Molecular Correlates of Hemorrhage and Edema Volumes Following Human Intracerebral Hemorrhage Implicate Inflammation, Autophagy, mRNA Splicing, and T Cell Receptor Signaling

Marc Durocher,Hajar Amini,Eva Ferino,Bodie Knepp,Glen Jickling,Xinhua Zhan,Farah Hamade,Frank R Sharp,Fernando Rodriguez,Paulina Carmona-Mora,Boryana Stamova,Heather Hull,Bradley P Ander,Kwan Ng,Alan Yee

doi:10.1007/s12975-020-00869-y

Marc Durocher, Hajar Amini + Show 13 more

Open Access

https://doi.org/10.1007/s12975-020-00869-y

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Abstract

Intracerebral hemorrhage (ICH) and perihematomal edema (PHE) volumes are major determinants of ICH outcomes as is the immune system which plays a significant role in damage and repair. Thus, we performed whole-transcriptome analyses of 18 ICH patients to delineate peripheral blood genes and networks associated with ICH volume, absolute perihematomal edema (aPHE) volume, and relative PHE (aPHE/ICH; rPHE). We found 440, 266, and 391 genes correlated with ICH and aPHE volumes and rPHE, respectively (p < 0.005, partial-correlation > |0.6|). These mainly represented inflammatory pathways including NF-κB, TREM1, and Neuroinflammation Signaling—most activated with larger volumes. Weighted Gene Co-Expression Network Analysis identified seven modules significantly correlated with these measures (p < 0.05). Most modules were enriched in neutrophil, monocyte, erythroblast, and/or T cell-specific genes. Autophagy, apoptosis, HIF-1α, inflammatory and neuroinflammatory response (including Toll-like receptors), cell adhesion (including MMP9), platelet activation, T cell receptor signaling, and mRNA splicing were represented in these modules (FDR p < 0.05). Module hub genes, potential master regulators, were enriched in neutrophil-specific genes in three modules. Hub genes included NCF2, NCF4, STX3, and CSF3R, and involved immune response, autophagy, and neutrophil chemotaxis. One module that correlated negatively with ICH volume correlated positively with rPHE. Its genes and hubs were enriched in T cell-specific genes including hubs LCK and ITK, Src family tyrosine kinases whose modulation improved outcomes and reduced BBB dysfunction following experimental ICH. This study uncovers molecular underpinnings associated with ICH and PHE volumes and pathophysiology in human ICH, where knowledge is scarce. The identified pathways and hub genes may represent novel therapeutic targets.

Highlights

Intracerebral hemorrhage (ICH) accounts for 10–15% of all strokes, and has high morbidity and mortality [1,2,3,4]
We investigated the peripheral whole blood transcriptome to identify genes, coexpressed gene modules, and their hubs which correlate with ICH volume, absolute Perihematomal edema (PHE) volume, and relative PHE
Peripheral venous blood was collected from ICH subjects and RNA isolated and prepared for hybridization on GeneChip® Human Transcriptome Array (HTA) 2.0 as previously described [15]

Summary

Introduction

Intracerebral hemorrhage (ICH) accounts for 10–15% of all strokes, and has high morbidity and mortality [1,2,3,4]. The hematoma causes mechanical brain injury [3] and disrupts the blood–brain barrier (BBB), resulting in edema formation and leukocyte extravasation from peripheral blood into damaged tissues [5, 6]. Perihematomal edema (PHE) results from transcapillary efflux of electrolytes and water from blood vessels. (2021) 12:754–777 with neuronal energy failure result in a combination of vasogenic (BBB disruption) and cytotoxic edema (cell death) [7]. The inflammatory response, thrombin activation, coagulation factors, erythrocyte lysis, and various cytotoxic molecules contribute to PHE [7]

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