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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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Autores principales: Hey, Joschka, Paulsen, Michelle, Toth, Reka, Weichenhan, Dieter, Butz, Simone, Schatterny, Jolanthe, Liebers, Reinhard, Lutsik, Pavlo, Plass, Christoph, Mall, Marcus A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586227/
https://www.ncbi.nlm.nih.gov/pubmed/34764283
http://dx.doi.org/10.1038/s41467-021-26777-9
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author Hey, Joschka
Paulsen, Michelle
Toth, Reka
Weichenhan, Dieter
Butz, Simone
Schatterny, Jolanthe
Liebers, Reinhard
Lutsik, Pavlo
Plass, Christoph
Mall, Marcus A.
author_facet Hey, Joschka
Paulsen, Michelle
Toth, Reka
Weichenhan, Dieter
Butz, Simone
Schatterny, Jolanthe
Liebers, Reinhard
Lutsik, Pavlo
Plass, Christoph
Mall, Marcus A.
author_sort Hey, Joschka
collection PubMed
description 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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spelling pubmed-85862272021-11-15 Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease Hey, Joschka Paulsen, Michelle Toth, Reka Weichenhan, Dieter Butz, Simone Schatterny, Jolanthe Liebers, Reinhard Lutsik, Pavlo Plass, Christoph Mall, Marcus A. Nat Commun Article 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. Nature Publishing Group UK 2021-11-11 /pmc/articles/PMC8586227/ /pubmed/34764283 http://dx.doi.org/10.1038/s41467-021-26777-9 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Hey, Joschka
Paulsen, Michelle
Toth, Reka
Weichenhan, Dieter
Butz, Simone
Schatterny, Jolanthe
Liebers, Reinhard
Lutsik, Pavlo
Plass, Christoph
Mall, Marcus A.
Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease
title Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease
title_full Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease
title_fullStr Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease
title_full_unstemmed Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease
title_short Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease
title_sort epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8586227/
https://www.ncbi.nlm.nih.gov/pubmed/34764283
http://dx.doi.org/10.1038/s41467-021-26777-9
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