Abstract
After intracranial hemorrhage, heme is released from cell-free hemoglobin. This red blood cell component may drive secondary brain injury at the hematoma‒brain interface. This study aimed to generate a spatially resolved map of transcriptome-wide gene expression changes in the heme-exposed brain and to define the potential therapeutic activity of the heme-binding protein, hemopexin.We stereotactically injected saline, heme, or heme‒hemopexin into the striatum of C57BL/6J mice. After 24 h, we elucidated the two-dimensional spatial transcriptome by sequencing 21760 tissue-covered features, at a mean transcript coverage of 3849 genes per feature. In parallel, we studied the extravasation of systemically administered fluorescein isothiocyanate labeled (FITC)-dextran, magnetic resonance imaging features indicative of focal edema and perfusion, and neurological functions as translational correlates of heme toxicity.We defined a cerebral heme-response signature by performing bidimensional differential gene expression analysis, based on unsupervised clustering and manual segmentation of sequenced features. Heme exerted a consistent and dose-dependent proinflammatory activity in the brain, which occurred at minimal exposures, below the toxicity threshold for the induction of vascular leakage. We found dose-dependent regional divergence of proinflammatory heme signaling pathways, consistent with reactive astrocytosis and microglial activation. Co-injection of heme with hemopexin attenuated heme-induced gene expression changes and preserved the homeostatic microglia signature. Hemopexin also prevented heme-induced disruption of the blood‒brain barrier and radiological and functional signals of heme injury in the brain.In conclusion, we defined heme as a potent inflammatoxin that may drive secondary brain injury after intracerebral hemorrhage. Co-administration of hemopexin attenuated the heme-derived toxic effects on a molecular, cellular, and functional level, suggesting a translational therapeutic strategy.
Highlights
Intracerebral hemorrhage (ICH) accounts for 15%–20% of all strokes [1,2,3]
We studied the extravasation of systemically administered fluorescein isothiocyanate labeled (FITC)-dextran, magnetic resonance imaging features indicative of focal edema and perfusion, and neurological functions as translational correlates of heme toxicity
The acute mass effect of bleeding causes immediate brain damage, but functional outcomes are determined by secondary brain injuries (ICH-SBI) that evolve within days to a few weeks after ICH, often resulting in neurological deterioration [6]
Summary
Intracerebral hemorrhage (ICH) accounts for 15%–20% of all strokes [1,2,3]. A hallmark of ICH-SBI is the peri-hemorrhagic edema, which correlates with clinical outcomes [7]. Cell-free hemoglobin oxidizes to ferric (Fe3+) hemoglobin. Besides being a major source of superoxide generation in vivo [14], this one electron shift reaction is weakening the non-covalent bond between globin and iron‒ protoporphyrin [15]. This oxidative modification initiates a Please cite this article as: Raphael M.
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