A mast cell receptor mediates post-stroke brain inflammation via a dural-brain axis
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.
Authors
- Raymond C. Koehler (ORCID: https://orcid.org/0000-0002-5890-9992)
- Risheng Xu (ORCID: https://orcid.org/0000-0003-4288-1232)
- Bhanu Priya Ganesh (ORCID: https://orcid.org/0000-0003-1575-7914)
- Rafael J. Tamargo (ORCID: https://orcid.org/0000-0003-0923-1625)
- Mostafa Abdulrahim (ORCID: https://orcid.org/0009-0009-8631-0213)
- Sumil K. Nair (ORCID: https://orcid.org/0000-0002-9937-7478)
- Christopher M. Jackson (ORCID: https://orcid.org/0000-0002-5958-2004)
- Justin M. Caplan (ORCID: https://orcid.org/0000-0002-0289-3661)
- Jennifer E. Kim
- Judy Huang (ORCID: https://orcid.org/0000-0002-0675-1935)
- Louise D. McCullough (ORCID: https://orcid.org/0000-0002-8050-1686)
- Ruchita Kothari (ORCID: https://orcid.org/0000-0002-9575-6200)
- Xinzhong Dong (ORCID: https://orcid.org/0000-0002-9750-7718)
- Francisco Gabriel Salgado-González
- Sarbjit S. Saini (ORCID: https://orcid.org/0000-0001-8522-2742)
- Chunfeng Tan (ORCID: https://orcid.org/0000-0001-7083-1529)
- Chetan Bettegowda (ORCID: https://orcid.org/0000-0001-9991-7123)
- David M. Capuzzi
- Collin Kilgore (ORCID: https://orcid.org/0000-0002-7679-9969)
- Nathachit Limjunyawong (ORCID: https://orcid.org/0000-0002-9540-6171)
- Yaowu Zhang
- Hyun Jong Oh
Institutions
- Johns Hopkins University (US)
- Johns Hopkins Medicine (US)
- The University of Texas Health Science Center (US)
- The Ohio State University (US)
Publication Details
- Journal
- Cell
- Published
- 2025-07-24
- DOI
- https://doi.org/10.1016/j.cell.2025.06.045
- Citations
- 11
- Primary Topic
- Mast cells and histamine
- Type
- article
- Field-Weighted Citation Impact
- 8.77
Funders
- Howard Hughes Medical Institute
- American Heart Association
- National Institute of Neurological Disorders and Stroke