Faculty, Staff and Student Publications

Language

English

Publication Date

10-2-2025

Journal

Cell

DOI

10.1016/j.cell.2025.06.045

PMID

40712576

PMCID

PMC12313293

PubMedCentral® Posted Date

7-31-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

The immune environment surrounding the brain plays a fundamental role in monitoring signs of injury. Insults, including ischemic stroke, can disrupt this balance and incite an exaggerated inflammatory response, yet the underlying mechanism remains unclear. Here, we show that the mast-cell-specific receptor Mrgprb2 regulates post-stroke brain inflammation from the meninges. Mrgprb2 causes meningeal mast cell degranulation after stroke, releasing immune mediators. This process recruits skull bone marrow neutrophils into the dura and further promotes neutrophil migration from the dura into the brain by cleaving the chemorepellent semaphorin 3a. We demonstrate that the human ortholog, MRGPRX2, is expressed in human meningeal mast cells and is activated by upregulation of the neuropeptide substance P following stroke. Pharmacologically inhibiting Mrgprb2 reduces post-stroke inflammation and improves neurological outcomes in mice, providing a druggable target. Collectively, our study identifies Mrgprb2 as a critical meningeal gatekeeper for immune migration from skull bone marrow reservoirs into the brain.

Keywords

Animals, Mast Cells, Mice, Humans, Stroke, Brain, Mice, Inbred C57BL, Receptors, G-Protein-Coupled, Male, Dura Mater, Meninges, Neutrophils, Inflammation, Receptors, Neuropeptide, Substance P, Cell Movement, Cell Degranulation, Female, Neuroinflammatory Diseases

Published Open-Access

yes

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