Key Points miR-155 in T cells contributes to the shortened lifespan of miR-146a−/− mice. Autoimmunity in aged miR-146a−/− mice is mediated in part by T cell miR-155. Aerobic glycolysis is associated with increased Tfh and GC B cells during aging. Visual Abstract Aging-related chronic inflammation is a risk factor for many human disorders through incompletely understood mechanisms. Aged mice deficient in microRNA (miRNA/miR)-146a succumb to life-shortening chronic inflammation. In this study, we report that miR-155 in T cells contributes to shortened lifespan of miR-146a−/− mice. Using single-cell RNA sequencing and flow cytometry, we found that miR-155 promotes the activation of effector T cell populations, including T follicular helper cells, and increases germinal center B cells and autoantibodies in mice aged over 15 months. Mechanistically, aerobic glycolysis genes are elevated in T cells during aging, and upon deletion of miR-146a, in a T cell miR-155-dependent manner. Finally, skewing T cell metabolism toward aerobic glycolysis by deleting mitochondrial pyruvate carrier recapitulates age-dependent T cell phenotypes observed in miR-146a−/− mice, revealing the sufficiency of metabolic reprogramming to influence immune cell functions during aging. Altogether, these data indicate that T cell–specific miRNAs play pivotal roles in regulating lifespan through their influences on inflammaging.

中文翻译：

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T 细胞表达的 microRNA-155 缩短了与年龄相关的慢性炎症小鼠模型的寿命


要点 T 细胞中的 miR-155 导致 miR-146a−/− 小鼠寿命缩短。老年 miR-146a−/− 小鼠的自身免疫部分由 T 细胞 miR-155 介导。有氧糖酵解与衰老过程中 Tfh 和 GC B 细胞的增加有关。视觉摘要 与衰老相关的慢性炎症是许多人类疾病的危险因素，其机制尚不完全清楚。缺乏 microRNA (miRNA/miR)-146a 的老年小鼠会死于慢性炎症，从而缩短寿命。在这项研究中，我们报告 T 细胞中的 miR-155 会导致 miR-146a−/− 小鼠的寿命缩短。使用单细胞 RNA 测序和流式细胞术，我们发现 miR-155 促进效应 T 细胞群（包括滤泡辅助 T 细胞）的激活，并增加 15 个月以上小鼠的生发中心 B 细胞和自身抗体。从机制上讲，T细胞中的有氧糖酵解基因在衰老过程中以及miR-146a缺失后以T细胞miR-155依赖性方式升高。最后，通过删除线粒体丙酮酸载体使 T 细胞代谢偏向有氧糖酵解，重现了在 miR-146a−/− 小鼠中观察到的年龄依赖性 T 细胞表型，揭示了代谢重编程足以影响衰老过程中的免疫细胞功能。总而言之，这些数据表明 T 细胞特异性 miRNA 通过影响炎症而在调节寿命方面发挥着关键作用。