Journal Article

C-C chemokine receptor 4 deficiency exacerbates early atherosclerosis in mice

Tanaka, Toru, Ito, Ken, Rikitake, Yoshiyuki, Horibe, Sayo, Hirata, Ken-ichi, Krisnanda, Aga, Nakayama, Takashi, Matsuo, Kazuhiko, Amin, Hilman Zulkifli, Sasaki, Naoto

2025

Overview

Chronic inflammation via dysregulation of T cell immune responses is critically involved in the pathogenesis of atherosclerotic cardiovascular disease. Improving the balance between proinflammatory T cells and anti-inflammatory regulatory T cells (Tregs) may be an attractive approach for treating atherosclerosis. Although C-C chemokine receptor 4 (CCR4) has been shown to mediate the recruitment of T cells to inflamed tissues, its role in atherosclerosis is unclear. Here, we show that genetic deletion of CCR4 in hypercholesterolemic mice accelerates the development of early atherosclerotic lesions characterized by an inflammatory plaque phenotype. This was associated with the augmentation of proinflammatory T helper type 1 (Th1) cell responses in peripheral lymphoid tissues, para-aortic lymph nodes, and atherosclerotic aorta. Mechanistically, CCR4 deficiency in Tregs impaired their suppressive function and tended to inhibit their migration to the atherosclerotic aorta, and subsequently augmented Th1 cell-mediated immune responses through defective regulation of dendritic cell function, which accelerated aortic inflammation and atherosclerotic lesion development. Thus, we revealed a previously unrecognized role for CCR4 in controlling the early stage of atherosclerosis via Treg-dependent regulation of proinflammatory T cell responses. Our data suggest that CCR4 is an important negative regulator of atherosclerosis.

• Publisher: eLife Science Publications, Ltd,eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Animals / Aorta / Aorta - pathology / Apolipoproteins / Arteriosclerosis / Atherosclerosis / Atherosclerosis - genetics / Atherosclerosis - immunology / Atherosclerosis - pathology / B cells / Cardiovascular disease / Cardiovascular diseases / Cells / chemokine receptor / Chemokine receptors / Chemokines / Cholesterol / Coronary vessels / Cytokines / Dendritic cells / Dendritic Cells - immunology / Disease Models, Animal / Hypercholesterolemia / Immune response / Immune response (cell-mediated) / Immunohistochemistry / Immunology and Inflammation / Immunoregulation / Inflammation / Ligands / Lymph nodes / Lymphocytes / Lymphocytes T / Lymphoid tissue / Medicine / Mice / Mice, Inbred C57BL / Mice, Knockout / Mortality / Phenotypes / Quantitative analysis / Receptors, CCR4 - deficiency / Receptors, CCR4 - genetics / Sinuses / T cell / T cells / T-Lymphocytes, Regulatory - immunology / Th1 Cells - immunology