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
Department of Human Anatomy, School of Basic Medical Sciences, Key Laboratory for Aging and Disease, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
Department of Cardiology, The Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu 214062, China.
Proc Natl Acad Sci U S A. 2025 May 20;122(20):e2414717122. doi: 10.1073/pnas.2414717122. Epub 2025 May 14.
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. mice and littermates 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 γδT17 cells by downregulating γδT17 cell differentiation signaling. Bmi-1 upregulated Notch signaling by inhibiting p53-mediated transcription at the -1,863 to -1,849 promoter region. Bmi-1-RING1B promoted RORγt ubiquitination and degradation by proteasome to inhibit the production of IL-17A in γδT17 cells. Bmi-1 also downregulated transcribed by c-Maf by trimethylating H3K27 at the -1,511 to -1,497 promoter region. Subsequently, the number of peripheral γδT17 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 RORγt inhibitor SR1001 and IL-17A neutralizing antibody ixekizumab prevented thymic RORγt-IL-17A-dependent SA-PCH. Furthermore, RORγt 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 RORγt and degrading RORγt for inhibiting γδT17 cell differentiation and IL-17A production. Thus, thymic Bmi-1 prevented IL-17A-dependent SA-PCH by decreasing γδT17 cell numbers.
需要探索预防衰老相关病理性心脏肥大（SA-PCH）的新免疫衰老靶点。在本研究中，利用生理衰老的人类和小鼠样本，白细胞介素-17A（IL-17A）水平随生理衰老、心力衰竭（HF）和SA-PCH而升高，且与胸腺中Bmi-1的表达呈负相关。构建了Bmi-1基因敲除小鼠及其同窝对照小鼠，以确定Bmi-1是否通过维持胸腺T细胞发育来延缓T细胞衰老，从而预防SA-PCH。结果显示，Bmi-1通过上调Notch信号促进胸腺T细胞发育，并通过下调γδT17细胞分化信号，阻止双阴性1（DN1）T细胞分化为γδT17细胞。Bmi-1通过在-1863至-1849启动子区域抑制p53介导的转录来上调Notch信号。Bmi-1-RING1B通过蛋白酶体促进维甲酸相关孤儿受体γt（RORγt）泛素化和降解，从而抑制γδT17细胞中IL-17A的产生。Bmi-1还通过在-1511至-1497启动子区域对组蛋白H3第27位赖氨酸进行三甲基化，下调由原癌基因c-Maf转录的相关因子。随后，浸润心脏组织的外周γδT17细胞数量减少，同时减轻了IL-17A依赖性心脏衰老、肥大、功能障碍、衰老相关分泌表型（SASP）以及巨噬细胞-肌成纤维细胞转化，最终改善了SA-PCH。RORγt抑制剂SR1001和IL-17A中和抗体ixekizumab可预防胸腺中RORγt-IL-17A依赖性SA-PCH。此外，RORγt通过精氨酸237与Bmi-1结合，并通过谷氨酸235与RING1B结合，这可作为SA-PCH的一种治疗策略，构建促进Bmi-1-RING1B与RORγt结合并降解RORγt的结合肽，以抑制γδT17细胞分化和IL-17A产生。因此，胸腺Bmi-1通过减少γδT17细胞数量预防了IL-17A依赖性SA-PCH。
