Division of Cancer Epigenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ruprecht Karl University of Heidelberg, Heidelberg, Germany.
Nat Commun. 2021 Nov 11;12(1):6520. doi: 10.1038/s41467-021-26777-9.
Lung diseases, such as cystic fibrosis and COPD, are characterized by mucus obstruction and chronic airway inflammation, but their mechanistic link remains poorly understood. Here, we focus on the function of the mucostatic airway microenvironment on epigenetic reprogramming of airway macrophages (AM) and resulting transcriptomic and phenotypical changes. Using a mouse model of muco-obstructive lung disease (Scnn1b-transgenic), we identify epigenetically controlled, differentially regulated pathways and transcription factors involved in inflammatory responses and macrophage polarization. Functionally, AMs from Scnn1b-transgenic mice have reduced efferocytosis and phagocytosis, and excessive inflammatory responses upon lipopolysaccharide challenge, mediated through enhanced Irf1 function and expression. Ex vivo stimulation of wild-type AMs with native mucus impairs efferocytosis and phagocytosis capacities. In addition, mucus induces gene expression changes, comparable with those observed in AMs from Scnn1b-transgenic mice. Our data show that mucostasis induces epigenetic reprogramming of AMs, leading to changes favoring tissue damage and disease progression. Targeting these altered AMs may support therapeutic approaches in patients with muco-obstructive lung diseases.
肺部疾病，如囊性纤维化和 COPD，以粘液阻塞和慢性气道炎症为特征，但它们的机制联系仍知之甚少。在这里，我们专注于粘液稳定的气道微环境对气道巨噬细胞（AM）的表观遗传重编程以及由此产生的转录组和表型变化的功能。使用粘液阻塞性肺疾病的小鼠模型（Scnn1b-转基因），我们确定了涉及炎症反应和巨噬细胞极化的受表观遗传控制的、差异调节的途径和转录因子。功能上，Scnn1b-转基因小鼠的 AM 具有降低的胞噬作用和吞噬作用，并且在脂多糖刺激下表现出过度的炎症反应，这是通过增强 Irf1 功能和表达介导的。用天然粘液体外刺激野生型 AM 会损害胞噬作用和吞噬作用能力。此外，粘液诱导基因表达变化，与在 Scnn1b-转基因小鼠的 AM 中观察到的变化相当。我们的数据表明，粘液稳定导致 AM 的表观遗传重编程，导致有利于组织损伤和疾病进展的变化。针对这些改变的 AM 可能支持粘液阻塞性肺部疾病患者的治疗方法。
