Spatial transcriptome analysis defines heme as a hemopexin-targetable inflammatoxin in the brain

Area of Science:

• Neuroscience
• Molecular Biology
• Biochemistry

Background:

• Intracranial hemorrhage releases cell-free hemoglobin, leading to heme accumulation.
• Heme at the hematoma-brain interface may contribute to secondary brain injury.
• Understanding heme's molecular effects is crucial for developing therapeutic strategies.

Purpose of the Study:

• To map gene expression changes in the heme-exposed brain.
• To investigate the therapeutic potential of the heme-binding protein, hemopexin.

Main Methods:

• Stereotactic injection of saline, heme, or heme-hemopexin into mouse striatum.
• Spatial transcriptome sequencing of 21,760 tissue features.
• Assessment of blood-brain barrier integrity, edema, perfusion, and neurological function.

Main Results:

• Heme induced dose-dependent, proinflammatory gene expression changes in the brain.
• Heme triggered reactive astrocytosis and microglial activation.
• Hemopexin attenuated heme-induced molecular and cellular damage, preserving microglial homeostasis.
• Hemopexin prevented blood-brain barrier disruption and reduced radiological/functional signs of injury.

Conclusions:

• Heme acts as a potent inflammatoxin, driving secondary brain injury post-intracerebral hemorrhage.
• Hemopexin demonstrates significant therapeutic potential by mitigating heme's toxic effects.
• Hemopexin represents a promising translational strategy for treating intracerebral hemorrhage.