TY - JOUR
T1 - Epigenetic reprogramming of airway macrophages promotes polarization and inflammation in muco-obstructive lung disease
AU - Hey, Joschka
AU - Paulsen, Michelle
AU - Toth, Reka
AU - Weichenhan, Dieter
AU - Butz, Simone
AU - Schatterny, Jolanthe
AU - Liebers, Reinhard
AU - Lutsik, Pavlo
AU - Plass, Christoph
AU - Mall, Marcus A.
N1 - Funding Information:
We thank Dr. Malte Paulsen, Dr. Diana Ordonez, and the Flow Cytometry Core Facility team (EMBL, Heidelberg), Dr. V. Benes, Dr. J. Landry, and J. Pistolic of the Gene Core Facility EMBL, Heidelberg, for their continuous support and assistance. Furthermore, we greatly acknowledge the service provided by the Genomics and Proteomics Core Facility (DKFZ, Heidelberg) and Omics IT and Data Management Core Facility (DKFZ, Heidelberg). The work was supported in part by the German Ministry for Education and Research (82DZL004A1 and 82DZL009B1 to M.A.M.), the German Research Foundation (SFB-TR84TP B08 and SFB 1449 A01 and Z02 to M.A.M.), the Helmholtz Foundation, and the German-Israeli Helmholtz Research School in Cancer Biology, Cancer-Transitional Research and Exchange Program (Cancer-TRAX) to J.H.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85118957502&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/34764283
U2 - 10.1038/s41467-021-26777-9
DO - 10.1038/s41467-021-26777-9
M3 - Article
C2 - 34764283
AN - SCOPUS:85118957502
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 6520
ER -