Epigenetic alterations underlie airway macrophage differentiation and phenotype during lung fibrosis. Epigenetic alterations underlie airway macrophage differentiation and phenotype during lung fibrosis

Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, the epigenetics of AMs development and influence of disease on these processes remain limited. Using EPIC arrays, we undertook DNA methylation profiling in AMs from Healthy (n=14) and IPF (n=30) donors. Deconvolution using reference myeloid-cell methylomes identified epigenetic heterogeneity was a key characteristic of both AMs and IPF and adjustment for myeloid methylome composition was critical in differential methylation analysis. We identified n=11 and n=49 differentially methylated positions (DMPs) and regions (DMRs) between healthy and IPF AMs respectively. Both DMPs and DMRs encompassed genes involved in lipid (LPCAT1) and glucose (PFKB3) metabolism and processes and pathways pertinent to macrophage biology (e.g. extravasations) and IPF pathogenesis (e.g. wound healing). These data identify that changes in the epigenome underpin the development and function of AMs in the IPF lung. Overall design: DNA methylation profiling of airway macrophages from IPF and Healthy lungs.

气道巨噬细胞（Airway macrophages, AMs）是肺微环境的关键调控因子，与特发性肺纤维化（idiopathic pulmonary fibrosis, IPF）的发病机制密切相关。然而，目前关于气道巨噬细胞发育的表观遗传调控机制，以及疾病对该过程的影响，相关研究仍较为有限。本研究利用EPIC芯片（EPIC arrays），对来自n=14名健康供者与n=30名特发性肺纤维化供者的气道巨噬细胞开展DNA甲基化谱分析。通过参考髓系细胞甲基组（myeloid-cell methylomes）进行反卷积分析，本研究发现表观遗传异质性是气道巨噬细胞与特发性肺纤维化样本共有的关键特征，且在差异甲基化分析中，对髓系甲基组组成进行校正是至关重要的环节。本研究分别在健康供者与特发性肺纤维化供者的气道巨噬细胞之间，鉴定出n=11个差异甲基化位点（differentially methylated positions, DMPs）与n=49个差异甲基化区域（differentially methylated regions, DMRs）。上述差异甲基化位点与区域所覆盖的基因，既参与脂质（LPCAT1）、葡萄糖（PFKB3）代谢过程，也涉及与巨噬细胞生物学（如细胞外渗）及特发性肺纤维化发病机制（如伤口愈合）相关的生物学过程与信号通路。本研究数据表明，表观基因组的改变是特发性肺纤维化肺内气道巨噬细胞发育与功能异常的核心基础。整体实验设计：对来自特发性肺纤维化与健康肺组织的气道巨噬细胞进行DNA甲基化谱分析。