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, 34 (3), 763-774

Intracerebral Hemorrhage Induces Monocyte-Related Gene Expression Within Six Hours: Global Transcriptional Profiling in Swine ICH

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Intracerebral Hemorrhage Induces Monocyte-Related Gene Expression Within Six Hours: Global Transcriptional Profiling in Swine ICH

Kyle B Walsh et al. Metab Brain Dis.

Abstract

Intracerebral hemorrhage (ICH) is a severe neurological disorder with no proven treatment. Our prior research identified a significant association with monocyte level and ICH mortality. To advance our understanding, we sought to identify gene expression after ICH using a swine model to test the hypothesis that ICH would induce peripheral blood mononuclear cell (PBMC) gene expression. In 10 pigs with ICH, two PBMC samples were drawn from each with the first immediately prior to ICH induction and the second six hours later. RNA-seq was performed with subsequent bioinformatics analysis using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Ingenuity® Pathway Analysis (IPA). There were 182 significantly upregulated and 153 significantly down-regulated differentially expressed genes (DEGs) after ICH. Consistent with findings in humans, significant GO and KEGG pathways were primarily related to inflammation and the immune response. Five genes, all upregulated post-ICH and known to be associated with monocyte activation, were repeatedly DEGs in the significant KEGG pathways: CD14, TLR4, CXCL8, IL-18, and CXCL2. In IPA, the majority of upregulated disease/function categories were related to inflammation and immune cell activation. TNF and LPS were the most significantly activated upstream regulators, and ERK was the most highly connected node in the top network. ICH induced changes in PBMC gene expression within 6 h of onset related to inflammation, the immune response, and, more specifically, monocyte activation. Further research is needed to determine if these changes affect outcomes and may represent new therapeutic targets.

Keywords: Gene expression; Intracerebral hemorrhage; Monocyte; Neuroinflammation; RNA sequencing; Stroke.

Conflict of interest statement

Disclosure of potential conflicts of interest The authors Walsh, Zhang, Zhu, Wohleb, Woo, and Lu no conflicts of interest to report.

The author Adeoye holds equity in Sense Diagnostics, LLC, Cincinnati, Ohio. For the submitted manuscript, financial support for the swine experiments only was provided by Sense Diagnostics. To further clarify, the financial support for blood sample collection, processing, storage, RNA sequencing, and bioinformatics analysis was not provided by Sense Diagnostics but by the University of Cincinnati Gardner Neuroscience Institute. The research reported in the submitted manuscript was performed as a substudy to the swine intracerebral hemorrhage study performed by Sense Diagnostics for the testing of a non-invasive brain monitor. The reported results in this manuscript, and the RNA-seq data overall, have no bearing on the development of this non-invasive brain monitoring device.

Figures

Fig. 1
Fig. 1
The top 100 annotated differentially expressed genes for which the expression was most changed six hours following versus prior to swine ICH induction (gene counts were log normalized and clustered by correlation)
Fig. 2
Fig. 2
The normalized expression of the genes TLR4, CD14, IL18, CXCL2, and CXCL8 comparing prior to (control) and six hours following ICH
Fig. 3
Fig. 3
IPA generated heatmap of diseases and functions from the swine ICH RNA-seq data. The majority of the significantly upregulated categories (based on Z-score and with greater upregulation represented by progressively brighter orange to red colors) involve inflammation and activation of the immune system/cellular processes
Fig. 4
Fig. 4
The top IPA generated network based on the swine ICH RNA-seq data. The node with the most interactions with other molecules is extra cellular signal-related kinase (ERK, highlighted in the figure by cyan colored lines)

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