IL-27 blockade suppresses IL-10 modification in Th1 cells and promotes intracranial aneurysms rupture.

Intracranial aneurysms (IA) stability is regulated by helper T (Th)-cell homeostasis, but the role of IL-27, a key cytokine inducing regulatory T-cell phenotypes, remains unexplored. This study aimed to determine the role of IL-27 insufficiency in IA rupture and to elucidate the underlying immunopathological mechanisms. We integrated transcriptomic data from human IA tissues with an elastase-induced hypertensive mouse model. Findings were gained through IL-27 blockade in vivo, immunofluorescence staining, and in vitro co-culture systems involving bone marrow-derived macrophages (BMDMs) with IL-27 blockade, CD4+ T cells, and cerebrovascular endothelial system. IL-27 expression was markedly reduced in ruptured human and mouse IA tissues. In mice, IL-27 blockade increased the IA rupture rate, exacerbated vascular remodeling, and promoted endothelial injury. This was accompanied by a systemic inflammatory shift, with decreased IL-10 and increased IFN-γ levels, alongside localized expansion of T-bet+ Th1 cells and depletion of IL-10+ type 1 regulatory T (Tr1) cells in IA wall. Although CD68+ macrophages abundantly infiltrated IA lesions, their IL-27 production was impaired. In vitro IL-27 blockade in BMDMs promoted Th1 polarization, suppressed Tr1 differentiation, and rendered CD4+ T cells capable of inducing endothelial damage and soluble adhesion molecule release. IL-27 blockade promotes IA rupture by disrupting Th1/Tr1 balance, which may through impaired macrophage function, revealing a novel immunopathological mechanism and potential therapeutic target for IA management.