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.
HIGHLIGHTS
• Mrgprb2/MRGPRX2 is a key receptor that activates meningeal mast cells after stroke
• Mrgprb2 regulates skull bone marrow neutrophil recruitment into the brain post-stroke
• Mast cell proteases cleave semaphorin, mediating neutrophil infiltration into the brain
• Inhibiting Mrgprb2 alleviates post-stroke brain inflammation and improves survival
Web | PDF | Cell | Open Access
Ruchita Kothari; Mostafa W. Abdulrahim; Hyun Jong Oh; Daniel H. Capuzzi; Collin B. Kilgore; Sumil K. Nair; Yaowu Zhang; Nathachit Limjunyawong; Sarbjit S. Saini; Jennifer E. Kim; Justin M. Caplan; Fernanado L. Gonzalez; Christopher M. Jackson; Chetan Bettegowda; Judy Huang; Bhanu P. Ganesh; Chunfeng Tan; Raymond C. Koehler; Rafael J. Tamargo; Louise D. McCullough; Risheng Xu; Xinzhong Dong
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.
HIGHLIGHTS
• Mrgprb2/MRGPRX2 is a key receptor that activates meningeal mast cells after stroke
• Mrgprb2 regulates skull bone marrow neutrophil recruitment into the brain post-stroke
• Mast cell proteases cleave semaphorin, mediating neutrophil infiltration into the brain
• Inhibiting Mrgprb2 alleviates post-stroke brain inflammation and improves survival
Web | PDF | Cell | Open Access
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