Ezh2 塑造T细胞以驱动动动脉硬化
Cecilia Assunta Bonfiglio1,2, Michael Lacy1,3, Vasiliki Triantafyllidou1
1Institute for Cardiovascular Prevention (C.A.B., M.L., V.T., F.M.F., K.N., Y.W., V.B., I.A-K., Y.F.S.M., M.K., K.R., C.W., D.S., E.L., D.A.), Ludwig Maximilians Universität, Munich, Germany.
Circulation
|February 7, 2025
概括
通过促进2型免疫反应,抑制CD4+T细胞中的增强酶同源2 (EZH2) 降低了动脉样硬化. 这导致有益的免疫细胞积累,限制斑块的进展.
科学领域:
- 免疫学
- 表观遗传学
- 心血管疾病
背景情况:
- 在动脉样硬化和动脉炎症中,T细胞的激活和两极化是至关重要的.
- 皮质同源2 (EZH2) 的表观酶增强剂通过H3K27me3控制T细胞反应.
- 在动脉样硬化期间EZH2在T细胞中的作用需要进一步阐明.
研究的目的:
- 研究T细胞EZH2在动脉样硬化发展中的作用.
- 确定EZH2删除在CD4+和CD8+T细胞对其他炎症的影响.
- 了解T细胞EZH2在动脉样硬化中的潜在免疫机制.
主要方法:
- 在人动脉内切除样本中分析EZH2表达.
- 产生和分析易患动脉样硬化症的Apoe缺陷小鼠,具有CD4+或CD8+T细胞特异性的Ezh2删除 (Ezh2cd4-KO,Ezh2cd8-KO).
- 在体外对缺少EZH2的T细胞和巨细胞的研究.
- 单细胞RNA测序和脏T细胞的流细胞计.
- 染色体免疫沉,然后进行qPCR以评估基因调节.
主要成果:
- 在先进的人类动脉样硬化斑块中增加EZH2表达,主要在T细胞核内.
- Ezh2cd4-KO小鼠表现出降低的动脉样硬化,较少的晚期斑块含有较少的原和巨细胞.
- 在CD4+T细胞中缺少EZH2促进了2型免疫反应,增加了IL-4表达,并使巨细胞偏向抗炎类型.
- 在Ezh2cd4-KO小鼠中,单细胞分析显示原始和调节性T细胞减少,记忆力增加和不变的自然杀手T (iNKT) 细胞,特别是iNKT2子集.
- 显示T细胞EZH2可以调节IL-4和Zbtb16 (Plzf) 的转录.
结论:
- T细胞EZH2在人类和小鼠动脉样硬化中起着重要作用.
- 在CD4+T细胞中抑制EZH2将免疫反应转移到保护性2型特征.
- 这种转变涉及iNKT2和Th2细胞,记忆T细胞和抗炎性巨细胞的积累,最终限制了动脉样硬化的进展.
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