2. Academic Validation
  3. A mast cell receptor mediates post-stroke brain inflammation via a dural-brain axis

A mast cell receptor mediates post-stroke brain inflammation via a dural-brain axis

  • Cell. 2025 Jul 24:S0092-8674(25)00747-0. doi: 10.1016/j.cell.2025.06.045.
Ruchita Kothari 1,  Mostafa W Abdulrahim 2,  Hyun Jong Oh 1,  Daniel H Capuzzi 1,  Collin B Kilgore 1,  Sumil K Nair 2,  Yaowu Zhang 2,  Nathachit Limjunyawong 1,  Sarbjit S Saini 3,  Jennifer E Kim 4,  Justin M Caplan 2,  Fernanado L Gonzalez 2,  Christopher M Jackson 2,  Chetan Bettegowda 2,  Judy Huang 2,  Bhanu P Ganesh 5,  Chunfeng Tan 5,  Raymond C Koehler 6,  Rafael J Tamargo 2,  Louise D McCullough 5,  Risheng Xu 7,  Xinzhong Dong 8
Affiliations

Affiliations

  • 1 The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 2 Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 3 Johns Hopkins Asthma and Allergy Center, Baltimore, MD 21224, USA.
  • 4 Department of Neurosurgery, The Ohio State University College of Medicine, Columbus, OH 43210, USA.
  • 5 Department of Neurology, The University of Texas Health Science Center Houston, McGovern Medical School, Houston, TX 77030, USA.
  • 6 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
  • 7 Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: rxu4@jhmi.edu.
  • 8 The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Dermatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: xdong2@jhmi.edu.
PMID: 40712576 DOI: 10.1016/j.cell.2025.06.045
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

Mrgpr receptor; inflammation; ischemic stroke; mast cell; meninges; semaphorin; skull bone marrow; substance P.

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