Abstract TP421: Immune, Autophagy and Regulatory Co-Expression Modules Underlie the Peripheral Immune Response to Human Intracerebral Hemorrhage

Abstract

Background: The peripheral immune system is involved in the damage and repair following intracerebral hemorrhage (ICH). Nevertheless, little is known about the transcriptional response following human ICH. Thus, we aimed to define the co-expression networks in the peripheral blood transcriptome of ICH patients compared to controls and identified the genes with highest connectivity which are potential immune response master-regulators. Methods: We performed transcriptomic analysis on 66 human peripheral whole-blood samples (33 ICH, 33 vascular risk factor controls) using GeneChip® HTA 2.0 arrays. Weighted gene co-expression network analysis (WGCNA) of ICH compared to matched controls identified groups of co-expressed genes (modules) associated with ICH and their most interconnected genes (hubs). Results: We identified seven modules of co-expressed genes associated with ICH. Six modules were enriched with cell-specific genes including 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, while the T-cell module was enriched for T-cell receptor and other T-cell signaling genes. The natural killer cell module was enriched in genes that regulate alternative splicing, and epigenetic regulation. One erythroblast module was enriched in autophagy pathways implicated in experimental ICH, and in NRF2 signaling implicated in hematoma clearance. Many hub and module genes such as 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 and translational regulation, and some as experimental ICH therapeutic targets. Conclusion: This study defined coordinately expressed modules of genes in the peripheral immune response underlying ICH pathophysiology. Some of the results complement experimental ICH findings. The identified hub genes and their networks may help guide the search for novel therapeutic targets for ICH.