Neutrophil RAGE drives early cerebrovascular injury after subarachnoid hemorrhage
· Medical Xpressedited by Sadie Harley, reviewed by Andrew Zinin
Sadie Harley
Scientific Editor
Meet our editorial team
Behind our editorial process
Andrew Zinin
Chief Editor
Meet our editorial team
Behind our editorial process Editors' notes
This article has been reviewed according to Science X's editorial process and policies. Editors have highlighted the following attributes while ensuring the content's credibility:
fact-checked
peer-reviewed publication
trusted source
proofread
The GIST Add to Preferred Sources
An international research team from Japan and the United States, led by Assistant Professor Hiroshi Ishii and Professor Osamu Hori, together with Professors Yasuhiko Yamamoto and Mitsutoshi Nakada of Kanazawa University, has identified neutrophil RAGE (receptor for advanced glycation end products) as a key driver of early cerebrovascular injury after subarachnoid hemorrhage (SAH).
The study, published in the Journal of Cerebral Blood Flow & Metabolism, shows that neutrophil RAGE promotes neutrophil accumulation around cerebral arteries, cerebral vasospasm, impaired cortical circulation and neurological dysfunction.
SAH is a severe form of stroke most often caused by rupture of a cerebral aneurysm. Even after the bleeding source is secured, reductions in cerebral blood flow, vasospasm, inflammation and brain edema can continue to worsen neurological outcome. The mechanisms linking these early events to later brain injury, however, remain incompletely understood.
In 2023, the group reported in Stroke that sympathetic hyperactivity immediately after SAH impairs cerebral circulation and worsens neurological outcome. The new study extends this work by identifying a subsequent inflammatory cerebrovascular phase driven by neutrophil RAGE.
Key findings
In wild-type mice, SAH caused neurological deterioration, marked vasospasm of major cerebral arteries and a substantial loss of cortical vascular perfusion. In RAGE-knockout mice, neurological function and cortical perfusion were markedly improved, while vasospasm was reduced.
The researchers also found that MPO-positive neutrophils accumulated around cerebral arteries early after SAH, with a prominent increase by six hours. This perivascular neutrophil accumulation was strongly suppressed in RAGE-knockout mice. Analyses using bone marrow–derived cells and myeloid-cell-specific RAGE deletion further supported a central role for neutrophil RAGE in the development of cerebrovascular injury.
Mechanistically, damage-associated molecular patterns (DAMPs), including HMGB1 released from the hematoma and injured tissue, activated RAGE-dependent inflammatory responses in neutrophils and promoted their migration. Pharmacological suppression of RAGE signaling or neutrophil-derived inflammatory responses also improved vasospasm and neurological deficits.
"Subarachnoid hemorrhage is not a single event that ends when the bleeding is controlled," said Ishii, the corresponding author. "Our studies suggest that an immediate sympathetic vascular response is followed by a neutrophil RAGE-dependent inflammatory phase. Understanding how these responses evolve in space and time may help us identify earlier, mechanism-based therapeutic strategies for SAH."
A time-dependent sequence of brain injury
Taken together with the group's 2023 findings, the results support a time-dependent pathophysiological sequence after SAH: an immediate sympathetic response with alpha1 receptor-mediated cerebral arterial constriction and circulatory impairment, followed during the hyperacute-to-acute phase by neutrophil RAGE-dependent inflammatory cerebrovascular injury. How the sympathetic response and the neutrophil RAGE response interact mechanistically remains to be determined.
Current SAH treatment focuses on preventing rebleeding and limiting downstream complications such as cerebral vasospasm and impaired cerebral blood flow. The present study identifies neutrophil RAGE as an upstream pathological mechanism that may provide a new point of therapeutic intervention.
Future work will examine how neural, vascular and immune responses evolve spatially and temporally after SAH and how they collectively lead to brain injury.
Publication details
Hiroshi Ishii et al., RAGE in neutrophils triggers cerebral vasospasm in the hyperacute phase after subarachnoid hemorrhage, Journal of Cerebral Blood Flow & Metabolism (2026). DOI: 10.1177/0271678x261454113
Journal information: Stroke
Key medical concepts
Clinical categories
Neurology Provided by Kanazawa University Who's behind this story?
Sadie Harley
BSc Life Sciences & Ecology. Microbiology lab background with pharmaceutical news experience in oil, gas, and renewable industries. Full profile →
Andrew Zinin
Master's in physics with research experience. Long-time science news enthusiast. Plays key role in Science X's editorial success. Full profile →
Citation: Neutrophil RAGE drives early cerebrovascular injury after subarachnoid hemorrhage (2026, October 31) retrieved 31 October 2026 from https://medicalxpress.com/news/2026-10-neutrophil-rage-early-cerebrovascular-injury.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.