Longitudinal transcriptomics define the stages of myeloid activation in the living human brain after intracerebral hemorrhage
- 19 February 2021
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Immunology
- Vol. 6 (56)
- https://doi.org/10.1126/sciimmunol.abd6279
Abstract
Opportunities to interrogate the immune responses in the injured tissue of living patients suffering from acute sterile injuries such as stroke and heart attack are limited. We leveraged a clinical trial of minimally invasive neurosurgery for patients with intracerebral hemorrhage (ICH), a severely disabling subtype of stroke, to investigate the dynamics of inflammation at the site of brain injury over time. Longitudinal transcriptional profiling of CD14+ monocytes/macrophages and neutrophils from hematomas of patients with ICH revealed that the myeloid response to ICH within the hematoma is distinct from that in the blood and occurs in stages conserved across the patient cohort. Initially, hematoma myeloid cells expressed a robust anabolic proinflammatory profile characterized by activation of hypoxia-inducible factors (HIFs) and expression of genes encoding immune factors and glycolysis. Subsequently, inflammatory gene expression decreased over time, whereas anti-inflammatory circuits were maintained and phagocytic and antioxidative pathways up-regulated. During this transition to immune resolution, glycolysis gene expression and levels of the potent proresolution lipid mediator prostaglandin E2 remained elevated in the hematoma, and unexpectedly, these elevations correlated with positive patient outcomes. Ex vivo activation of human macrophages by ICH-associated stimuli highlighted an important role for HIFs in production of both inflammatory and anti-inflammatory factors, including PGE2, which, in turn, augmented VEGF production. Our findings define the time course of myeloid activation in the human brain after ICH, revealing a conserved progression of immune responses from proinflammatory to proresolution states in humans after brain injury and identifying transcriptional programs associated with neurological recovery.Keywords
Funding Information
- National Institutes of Health (UO1NS106513)
- National Institute of Allergy and Infectious Diseases (F32-AI136459)
- National Institute of Allergy and Infectious Diseases (5U24AI118672)
- National Institute of Neurological Disorders and Stroke (R01NS097728)
- National Institute of Neurological Disorders and Stroke (U01NS080824)
- National Institute of Neurological Disorders and Stroke
- Alfred P. Sloan Foundation
- American Heart Association (17POST33660872)
- Arnold and Mabel Beckman Foundation
- Searle Scholars Program
This publication has 76 references indexed in Scilit:
- Inflammatory monocytes regulate pathologic responses to commensals during acute gastrointestinal infectionNature Medicine, 2013
- Enrichr: interactive and collaborative HTML5 gene list enrichment analysis toolBMC Bioinformatics, 2013
- Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiationNature Immunology, 2013
- Activation of a Metabolic Gene Regulatory Network Downstream of mTOR Complex 1Molecular Cell, 2010
- The COX‐2 inhibitors, meloxicam and nimesulide, suppress neurogenesis in the adult mouse brainBritish Journal of Pharmacology, 2010
- A scaling normalization method for differential expression analysis of RNA-seq dataGenome Biology, 2010
- Vascular Endothelial Growth Factor Increases Neurogenesis after Traumatic Brain InjuryJournal of Cerebral Blood Flow & Metabolism, 2010
- Exploring the full spectrum of macrophage activationNature Reviews Immunology, 2008
- GenePattern 2.0Nature Genetics, 2006
- Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction NetworksGenome Research, 2003