Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease
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 (A...
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| Hauptverfasser: | , , , , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
11 November 2021
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| In: |
Nature Communications
Year: 2021, Jahrgang: 12, Pages: 1-18 |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-021-26777-9 |
| Online-Zugang: | Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.1038/s41467-021-26777-9 Verlag, lizenzpflichtig, Volltext: https://www.nature.com/articles/s41467-021-26777-9 
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| Verfasserangaben: | Joschka Hey, Michelle Paulsen, Reka Toth, Dieter Weichenhan, Simone Butz, Jolanthe Schatterny, Reinhard Liebers, Pavlo Lutsik, Christoph Plass, Marcus A. Mall |
| Zusammenfassung: | 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. |
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| Beschreibung: | Gesehen am 12.11.2021 |
| Beschreibung: | Online Resource |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-021-26777-9 |