Longitudinal transcriptomics define the stages of myeloid activation in the living human brain after intracerebral hemorrhage

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Science Immunology  19 Feb 2021:
Vol. 6, Issue 56, eabd6279
DOI: 10.1126/sciimmunol.abd6279

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Time lapse of reparative myeloid cells

Myeloid cells can contribute to inflammation-associated tissue damage to the brain after stroke but can also facilitate repair by clearing debris and promoting tissue remodeling. Askenase et al. examined the dynamics of human myeloid cell transcriptomes in patients with intracerebral hemorrhage using RNA sequencing of neutrophils and monocytes/macrophages collected longitudinally from peripheral blood and hematomas. The acute response was characterized by elevated expression of genes associated with glycolysis, hypoxia response, and prostaglandin E2 synthesis in hematoma myeloid cells, and patients with superior neurological recovery displayed sustained engagement of these pathways. This resource provides insight into temporal regulation of transcriptional states in human myeloid cells after brain injury, highlighting glucose metabolism and lipid synthesis pathways in the reprogramming that occurs during the early stages of repair.


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.

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