RAGE in neutrophils triggers cerebral vasospasm in the hyperacute phase after subarachnoid hemorrhage.

Abstract

Subarachnoid hemorrhage (SAH) due to the rupture of an intracranial aneurysm is a highly fatal type of stroke. Cerebral vasospasm (CVS) is a major post-SAH complication leading to delayed ischemic neurological deficits, thereby worsening patient outcomes. Previously, we found that lower plasma levels of the soluble receptor for advanced glycation end products (RAGE) predict symptomatic CVS in patients with SAH. However, the molecular mechanisms underlying CVS remain unclear. Here, using an SAH mouse model with endovascular perforation, we found that neurological deficits, CVS in the circle of Willis, and impaired cortical microarterial perfusion observed in wild-type (WT) mice after SAH were markedly ameliorated in RAGE-deficient mice. Neutrophils accumulated in the cerebral perivascular space as early as 3-6 h after SAH in WT mice but were profoundly reduced in RAGE-deficient mice. Myeloid lineage-targeted deletion of RAGE improved CVS after SAH. Inhibition of the high mobility group box 1 (HMGB1)/RAGE axis or neutrophil elastase ameliorated CVS. In a transwell assay, the HMGB1/RAGE axis drove neutrophil migration and NETosis. These findings indicate that neutrophil RAGE signaling contributes to cerebrovascular dysfunction after SAH and suggest that RAGE-mediated neutrophil inflammation may be a therapeutic target in the hyperacute phase to mitigate early brain injury.