Thymic Bmi-1 hampers γδT 17 generation and its derived RORγt-IL-17A signaling to delay cardiac aging

• 成果类型: Article
• 署名作者: Wang, Qiuyi; Wang, Yue; Lin, Yujie; Zhou, Jiawen; Mao, Zhiyuan; Gu, Xin; Chen, Haiyun; Li, Jiyu; Chen, Ao; Zhang, Jin'ge; Wang, Rong; Zhao, Yingming; Gu, Mufeng; Li, Qing; Zhang, Yongjie; Jin, Jianliang
• 署名单位: Nanjing Medical University; Jiangnan University; Nanjing University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11964
• DOI: 10.1073/pnas.2414717122
• 发表日期: 2025-05-14
• 关键词: cell; proliferation; transcription; RECOGNITION; specificity

摘要

New immunosenescence targets for preventing senescence-associated pathological cardiac hypertrophy (SA-PCH) need to be explored. In the present study, with physiologically aged human and mouse samples, the IL-17A level increased with physiological aging, heart failure (HF), and SA-PCH and was negatively correlated with thymic Bmi-1 expression. Bmi-1f/fLckCre+ mice and Bmi-1f/flittermates were generated to determine whether Bmi-1 delayed T cell aging by maintaining thymic T cell development to prevent SA-PCH. As a result, Bmi-1 promoted thymic T cell development by upregulating Notch signaling and prevented DN1 T cells from differentiating into gamma delta T17 cells by downregulating gamma delta T17 cell differentiation signaling. Bmi-1 upregulated Notch signaling by inhibiting p53-mediated Ikzf1 transcription at the-1,863 to-1,849 Ikzf1 promoter region. Bmi-1-RING1B promoted ROR gamma t ubiquitination and degradation byproteas-ome to inhibit the production of IL-17A in gamma delta T17 cells. Bmi-1 also downregulated Rorc transcribed by c-Maf by trimethylating H3K27 at the-1,511 to-1,497 Rorc promoter region. Subsequently, the number of peripheral gamma delta T17 cells infiltrating the heart tissues was reduced, while alleviating IL-17A-dependent cardiac aging, hypertrophy, dysfunction, senescence-associated secretory phenotype (SASP), and macrophage-myofibroblast transition, ultimately improving SA-PCH. The ROR gamma t inhibitor SR1001 and IL-17A neutralizing antibody ixekizumab prevented thymic ROR gamma t-IL-17A-dependent SA-PCH. Furthermore, ROR gamma t bound to Bmi-1 through ARG237 and to RING1B through GLU235, which could be used as a therapeutic strategy for SA-PCH to construct binding peptides promoting Bmi-1-RING1B binding to ROR gamma t and degrading ROR gamma t for inhibiting gamma delta T17 cell differentiation and IL-17A production. Thus, thymic Bmi-1 prevented IL-17A-dependent SA-PCH by decreasing gamma delta T17 cell numbers.