Intracerebral hemorrhage induces monocyte-related gene expression within six hours: Global transcriptional profiling in swine ICH

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.

The Changes of Leukocytes in Brain and Blood After Intracerebral Hemorrhage

“…The aforementioned results suggested that the infiltration of peripheral immune cells may be vital in ICH-induced brain injury. Consequently, we used expression matrixes downloaded from GSE124624 and GSE125512 ( 40 , 41 ) to explore the peripheral blood changes at different stages of the disease. First, we utilized the GSEA to evaluate the pathways that changed in peripheral leukocytes in the early stage (6 h after onset) of ICH.…”

Effects of Acute Subdural Hematoma-Induced Brain Injury On Energy Metabolism in Peripheral Blood Mononuclear Cells

“…Recent studies report peripheral immune cell activation indicated by RNAseq data following intracerebral hemorrhage (ICH) in swine and human patients. Walsh et al (36) highlighted especially the monocytic activation at the early 6 h time point in their porcine model whereas Durocher et al (37) found many immune cell subsets to be activated by means of their RNA data also later after ICH onset. However, ICH represents a different type of injury than ASDH and moreover, none of these groups reported hemodynamic data.…”

Unraveling the complex pathophysiology of white matter hemorrhage in intracerebral stroke: A single‐cell RNA sequencing approach

“…Prior investigations have emphasized ICH‐induced alterations in PBMC gene expression, particularly accentuating monocyte activation. 38 Moreover, monocyte activation has been associated with metabolic processes including oxidative phosphorylation, fatty acid elongation, unsaturated fatty acid synthesis, and fatty acid degradation, predominantly identified within the WMH group. The augmented macrophage presence may facilitate the processing of erythrocytes and hemoglobin at hemorrhagic sites and engage in the catabolism of iron.…”