Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease

Joschka Hey,Pavlo Lutsik,Dieter Weichenhan,Jolanthe Schatterny,Simone Butz,Michelle Paulsen,Marcus A Mall,Reka Toth,Reinhard Liebers,Christoph Plass

doi:10.1038/s41467-021-26777-9

Abstract

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.

Highlights

Lung diseases, such as cystic fibrosis and chronic obstructive pulmonary disease (COPD), are characterized by mucus obstruction and chronic airway inflammation, but their mechanistic link remains poorly understood
We evaluate the response to bacterial-derived lipopolysaccharides (LPS) on cytokine expression and perform an integrated analysis of assay for transposase accessible chromatin sequencing (ATACseq) and RNA sequencing (RNAseq) to identify differentially active transcription factors involved in the transcriptional induction of inflammatory programs in airway macrophages (AM)
We found that Scnn1b-Tg AMs are altered in the DNA methylation and chromatin accessibility levels, with changes enriched in promoter and enhancer regions, favoring the binding of TFs involved in macrophage inflammation and polarization

Summary

Introduction

Lung diseases, such as cystic fibrosis and COPD, are characterized by mucus obstruction and chronic airway inflammation, but their mechanistic link remains poorly understood. Excess mucus production and plugging, as common features of the microenvironment of chronic obstructive lung diseases, could potentially drive dysregulated responses of AMs through epigenetic priming and thereby support disease progression[12]. These interactions have not been addressed to date. We evaluate the response to bacterial-derived lipopolysaccharides (LPS) on cytokine expression and perform an integrated analysis of assay for transposase accessible chromatin sequencing (ATACseq) and RNA sequencing (RNAseq) to identify differentially active transcription factors involved in the transcriptional induction of inflammatory programs in AMs. the effects of native mucus on AM activation and plasticity are evaluated on gene and protein expression levels, and functional changes are assessed via flow cytometry. This showed that muco-obstruction and mucus exposure is associated with a mixed AM phenotype and pathophysiologically relevant changes in AM immune responses and functions

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Results

Conclusion