples. Biological pathway enrichment analysis was performed with Ingenuity<sup><b>®</b></sup> Pathway Analysis (IPA). A tot ...[more]

PMID: 31120332

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Project description:BackgroundIntracerebral hemorrhage (ICH) has a high morbidity and mortality. The peripheral immune system and cross-talk between peripheral blood and brain have been implicated in the ICH immune response. Thus, we delineated the gene networks associated with human ICH in the peripheral blood transcriptome. We also compared the differentially expressed genes in blood following ICH to a prior human study of perihematomal brain tissue.MethodsWe performed peripheral blood whole-transcriptome analysis of ICH and matched vascular risk factor control subjects (n = 66). Gene co-expression network analysis identified groups of co-expressed genes (modules) associated with ICH and their most interconnected genes (hubs). Mixed-effects regression identified differentially expressed genes in ICH compared to controls.ResultsOf seven ICH-associated modules, six were enriched with cell-specific genes: one neutrophil module, one neutrophil plus monocyte module, one T cell module, one Natural Killer cell module, and two erythroblast modules. The neutrophil/monocyte modules were enriched in inflammatory/immune pathways; the T cell module in T cell receptor signaling genes; and the Natural Killer cell module in genes regulating alternative splicing, epigenetic, and post-translational modifications. One erythroblast module was enriched in autophagy pathways implicated in experimental ICH, and NRF2 signaling implicated in hematoma clearance. Many hub genes or module members, such as IARS, mTOR, S1PR1, LCK, FYN, SKAP1, ITK, AMBRA1, NLRC4, IL6R, IL17RA, GAB2, MXD1, PIK3CD, NUMB, MAPK14, DDX24, EVL, TDP1, ATG3, WDFY3, GSK3B, STAT3, STX3, CSF3R, PIP4K2A, ANXA3, DGAT2, LRP10, FLOT2, ANK1, CR1, SLC4A1, and DYSF, have been implicated in neuroinflammation, cell death, transcriptional regulation, and some as experimental ICH therapeutic targets. Gene-level analysis revealed 1225 genes (FDR p < 0.05, fold-change > |1.2|) have altered expression in ICH in peripheral blood. There was significant overlap of the 1225 genes with dysregulated genes in human perihematomal brain tissue (p = 7 × 10-3). Overlapping genes were enriched for neutrophil-specific genes (p = 6.4 × 10-08) involved in interleukin, neuroinflammation, apoptosis, and PPAR signaling.ConclusionsThis study delineates key processes underlying ICH pathophysiology, complements experimental ICH findings, and the hub genes significantly expand the list of novel ICH therapeutic targets. The overlap between blood and brain gene responses underscores the importance of examining blood-brain interactions in human ICH.

Project description:Disruption of the blood-brain barrier (BBB) and the subsequent formation of brain edema is the most severe consequence of intracerebral hemorrhage (ICH), leading to drastic neuroinflammatory responses and neuronal cell death. A better understanding of ICH pathophysiology to develop effective therapy relies on selecting appropriate animal models. The collagenase injection ICH model and the autologous arterial whole blood infusion ICH model have been developed to investigate the pathophysiology of ICH. However, it remains unclear whether the temporal progression and the underlying mechanism of BBB breakdown are similar between these two ICH models. In this study, we aimed to determine the progression and the mechanism of BBB disruption via the two commonly used murine ICH models: the collagenase-induced ICH model (c-ICH) and the double autologous whole blood ICH model (b-ICH). Intrastriatal injection of 0.05 U collagenase or 20 μL autologous blood was used for a comparable hematoma volume in these two ICH models. Then we analyzed BBB permeability using Evan's blue and IgG extravasation, evaluated tight junction (TJ) damage by transmission electron microscope (TEM) and Western blotting, and assessed matrix metalloproteinase-9 (MMP-9) activity and aquaporin 4 (AQP4) mRNA expression by Gelatin gel zymography and RT-PCR, respectively. The results showed that the BBB leakage was associated with a decrease in TJ protein expression and an increase in MMP-9 activity and AQP4 expression on day 3 in the c-ICH model compared with that on day 5 in the b-ICH model. Additionally, using TEM, we found that the TJ was markedly damaged on day 3 in the c-ICH model compared with that on day 5 in the b-ICH model. In conclusion, the BBB was disrupted in the two ICH models; compared to the b-ICH model, the c-ICH model presented with a more pronounced disruption of BBB at earlier time points, suggesting that the c-ICH model might be a more suitable model for studying early BBB damage and protection after ICH.

Dataset Information

Intracerebral Hemorrhage Induces Inflammatory Gene Expression in Peripheral Blood: Global Transcriptional Profiling in Intracerebral Hemorrhage Patients.

Publications

Intracerebral Hemorrhage Induces Inflammatory Gene Expression in Peripheral Blood: Global Transcriptional Profiling in Intracerebral Hemorrhage Patients.

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