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. DNA methylation profiling of airway macrophages from IPF and Healthy lungs.