A mast cell receptor mediates post-stroke brain inflammation via a dural-brain axis
Our research identified the mast cell receptor Mrgprb2 (and its human equivalent MRGPRX2) as a critical driver of harmful brain inflammation after stroke. We discovered that following a stroke, the injured brain releases substance P, which activates Mrgprb2 on mast cells in the meninges. This triggers a cascade: these mast cells recruit neutrophils from the skull bone marrow and then cleave the “gatekeeper” protein semaphorin 3a, allowing those immune cells to invade the brain and worsen damage. We confirmed that human meningeal mast cells express MRGPRX2 and are activated by substance P in stroke patients. Crucially, we showed that blocking this receptor with a drug (osthole) reduced brain inflammation, decreased stroke size, and improved recovery and survival in mice, identifying Mrgprb2/X2 as a promising therapeutic target for stroke.
Spatial and Temporal Assessment of Cerebral Blood Flow in a Novel Piglet Model of Neonatal Arterial Ischemic Stroke
We developed a new piglet model of neonatal arterial ischemic stroke (NAIS) that closely mimics the human condition by temporarily blocking the middle cerebral artery with a clip. Using laser speckle contrast imaging, we tracked real-time blood flow changes and found a rapid compensatory increase in flow to the stroke core within 10 minutes, along with a 38% reduction in core size. The stroke piglets developed consistent motor deficits and showed substantial, reproducible brain infarcts (averaging 31.6% of the hemisphere) at 48 hours. This model provides a clinically relevant platform with long-term survival potential, offering valuable insights into blood flow dynamics during neonatal stroke and a robust tool for testing new therapies.
