C-C chemokine receptor 4 deficiency exacerbates early atherosclerosis in mice
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 at...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2025-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/101830 |
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| author | Toru Tanaka Naoto Sasaki Aga Krisnanda Hilman Zulkifli Amin Ken Ito Sayo Horibe Kazuhiko Matsuo Ken-ichi Hirata Takashi Nakayama Yoshiyuki Rikitake |
| author_facet | Toru Tanaka Naoto Sasaki Aga Krisnanda Hilman Zulkifli Amin Ken Ito Sayo Horibe Kazuhiko Matsuo Ken-ichi Hirata Takashi Nakayama Yoshiyuki Rikitake |
| author_sort | Toru Tanaka |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-59994a1ef36e46daaa33772569e59edc |
| institution | DOAJ |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj-art-59994a1ef36e46daaa33772569e59edc2025-08-20T03:15:24ZengeLife Sciences Publications LtdeLife2050-084X2025-07-011310.7554/eLife.101830C-C chemokine receptor 4 deficiency exacerbates early atherosclerosis in miceToru Tanaka0https://orcid.org/0000-0002-1054-9211Naoto Sasaki1https://orcid.org/0000-0002-7760-6129Aga Krisnanda2https://orcid.org/0009-0005-6417-2738Hilman Zulkifli Amin3Ken Ito4Sayo Horibe5https://orcid.org/0000-0002-4111-2426Kazuhiko Matsuo6https://orcid.org/0000-0001-5782-5300Ken-ichi Hirata7Takashi Nakayama8https://orcid.org/0000-0002-8493-899XYoshiyuki Rikitake9https://orcid.org/0000-0001-7207-4656Laboratory of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe, JapanLaboratory of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe, Japan; Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, JapanLaboratory of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe, JapanLaboratory of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe, JapanLaboratory of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe, JapanLaboratory of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe, JapanDivision of Chemotherapy, Faculty of Pharmacy, Kindai University, Higashi-osaka, JapanDivision of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, JapanDivision of Chemotherapy, Faculty of Pharmacy, Kindai University, Higashi-osaka, JapanLaboratory of Medical Pharmaceutics, Kobe Pharmaceutical University, Kobe, JapanChronic 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.https://elifesciences.org/articles/101830atherosclerosisT cellchemokine receptorinflammation |
| spellingShingle | Toru Tanaka Naoto Sasaki Aga Krisnanda Hilman Zulkifli Amin Ken Ito Sayo Horibe Kazuhiko Matsuo Ken-ichi Hirata Takashi Nakayama Yoshiyuki Rikitake C-C chemokine receptor 4 deficiency exacerbates early atherosclerosis in mice eLife atherosclerosis T cell chemokine receptor inflammation |
| title | C-C chemokine receptor 4 deficiency exacerbates early atherosclerosis in mice |
| title_full | C-C chemokine receptor 4 deficiency exacerbates early atherosclerosis in mice |
| title_fullStr | C-C chemokine receptor 4 deficiency exacerbates early atherosclerosis in mice |
| title_full_unstemmed | C-C chemokine receptor 4 deficiency exacerbates early atherosclerosis in mice |
| title_short | C-C chemokine receptor 4 deficiency exacerbates early atherosclerosis in mice |
| title_sort | c c chemokine receptor 4 deficiency exacerbates early atherosclerosis in mice |
| topic | atherosclerosis T cell chemokine receptor inflammation |
| url | https://elifesciences.org/articles/101830 |
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