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 ( Ccr4 −/− ) mice on an apolipoprotein E‐deficient ( Apoe −/− ) 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 an Apoe −/− background 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‐infused Ccr4 −/− Apoe −/− mice, 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.
Krisnanda et al. (Wed,) studied this question.