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circADAMTS6 via stabilizing CAMK2A is involved in smoking-induced emphysema through driving M2 macrophage polarization
Environment International ( IF 10.3 ) Pub Date : 2024-06-21 , DOI: 10.1016/j.envint.2024.108832 Jiaheng Lin 1 , Haibo Xia 2 , Jinyan Yu 3 , Yue Wang 1 , Hailan Wang 1 , Daxiao Xie 1 , Cheng Cheng 1 , Lu Lu 1 , Tao Bian 3 , Yan Wu 3 , Qizhan Liu 1
Environment International ( IF 10.3 ) Pub Date : 2024-06-21 , DOI: 10.1016/j.envint.2024.108832 Jiaheng Lin 1 , Haibo Xia 2 , Jinyan Yu 3 , Yue Wang 1 , Hailan Wang 1 , Daxiao Xie 1 , Cheng Cheng 1 , Lu Lu 1 , Tao Bian 3 , Yan Wu 3 , Qizhan Liu 1
Affiliation
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Cigarette smoke (CS), an indoor environmental pollutant, is a prominent risk factor for emphysema, which is a pathological feature of chronic obstructive pulmonary disease (COPD). Emerging function of circRNAs in immune responses and disease progression shed new light to explore the pathogenesis of emphysema. In this research, we demonstrated, by single-cell RNA sequencing (scRNAseq), that the ratio of M2 macrophages were increased in lung tissues of humans and mice with smoking-related emphysema. Further, our data showed that circADAMTS6 was associated with cigarette smoke extract (CSE)-induced M2 macrophage polarization. Mechanistically, in macrophages, circADAMTS6 stabilized CAMK2A mRNA via forming a circADAMTS6/IGF2BP2/CAMK2A RNA-protein ternary complex to activate CREB, which drives M2 macrophage polarization and leads to emphysema. In addition, in macrophages of mouse lung tissues, downregulation of circADAMTS6 reversed M2 macrophage polarization, the proteinase/anti-proteinase imbalance, and the elastin degradation, which protecting against CS-induced emphysema. Moreover, for macrophages and in a model with co-cultured lung organoids, the target of circADAMTS6 restored the growth of lung organoids compared to CSE-treated macrophages. Our results also demonstrated that, for smokers and COPD smokers, elevation of circADAMTS6 negatively correlated with lung function. Overall, this study reveals a novel mechanism for circADAMTS6-driven M2 macrophage polarization in smoking-related emphysema and postulates that circADAMTS6 could serve as a diagnostic and therapeutic marker for smoking-related emphysema.
中文翻译：
circADAMTS6 通过稳定 CAMK2A 通过驱动 M2 巨噬细胞极化参与吸烟诱发的肺气肿
香烟烟雾（CS）是一种室内环境污染物，是肺气肿的重要危险因素，而肺气肿是慢性阻塞性肺病（COPD）的病理特征。 circRNA 在免疫反应和疾病进展中的新功能为探索肺气肿的发病机制提供了新的线索。在这项研究中，我们通过单细胞 RNA 测序 (scRNAseq) 证明，患有吸烟相关肺气肿的人类和小鼠肺组织中 M2 巨噬细胞的比例有所增加。此外，我们的数据表明 circADAMTS6 与香烟烟雾提取物 (CSE) 诱导的 M2 巨噬细胞极化有关。从机制上讲，在巨噬细胞中，circADAMTS6通过形成circADAMTS6/IGF2BP2/CAMK2A RNA-蛋白三元复合物来稳定CAMK2A mRNA，从而激活CREB，从而驱动M2巨噬细胞极化并导致肺气肿。此外，在小鼠肺组织的巨噬细胞中，circADAMTS6的下调逆转了M2巨噬细胞的极化、蛋白酶/抗蛋白酶失衡以及弹性蛋白降解，从而防止CS诱导的肺气肿。此外，对于巨噬细胞以及在共培养肺类器官的模型中，与 CSE 处理的巨噬细胞相比，circADAMTS6 的靶标恢复了肺类器官的生长。我们的结果还表明，对于吸烟者和慢性阻塞性肺病吸烟者来说，circADAMTS6 的升高与肺功能呈负相关。总的来说，这项研究揭示了吸烟相关肺气肿中 circADAMTS6 驱动的 M2 巨噬细胞极化的新机制，并假设 circADAMTS6 可以作为吸烟相关肺气肿的诊断和治疗标志物。
更新日期：2024-06-21
中文翻译：
circADAMTS6 通过稳定 CAMK2A 通过驱动 M2 巨噬细胞极化参与吸烟诱发的肺气肿
香烟烟雾（CS）是一种室内环境污染物，是肺气肿的重要危险因素，而肺气肿是慢性阻塞性肺病（COPD）的病理特征。 circRNA 在免疫反应和疾病进展中的新功能为探索肺气肿的发病机制提供了新的线索。在这项研究中，我们通过单细胞 RNA 测序 (scRNAseq) 证明，患有吸烟相关肺气肿的人类和小鼠肺组织中 M2 巨噬细胞的比例有所增加。此外，我们的数据表明 circADAMTS6 与香烟烟雾提取物 (CSE) 诱导的 M2 巨噬细胞极化有关。从机制上讲，在巨噬细胞中，circADAMTS6通过形成circADAMTS6/IGF2BP2/CAMK2A RNA-蛋白三元复合物来稳定CAMK2A mRNA，从而激活CREB，从而驱动M2巨噬细胞极化并导致肺气肿。此外，在小鼠肺组织的巨噬细胞中，circADAMTS6的下调逆转了M2巨噬细胞的极化、蛋白酶/抗蛋白酶失衡以及弹性蛋白降解，从而防止CS诱导的肺气肿。此外，对于巨噬细胞以及在共培养肺类器官的模型中，与 CSE 处理的巨噬细胞相比，circADAMTS6 的靶标恢复了肺类器官的生长。我们的结果还表明，对于吸烟者和慢性阻塞性肺病吸烟者来说，circADAMTS6 的升高与肺功能呈负相关。总的来说，这项研究揭示了吸烟相关肺气肿中 circADAMTS6 驱动的 M2 巨噬细胞极化的新机制，并假设 circADAMTS6 可以作为吸烟相关肺气肿的诊断和治疗标志物。
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