Li Difei, Shi Xing, Yang Yuqiong, Deng Yao, Chen Dandan, Chen Shuyu, Wang Jinyong, Wen Guanxi, Liang Zhenyu, Wang Fengyan, Gao Jiaqi, Liu Yuanyuan, Wang Danna, Liang Ruifang, Xu Haizhao, Chen Rongchang, Chen Shanze, Wang Lingwei
Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, The First Affiliated Hospital (Shenzhen People's Hospital) and School of Medicine, Southern University of Science and Technology, Shenzhen, 518055, China.
National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guang Zhou, 510150, China.
Respir Res. 2025 Jan 31;26(1):46. doi: 10.1186/s12931-025-03120-0.
Chronic obstructive pulmonary disease (COPD) is a progressive chronic lung disease characterized by chronic airway inflammation and emphysema. Macrophage polarization plays an important role in COPD pathogenesis by secreting inflammatory mediators. Bromodomain-containing protein 4 (BRD4), an epigenetic reader that specifically binds to histones, plays a crucial role in inflammatory diseases by regulating macrophage polarization. Herein, we attempted to examine the hypothesis that modulating alveolar macrophage polarization via BRD4 inhibitors might has a potential for COPD treatment.
We firstly analyzed BRD4 expression and its correlation with clinical parameters and macrophage polarization markers in sputum transcriptomes from 94 COPD patients and 36 healthy individuals. In vivo, BRD4 inhibitor JQ1 and degrader ARV-825 were intraperitoneally administrated into emphysema mice to assess their effects on lung emphysema and inflammation. In vitro, RNA-seq and CUT&Tag assay of BRD4 and H3K27ac were applied for elucidating how BRD4 regulates macrophage polarization.
We found an increased expression of BRD4 in the induced sputum from patients with COPD and unveiled a strong correlation between BRD4 expression and clinical parameters as well as macrophage polarization. Subsequently, BRD4 inhibitor JQ1 and degrader ARV-825 significantly mitigated emphysema and airway inflammation along with better protection of lung function in mice. BRD4 inhibition also suppressed both M1 and M2 alveolar macrophage polarization. The CUT&Tag assay of BRD4 and H3K27ac, revealed that BRD4 inhibition disrupted the super-enhancers (SEs) of IRF4 (a crucial transcription factor for M2 macrophage), and subsequently affected the expression of matrix metalloproteinase 12 (MMP12) which is vital for emphysema development.
This study suggested that downregulation of BRD4 might suppress airway inflammation and emphysema through disrupting the SEs of IRF4 and alveolar macrophages polarization, which might be a potential target of therapeutic intervention in COPD. A diagram of the mechanism by which BRD4 mediated super-enhancer of IRF4 in M2 AMs. Graphic illustration showed targeting BRD4 in M2 polarized AMs lead to the downregulation of MMP12 expression, resulting in the amelioration of experimental emphysema by disrupting the super-enhancer of IRF4.
慢性阻塞性肺疾病（COPD）是一种进行性慢性肺部疾病，其特征为慢性气道炎症和肺气肿。巨噬细胞极化通过分泌炎症介质在COPD发病机制中起重要作用。含溴结构域蛋白4（BRD4）是一种特异性结合组蛋白的表观遗传阅读器，通过调节巨噬细胞极化在炎症性疾病中起关键作用。在此，我们试图检验通过BRD4抑制剂调节肺泡巨噬细胞极化可能具有COPD治疗潜力这一假说。
我们首先分析了94例COPD患者和36名健康个体痰液转录组中BRD4的表达及其与临床参数和巨噬细胞极化标志物的相关性。在体内，将BRD4抑制剂JQ1和降解剂ARV-825腹腔注射到肺气肿小鼠中，以评估它们对肺气肿和炎症的影响。在体外，应用BRD4和H3K27ac的RNA测序和CUT&Tag分析来阐明BRD4如何调节巨噬细胞极化。
我们发现COPD患者诱导痰液中BRD4表达增加，并揭示了BRD4表达与临床参数以及巨噬细胞极化之间的强相关性。随后，BRD4抑制剂JQ1和降解剂ARV-825显著减轻了小鼠的肺气肿和气道炎症，并更好地保护了肺功能。BRD4抑制还抑制了M1和M2肺泡巨噬细胞极化。BRD4和H3K27ac的CUT&Tag分析表明，BRD4抑制破坏了IRF4（M2巨噬细胞的关键转录因子）的超级增强子（SEs），随后影响了对肺气肿发展至关重要的基质金属蛋白酶12（MMP12）的表达。
本研究表明，BRD4的下调可能通过破坏IRF4的SEs和肺泡巨噬细胞极化来抑制气道炎症和肺气肿，这可能是COPD治疗干预的潜在靶点。BRD4介导M2AMs中IRF4超级增强子的机制图。图示显示靶向M2极化AMs中的BRD4导致MMP12表达下调，通过破坏IRF4的超级增强子改善实验性肺气肿。
