THBS1high macrophages promote aortic aneurysm formation by orchestrating an inflammatory and smooth muscle cell phenotypic transition program in vascular Behçet's disease.

BACKGROUND: Vascular Behçet's disease (VBD), a representative autoimmune inflammatory disorder, is a leading cause of mortality in BD, primarily due to the formation of inflamed aneurysms. However, both the histopathological features and the underlying mechanism of VBD remain elusive. Identifying specific VBD-associated cell populations and unravel their participation within the aorta microenvironment is crucial for deciphering the pathogenesis of VBD. METHODS: We conducted immunohistochemistry and single-cell RNA sequencing to comprehensively characterize the ascending aorta in VBD patients. Immunofluorescence staining, bulk RNA sequencing, and functional co-culture system were employed to investigate the phenotypic characteristics of pathological subsets and potential cell-cell interactions. A CaCl2-induced humanized VBD model was established to validate the transcriptomic and cellular results. RESULTS: We identified an expansion of THBS1high macrophages in VBD, particular in active VBD. These THBS1high macrophages exhibited a proinflammatory profile and promoted the phenotypic transition of smooth muscle cells. Mechanistically, transcription factor ETS2 mediated the proinflammatory development of this macrophage subset, while tumor necrosis factor-α (TNF-α) upregulated THBS1 expression in macrophages. The adoptive transfer of THBS1high macrophages exacerbated vascular inflammation and aneurysm formation in CaCl2-induced humanized VBD mice, which could be mitigated by TNF inhibitor. Clinically, plasma THBS1 levels were positively correlated with disease activity and inversely associated with the clinical benefits of TNF inhibitor, both observed at the systemic level. CONCLUSIONS: Overall, our findings underscore the pivotal role of THBS1high macrophages in vascular degeneration, highlighting the therapeutic potential of anti-TNF therapy in VBD and the THBS1's potential as a biomarker for clinical evaluation.