C-C Chemokine Receptor 4 Deficiency Protects Against Abdominal Aortic Aneurysm Formation.

Abstract

BACKGROUND: The dysregulated immune system, which drives chronic vascular inflammation and remodeling, plays a critical role in the pathogenesis of abdominal aortic aneurysm (AAA). CCR4 (C-C chemokine receptor 4), which is predominantly expressed on T cells and mediates their responses, has been shown to protect against inflammatory diseases including atherosclerosis. However, its role in AAA remains unknown. METHODS: By analyzing hypercholesterolemic CCR4-deficient () mice on an apolipoprotein E-deficient () background, we investigated the role of CCR4 in the development of angiotensin II-induced AAA, with a particular focus on T-cell-mediated immune responses, by performing histological analysis, flow cytometry, biochemical assays, and single-cell RNA sequencing analysis. RESULTS: Genetic deletion of CCR4 on anbackground dramatically reduced the incidence and severity of angiotensin II-induced AAA without affecting mortality due to rupture, along with attenuated inflammatory cell recruitment and preserved elastic lamellae in the aorta. This protective effect was associated with a shift in the T helper cell balance toward T helper type 1 predominance, characterized by promoted IFN-γ (interferon-gamma) production and suppressed B-cell-mediated IgE production. Single-cell RNA sequencing analysis of abdominal aortic tissues revealed lower proportions of myofibroblasts and modulated smooth muscle cells highly expressing genes associated with extracellular matrix remodeling in angiotensin II-infusedmice, potentially driven by downregulated TGF-β (transforming growth factor-beta) signaling due to increased T helper type 1 cell-derived IFN-γ. CONCLUSIONS: CCR4 may serve as a potential therapeutic target for AAA.