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

Marc Durocher, Bradley Ander, Glen Jickling, Farah Hamade, Heather Hull, Bodie Knepp, Da Liu, Xinhua Zhan, Anh Tran, Xiyuan Cheng, Kwan Ng, Alan Howe Yee, Frank R Sharp, Boryana Stamova

Research output: Contribution to journalArticle

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Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Article number56
JournalJournal of Neuroinflammation
Volume16
Issue number1
DOIs
StatePublished - Mar 5 2019

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Gene Regulatory Networks
Autophagy
Cerebral Hemorrhage
Genes
Neutrophils
Brain
Erythroblasts
Natural Killer Cells
Monocytes
Mitogen-Activated Protein Kinase 14
Overlapping Genes
T-Lymphocytes
T-Cell Receptor Genes
Peroxisome Proliferator-Activated Receptors
Interleukins
Alternative Splicing
Gene Expression Profiling
Post Translational Protein Processing
Transcriptome
Epigenomics

Keywords

  • Autophagy
  • Co-expression networks
  • Gene expression
  • Gene networks
  • Hematoma
  • Hematoma clearance
  • ICH
  • Intracerebral hemorrhage
  • NRF2
  • Src kinase inhibitors

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Inflammatory, regulatory, and autophagy co-expression modules and hub genes underlie the peripheral immune response to human intracerebral hemorrhage. / Durocher, Marc; Ander, Bradley; Jickling, Glen; Hamade, Farah; Hull, Heather; Knepp, Bodie; Liu, Da; Zhan, Xinhua; Tran, Anh; Cheng, Xiyuan; Ng, Kwan; Yee, Alan Howe; Sharp, Frank R; Stamova, Boryana.

In: Journal of Neuroinflammation, Vol. 16, No. 1, 56, 05.03.2019.

Research output: Contribution to journalArticle

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abstract = "Background: 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. Methods: 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. Results: 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. Conclusions: 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.",
keywords = "Autophagy, Co-expression networks, Gene expression, Gene networks, Hematoma, Hematoma clearance, ICH, Intracerebral hemorrhage, NRF2, Src kinase inhibitors",
author = "Marc Durocher and Bradley Ander and Glen Jickling and Farah Hamade and Heather Hull and Bodie Knepp and Da Liu and Xinhua Zhan and Anh Tran and Xiyuan Cheng and Kwan Ng and Yee, {Alan Howe} and Sharp, {Frank R} and Boryana Stamova",
year = "2019",
month = "3",
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volume = "16",
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TY - JOUR

T1 - Inflammatory, regulatory, and autophagy co-expression modules and hub genes underlie the peripheral immune response to human intracerebral hemorrhage

AU - Durocher, Marc

AU - Ander, Bradley

AU - Jickling, Glen

AU - Hamade, Farah

AU - Hull, Heather

AU - Knepp, Bodie

AU - Liu, Da

AU - Zhan, Xinhua

AU - Tran, Anh

AU - Cheng, Xiyuan

AU - Ng, Kwan

AU - Yee, Alan Howe

AU - Sharp, Frank R

AU - Stamova, Boryana

PY - 2019/3/5

Y1 - 2019/3/5

N2 - Background: 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. Methods: 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. Results: 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. Conclusions: 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.

AB - Background: 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. Methods: 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. Results: 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. Conclusions: 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.

KW - Autophagy

KW - Co-expression networks

KW - Gene expression

KW - Gene networks

KW - Hematoma

KW - Hematoma clearance

KW - ICH

KW - Intracerebral hemorrhage

KW - NRF2

KW - Src kinase inhibitors

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U2 - 10.1186/s12974-019-1433-4

DO - 10.1186/s12974-019-1433-4

M3 - Article

C2 - 30836997

AN - SCOPUS:85062521186

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JO - Journal of Neuroinflammation

JF - Journal of Neuroinflammation

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