Thymic stromal lymphopoietin promotes abdominal aortic aneurysm formation by regulating macrophage polarization.

Abstract

BACKGROUND: The inflammatory cytokine thymic stromal lymphopoietin (TSLP) has pleiotropic roles in immune response and tissue homeostasis, yet its function in abdominal aortic aneurysm (AAA) remains entirely unexplored. METHODS: We integrated clinical epidemiology,experimental models, andmechanistic assays. Using the UK Biobank (UKB), we analyzed serum TSLP levels in 632 AAA patients and 24,036 controls. Using two murine AAA models (porcine pancreatic elastase and calcium phosphate), function of TSLP was evaluated by genetic deletion of Tslp receptor (Tslpr), administration of a neutralizing anti-TSLP monoclonal antibody, and exogenous TSLP delivery. The immune landscape of aorta was profiled by mass cytometry (CyTOF). The effects of TSLP on macrophage polarization was assessed. Underlying mechanisms were probed by bulk RNA sequencing. RESULTS: AAA patients showed a markedly elevated serum TSLP. In murine models, TSLP was increased in the aortic tissues, primarily derived from fibroblasts. Genetic ablation of Tslpr and pharmacological neutralization of TSLP attenuated the severity of AAA, while exogenous TSLP exacerbated the disease. CyTOF analysis revealed that TSLP signaling skewed the aortic macrophage balance toward the pro-inflammatory M1 phenotype rather than the anti-inflammatory M2 phenotype., TSLP directly induced M1 while inhibited M2 macrophage polarization. Transcriptomics identified that TSLP upregulated pro-inflammatory pathways in macrophages, including positive regulation of cytokine production, regulation of immune effector process, cytokine-cytokine receptor interaction and chemokine signaling pathway. CONCLUSIONS: Our integrated multi-level analysis has identified TSLP as a novel pathogenic driver of AAA, which promotes disease progression by reprogramming macrophage polarization. These findings nominate TSLP signaling as a mechanistically grounded and therapeutically promising target for AAA.