Tertiary Lymphoid Structures and CXCL13 as Targets in Intracranial Aneurysm.

Abstract

Intracranial aneurysms (IAs) are localized dilations of cerebral arteries that pose a significant threat of rupture, leading to fatal subarachnoid hemorrhage. The inflammation driven by immune cell infiltration is believed to be a key driver for the pathogenesis of IAs; however, the detailed immune cell landscape and spatial composition of immune cells remain unclear. In this study, we employed an integrated multi-omics approach using human IA tissues, including single‑cell RNA sequencing, spatial transcriptomics, microarray data, and multiplex immunofluorescence, to construct a comprehensive immune cell atlas of IAs, providing a systematic characterization of their immune composition and spatial architecture. Findings were further validated in a mouse model of IA. We identified, for the first time, tertiary lymphoid structures within the aneurysm wall and demonstrated that their presence strongly correlates with rupture. Furthermore, we observed a significant expansion of a specific T-cell subset, CXCL13⁺ T-follicular helper cells. These cells were critical for B-cell recruitment and the structural organization of the tertiary lymphoid structures. In the IA mouse model, CXCL13 neutralization effectively suppressed both aneurysm formation and rupture. Our finding establishes tertiary lymphoid structures and CXCL13⁺ T follicular helper cells as central elements in IA progression and highlight the CXCL13 signaling axis as a promising therapeutic target for preventing aneurysm advancement.