IL-27 blockade promotes intracranial aneurysm rupture by disrupting Th1/Tr1 balance through impaired macrophage function, revealing a novel immunopathological mechanism and potential therapeutic target for IA management.
IL-27 expression was markedly reduced in ruptured human and mouse intracranial aneurysm tissues.
IL-27 blockade in mice increased the IA rupture rate and exacerbated vascular remodeling.
IL-27 blockade was associated with a systemic inflammatory shift characterized by decreased IL-10 and increased IFN-γ levels.
IL-27 blockade led to localized expansion of T-bet+ Th1 cells and depletion of IL-10+ type 1 regulatory T (Tr1) cells in the IA wall.
CD68+ macrophages abundantly infiltrated IA lesions but exhibited impaired IL-27 production.
In vitro IL-27 blockade in bone marrow-derived macrophages (BMDMs) promoted Th1 polarization and suppressed Tr1 differentiation.
CD4+ T cells conditioned under IL-27 blockade conditions were capable of inducing endothelial damage and soluble adhesion molecule release.
This research suggests that a protein called IL-27, produced by immune cells in the walls of brain aneurysms, plays a critical protective role in keeping aneurysms stable. The researchers found that IL-27 levels were significantly lower in ruptured aneurysms compared to unruptured ones, both in human tissue samples and in a mouse model of the disease. When they experimentally blocked IL-27 in mice, the aneurysms were much more likely to rupture, and the blood vessel walls showed more damage and inflammation. The study also suggests a specific immune mechanism behind this effect. Normally, IL-27 helps maintain a balance between two types of immune cells: pro-inflammatory Th1 cells and anti-inflammatory regulatory Tr1 cells that produce a calming molecule called IL-10. When IL-27 was blocked, this balance shifted dramatically toward inflammation—more Th1 cells accumulated in the aneurysm wall, Tr1 cells disappeared, and levels of the inflammatory molecule IFN-γ rose while IL-10 fell. The researchers traced the source of the problem to macrophages (immune cells that had infiltrated the aneurysm wall in large numbers) that had lost their ability to produce IL-27 properly. Laboratory experiments confirmed that blocking IL-27 in macrophages caused T cells to become more inflammatory and capable of directly damaging blood vessel lining cells. This research suggests that the immune environment inside an aneurysm wall—specifically the IL-27/macrophage/T-cell axis—plays an important role in determining whether an aneurysm stays stable or ruptures. IL-27 or the pathways it controls could represent new targets for treatments aimed at reducing the risk of aneurysm rupture without surgery, which remains a significant clinical challenge.
Zeng X, Zang F, Bu G, Yang Y, Fan H, Qiu R, et al.. (2026). IL-27 blockade suppresses IL-10 modification in Th1 cells and promotes intracranial aneurysms rupture.. Biochemical and biophysical research communications. https://doi.org/10.1016/j.bbrc.2026.154004