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

Joschka Hey, Michelle Paulsen (), Reka Toth, Dieter Weichenhan, Simone Butz, Jolanthe Schatterny, Reinhard Liebers, Pavlo Lutsik, Christoph Plass () and Marcus A. Mall ()
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Joschka Hey: German Cancer Research Center (DKFZ)
Michelle Paulsen: German Center for Lung Research (DZL)
Reka Toth: German Cancer Research Center (DKFZ)
Dieter Weichenhan: German Cancer Research Center (DKFZ)
Simone Butz: German Center for Lung Research (DZL)
Jolanthe Schatterny: German Center for Lung Research (DZL)
Reinhard Liebers: German Cancer Research Center (DKFZ)
Pavlo Lutsik: German Cancer Research Center (DKFZ)
Christoph Plass: German Cancer Research Center (DKFZ)
Marcus A. Mall: German Center for Lung Research (DZL)

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-26777-9

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