Inflammatory, regulatory, and autophagy co-expression modules and hub genes underlie the peripheral immune response to human intracerebral hemorrhage

• DOI: 10.1186/s12974-019-1433-4
• Publication Date: 2019-03-05T09:12:32Z
• Authors: Marc Durocher; Bradley P. Ander; Glen Jickling; Farah Hamade; Heather Hull; Bodie Knepp; Da Zhi Liu; Xinhua Zhan; Anh Tran; Xiyuan Cheng; Kwan Ng; Alan Yee; Frank R. Sharp; Boryana Stamova
• Keywords: Male; 0301 basic medicine; Cerebrovascular; NF-E2-Related Factor 2; 1.1 Normal biological development and functioning; Src kinase inhibitors; Immunology; Clinical Sciences; 610; Gene Expression; NRF2; 03 medical and health sciences; Clinical Research; Hematoma clearance; Genetics; Autophagy; 2.1 Biological and endogenous factors; Humans; Minority Health; Gene Regulatory Networks; RC346-429; Cerebral Hemorrhage; ICH; Hematoma; Neurology & Neurosurgery; Biomedical and Clinical Sciences; Co-expression networks; Research; Gene Expression Profiling; Human Genome; Gene networks; Neurosciences; Co-expression networks; Brain Disorders; 3. Good health; Stroke; Gene Expression Regulation; Case-Control Studies; Immune System; Cytokines; Female; Gene expression; Neurology. Diseases of the nervous system; Intracerebral hemorrhage; Transcriptome; Signal Transduction

Intracerebral 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.We 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.Of 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.This 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.