Legumain deficiency halts atherogenesis by modulating T cell receptor signaling

IF 7.8 1区 医学 Q1 Biochemistry, Genetics and Molecular Biology
Aging Cell Pub Date : 2024-10-29 DOI:10.1111/acel.14391
Xuying Xiang, Feng Zhang, Lei Nie, Xiaoqing Guo, Mengting Qin, Jiaojiao Chen, Dailiang Jiang, Zhentao Zhang, Ling Mao
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Abstract

Atherosclerosis is an age-related pathological process associated with elevated levels of legumain in plaques and plasma. However, the underlying mechanisms remain unclear. The aim of this study was to investigate the role of legumain in the progression of atherosclerotic plaques, with a particular focus on functional and phenotypic changes in CD4+ T cells. Apolipoprotein E-deficient (Apoe−/−) mice were crossed with legumain-deficient (Lgmn−/−) mice to generate Lgmn−/−Apoe−/− mice. CD4+ T cells accumulated in the atherosclerotic plaques of Apoe−/− mice fed a high-fat diet. Deletion of legumain attenuated the deposition of CD4+ T cells in plaques and reduced the number of atherosclerotic lesions. The levels of CD4+ T cells in the blood, lymph nodes, and spleen were decreased in Lgmn−/− mice. Transcriptomic analysis revealed that the deletion of legumain decreased the differentiation, survival, and function of CD4+ memory T cells by suppressing the T cell receptor (TCR) signaling pathway. These changes are accompanied by the downregulation of the antiapoptotic protein B-cell lymphoma 2 (Bcl-2) and the reduced release of interleukin (IL)-2 and interferon (IFN)-γ. These results suggest that legumain deficiency may play a role in the development of atherosclerosis by impairing the survival, proliferation, and function of CD4+ T cells. Inhibition of legumain activity may be an innovative therapy for the treatment of atherosclerosis.

Abstract Image

Legumain 缺乏症可通过调节 T 细胞受体信号阻止动脉粥样硬化的发生。
动脉粥样硬化是一种与年龄有关的病理过程,与斑块和血浆中豆固醇含量升高有关。然而,其潜在机制仍不清楚。本研究旨在探讨豆豆蛋白酶在动脉粥样硬化斑块进展过程中的作用,尤其关注 CD4+ T 细胞的功能和表型变化。载脂蛋白E缺陷(Apoe-/-)小鼠与豆豆蛋白酶缺陷(Lgmn-/-)小鼠杂交,产生Lgmn-/-Apoe-/-小鼠。以高脂肪饮食喂养的载脂蛋白-/-小鼠的动脉粥样硬化斑块中积累了CD4+ T细胞。缺失豆豆蛋白酶可减轻CD4+ T细胞在斑块中的沉积,并减少动脉粥样硬化病变的数量。Lgmn-/-小鼠血液、淋巴结和脾脏中的CD4+ T细胞水平下降。转录组分析表明,豆豆蛋白酶的缺失通过抑制 T 细胞受体(TCR)信号通路,降低了 CD4+ 记忆 T 细胞的分化、存活和功能。伴随这些变化的是抗凋亡蛋白 B 细胞淋巴瘤 2(Bcl-2)的下调以及白细胞介素(IL)-2 和干扰素(IFN)-γ 的释放减少。这些结果表明,豆豆蛋白酶缺乏可能会损害 CD4+ T 细胞的存活、增殖和功能,从而在动脉粥样硬化的发展中发挥作用。抑制豆豆蛋白酶的活性可能是治疗动脉粥样硬化的一种创新疗法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Aging Cell
Aging Cell 生物-老年医学
CiteScore
14.40
自引率
2.60%
发文量
212
审稿时长
8 weeks
期刊介绍: Aging Cell, an Open Access journal, delves into fundamental aspects of aging biology. It comprehensively explores geroscience, emphasizing research on the mechanisms underlying the aging process and the connections between aging and age-related diseases.
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