NLRP3 inflammasome inhibition protects against intracranial aneurysm rupture and alters the phenotype of infiltrating macrophages.

Background: Aneurysmal subarachnoid hemorrhage is a devastating cerebrovascular disease associated with high morbidity and mortality. Macrophage-mediated mural inflammation is a key pathogenic component contributing to aneurysm rupture.

Objective: To investigate the effect of pharmacological inhibition of the NLRP3 inflammasome on aneurysm rupture.

Methods: Cerebral aneurysms were induced in C57BL/6 mice with a combination of hypertension and an intracranial dose of elastase. Mice were treated with either 40 mg/kg of MCC950 or saline via intraperitoneal injections. Vascular tissue at the circle of Willis was harvested for analysis via immunofluorescent microscopy or qPCR.

Results: NLRP3⁺ cells are more common in the aneurysm tissue compared to the normal cerebral vasculature. The mRNA expression of the downstream NLRP3 pathway components caspase-1, IL-1β, and GSDMD is also increased in the aneurysm tissue compared to healthy vessels. There was no difference in the aneurysm formation rate between MCC950- and vehicle-treated mice; however, MCC950 treatment significantly reduced aneurysm rupture rate. There was no difference in systemic blood pressure between both groups. MCC950 treatment also extended the symptom-free survival of mice after aneurysm induction. Mechanistically, NLRP3 inhibition decreased the phenotype polarization of infiltrating macrophages without affecting the total number of macrophages in the vessel wall.

Conclusions: Our results indicate that the NLRP3 inflammasome contributes to aneurysm rupture and macrophage polarization within the vessel wall. The NLRP3 pathway is a promising therapeutic target for the development of therapeutics to prevent aneurysmal hemorrhagic stroke.