Epigenetic alterations underlie airway macrophage differentiation and phenotype during lung fibrosis

Abstract Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, the epigenetics of AMs development and function in IPF are limited. Here, we characterised the DNA-methylation (DNAm) profile of AMs from IPF (n=30) and healthy (n=14) donors. Our analysis revealed epigenetic heterogeneity was a key characteristic of IPF AMs. DNAm ‘clock’ analysis indicated epigenetic alterations in IPF-AMs was not associated with accelerated ageing. In differential DNAm analysis, we identified numerous differentially methylated positions (DMPs, n=11) and regions (DMRs, n=49) between healthy and IPF AMs respectively. DMPs and DMRs encompassed genes involved in lipid (LPCAT1) and glucose (PFKB3) metabolism and importantly, DNAm status was associated with disease severity in IPF. Collectively, our data identify that profound changes in the epigenome underpin the development and function of AMs in the IPF lung.