A brain-to-bone marrow circuit drives neutrophil mobilization and exacerbates ischaemic brain injury

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ID: 328224
2026
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Abstract
Ischaemic stroke triggers a detrimental inflammatory response, characterised by neutrophil mobilisation from the bone marrow to the injured brain. The neural circuits driving this response are poorly understood. Here we identify a brain-to-bone marrow axis that governs this process. We used transient middle cerebral artery occlusion, magnetic resonance imaging, neurological behavioural assessments and infarct volume analysis to establish and evaluate ischaemic brain injury. In addition, viral tracing, optogenetic and chemogenetic manipulation, chemical and surgical interruption of sympathetic signalling, flow cytometry, enzyme-linked immunosorbent assay, liquid chromatography-tandem mass spectrometry, immunofluorescence staining and neutrophil depletion were used to anatomically and functionally elucidate the brain-to-bone marrow axis that regulates neutrophil mobilisation. Peripheral blood samples from patients with acute ischaemic stroke were collected and examined to explore the clinical relevance of this pathway. Stroke activates excitatory neurons in the insular cortex, which project to and engage corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus, driving systemic sympathetic output. This leads to norepinephrine release in the bone marrow, triggering neutrophil mobilisation through a β2-adrenergic receptor-dependent mechanism. Crucially, selective inhibition of this insular cortex-paraventricular nucleus pathway or peripheral sympathetic blockade suppresses neutrophil mobilisation and confers neuroprotection. Consistent with this mechanism, stroke patients with insular cortex lesions exhibit significantly higher peripheral neutrophil counts than those without such lesions, reinforcing the clinical significance of this circuit. Our results define a precise circuit through which the brain translates a local ischaemic event into a harmful systemic immune response, revealing novel therapeutic targets.
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Authors Shenghan Gao, Shiji Deng, Huiya Li, Qi Li, Chao Zhou, Xiang Cao, Siyuan Zhang, Shengnan Xia, Haiyan Yang, Pinyi Liu, Yun Xu
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Journal Brain research
Year 2026
DOI
10.1093/brain/awag307
URL
https://doi.org/10.1093/brain/awag307
Keywords Keywords not found

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