期刊
EUROPEAN HEART JOURNAL
卷 40, 期 4, 页码 372-+出版社
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehy714
关键词
Atherosclerosis; Innate and adaptive immune system; Macrophages; T cells; CBL-B
资金
- Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation
- Dutch Federation of University Medical Centers
- Netherlands, Organization for Health Research and Development
- Royal Netherlands Academy of Sciences [CVON2018-19]
- Netherlands Organization for Scientific Research (NWO) (VICI) [016.130.676]
- EU [H2020-PHC-2015-667673]
- European Research Council (ERC) [CD40-INN 681492]
- German Science Foundation (DFG) [CRC1123]
- Amsterdam Cardiovascular Sciences
- Netherlands Heart Institute
- Dutch Heart Foundation
Aims The E3-ligase CBL-B (Casitas B-cell lymphoma-B) is an important negative regulator of T cell activation that is also expressed in macrophages. T cells and macrophages mediate atherosclerosis, but their regulation in this disease remains largely unknown; thus, we studied the function of CBL-B in atherogenesis. Methods and results The expression of CBL-B in human atherosclerotic plaques was lower in advanced lesions compared with initial lesions and correlated inversely with necrotic core area. Twenty weeks old Cblb(-/-) Apoe(-/-) mice showed a significant increase in plaque area in the aortic arch, where initial plaques were present. In the aortic root, a site containing advanced plaques, lesion area rose by 40%, accompanied by a dramatic change in plaque phenotype. Plaques contained fewer macrophages due to increased apoptosis, larger necrotic cores, and more CD8(+) T cells. Cblb(-/-) Apoe(-/-) macrophages exhibited enhanced migration and increased cytokine production and lipid uptake. Casitas B-cell lymphoma-B deficiency increased CD8(+) T cell numbers, which were protected against apoptosis and regulatory T cell-mediated suppression. IFN gamma and granzyme B production was enhanced in Cblb(-/-) Apoe(-/-) CD8(+) T cells, which provoked macrophage killing. Depletion of CD8(+) T cells in Cblb(-/-) Apoe(-/-) bone marrow chimeras rescued the phenotype, indicating that CBL-B controls atherosclerosis mainly through its function in CD8(+) T cells. Conclusion Casitas B-cell lymphoma-B expression in human plaques decreases during the progression of atherosclerosis. As an important regulator of immune responses in experimental atherosclerosis, CBL-B hampers macrophage recruitment and activation during initial atherosclerosis and limits CD8(+) T cell activation and CD8(+) T cell-mediated macrophage death in advanced atherosclerosis, thereby preventing the progression towards high-risk plaques.
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