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

Area of Science:

• Immunology
• Vascular Biology
• Genetics

Background:

• Abdominal aortic aneurysm (AAA) pathogenesis involves immune system dysregulation, chronic vascular inflammation, and remodeling.
• C-C chemokine receptor 4 (CCR4) is expressed on T cells and protects against inflammatory diseases like atherosclerosis, but its role in AAA is unknown.

Purpose of the Study:

• To investigate the role of CCR4 in the development of angiotensin II-induced AAA.
• To analyze the impact of CCR4 deficiency on T-cell-mediated immune responses in AAA development.

Main Methods:

• Utilized hypercholesterolemic CCR4-deficient (Ccr4-/-) mice on an apolipoprotein E-deficient (Apoe-/-) background.
• Administered angiotensin II to induce AAA and analyzed outcomes using histological analysis, flow cytometry, biochemical assays, and single-cell RNA sequencing.

Main Results:

• Genetic deletion of CCR4 significantly reduced AAA incidence and severity, with attenuated inflammatory cell recruitment and preserved aortic elastic lamellae.
• CCR4 deficiency shifted T helper cell balance toward T helper type 1 predominance, increasing IFN-γ production and decreasing B-cell IgE production.
• Single-cell RNA sequencing revealed reduced myofibroblasts and modulated smooth muscle cells in Ccr4-/- Apoe-/- mice, potentially due to downregulated TGF-β signaling.

Conclusions:

• CCR4 deficiency confers protection against AAA development.
• CCR4 influences T-cell balance, cytokine production, and extracellular matrix remodeling in AAA.
• CCR4 represents a potential therapeutic target for abdominal aortic aneurysm.