Skull Neutrophils after SAH

/Abstract Up to 30% of patients surviving aneurysmal subarachnoid hemorrhage (SAH) develop delayed neurological decline (DND) 4-10 days post-SAH which is a leading cause of morbidity and mortality. Recent clinical studies indicate that the cause of DND includes inflammation and microvessel occlusion. Neutrophils correlate with DND in humans with SAH. Experimentally, neutrophils are a therapeutic target, as depleting neutrophils in mice with SAH reduces microvascular injury and vasospasm, improves cerebral blood flow, attenuates blood-brain barrier disruption, and prevents DND. Experimentally, neutrophils are reported to cause microvessel occlusion, less cerebral blood flow, and be a factor linked to DND. Recently it has been described that skull bone marrow is a region that creates neutrophils, is a reservoir for neutrophils, and preferentially releases neutrophils in response to brain injury. Moreover, skull neutrophils are hyper-responsive to ischemic stroke, so skull neutrophils may also respond more/faster to SAH than peripheral neutrophils. Even though skull neutrophils respond more to brain injury, the reason why they preferentially respond is unknown. This gap in knowledge will be addressed by the experiments proposed in Aim 1. In rodents with SAH, it is reported that neutrophils are a therapeutic target, since depleting neutrophils in mice with SAH reduces microvascular injury and vasospasm, improves cerebral blood flow, attenuates blood-brain barrier disruption, and prevents DND. However, whole-body depletion of neutrophils is not clinically reasonable in humans as blood-borne PMNs are critical for preventing in-hospital infection. But, depleting neutrophils from another site, such as the skull bone marrow, may be a more relevant option. Thus, there is a critical gap in knowledge as to whether peripheral or skull neutrophils are the therapeutic target for SAH/brain injury. This gap in knowledge will be addressed by the experiments proposed in Aim 2. The long-term goals are to clarify the roles of the skull and peripheral neutrophils in response to brain injury, and to investigate the therapeutic potential of targeting skull versus peripheral neutrophils. Project Number: 1R21NS142863-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Devin McBride | Institution: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON, HOUSTON, TX | Award Amount: $429,000 | Activity Code: R21 | Study Section: Brain Injury and Neurovascular Pathologies Study Section[BINP] View on NIH RePORTER: https://reporter.nih.gov/project-details/11305039