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Epigenetic reprogramming of airway macrophages drives polarization and inflammation in muco-obstructive lung disease (WGBS_BL)

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 focused on the role of the mucostatic airway microenvironment on epigenetic reprogramming of airway macrophages (AM) and resulting transcriptomic and phenotypical changes. Using a muco-obstructive mouse model (Scnn1b-transgenic), we identified epigenetically controlled, differentially regulated pathways and transcription factors involved in inflammatory responses and macrophage polarization. Ex vivo stimulation of wild-type AMs with mucus induced gene expression changes, comparable with those observed in AMs from Scnn1b-transgenic mice. Functionally, AMs from Scnn1b-transgenic mice displayed impaired efferocytosis, phagocytosis and excessive inflammatory responses upon lipopolysaccharide challenge, mediated through enhanced Irf1 activity and expression. Our data show that mucostasis induces epigenetic reprogramming of AMs, leading to changes favoring tissue damage and disease progression. Targeting of these altered AMs may support therapeutic approaches in patients with muco-obstructive lung diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE154803 | GEO | 2021/09/10

REPOSITORIES: GEO

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Project description:Scnn1b-Tg mice overexpress the beta subunit of the epithelial sodium channel (Scnn1b) in airway Club cells. The general phenotype of these mice is described in three published manuscripts (Mall et al. 2004, Nature Medicine, 10(5):487-93; Mall et al. 2008, Am J Respir Crit Care Med. 177(7):730-42; Livraghi-Butrico et al. 2012, Physiol. Genomics 44(8):470-84; and Livraghi-Butrico et al. 2012, Mucosal Immunology 5(4):397-408). Briefly, overexpression of the Scnn1b transgene in airway Club cells leads to hyperabsorption of sodium from the airway surface liquid, which causes airway surface liquid and mucus dehydration, resulting in reduced mucus clearance and airway mucus obstruction. The data provided here represents mRNA expression data from disseccted whole lung from male WT and Scnn1b-transgenic littermates (C57Bl/6NTac background) at 4 time points [postnatal days (PND) 0, 3, 10, and 42]. Histologically, PND 0 lungs are normal, at PND 3 the intrapulmonary airways exhibit transient and spotty Club cell necrosis, and by PND 10 airway mucus obstruction is evident in the proximal portion of the intrapulmonary main stem bronchus. At PND 42, Scnn1b-Tg lungs are charactyerized by chronic low level inflammation, with activated macrophages, neutrophilia, eosinophilia and increased incidence of bronchus-associated lymphoid tissue. The data from the WT mice provides a global look at mRNA post-natal developmental changes, while the data from the Scnn1b-transgenic line allows differential gene expression due to airway surface liquid dehydration and mucus obstruction to be queried. The data presented for the lung is part of a larger body of work evaluating gene expression in lung (left lobe only), trachea, and purified macrophages (from bronchoalveolar lavage fluid). 24 Total lung (left lobe only) samples were analyzed; three from each timepoint for each genotype (wild type and Scnn1b-transgenic). In our manuscript, we were most interested in changes between WT and Scnn1b-Tg mice, however, the data can also be used to evaluate changes in gene expression across time (PND 0, 3, 10, and 42). We generated the following pairwise comparisons: Scnn1b-Tg vs WT mice for each PND time point; Intra-strain comparison between PND 3, or 10, or 42 vs PND 0.

Project description:Scnn1b-Tg mice overexpress the beta subunit of the epithelial sodium channel (Scnn1b) in airway Club cells. The general phenotype of these mice is described in three published manuscripts (Mall et al. 2004, Nature Medicine, 10(5):487-93; Mall et al. 2008, Am J Respir Crit Care Med. 177(7):730-42; and Livraghi-Butrico et al. 2012, Physiol. Genomics 44(8):470-84. Briefly, overexpression of the Scnn1b transgene in airway Club cells leads to hyperabsorption of sodium from the airway surface liquid, dehydrated airway surface liquid and mucus, and reduced mucus clearance associated with accumulation of mucus plugs/plaques. The data provided here represents mRNA expression data from disseccted whole trachea (distal and proximal ends cut 3-4 cartliage rings below the larynx and just above the bifurcation, respectively) from male WT and Scnn1b-Tg littermates (C57Bl/6NTac background) at 4 time points [postnatal days (PND) 0, 3, 10, and 42]. PND 0 trachea are histologically normal, a tracheal mucus plug/obstruction develops around PND 3, the plug is receding to more distal airways by PND 10, and the trachea is again histologically normal by PND 42. The data from the WT mice provides a global look at mRNA changes across time, while the data from the Scnn1b-Tg line provides mRNA data that allows differential gene expression due to mucus obstruction to be queried. The data presented for the purified is part of a larger body of work evaluating gene expression in whole lung, trachea, and purified macrophages. 30 total macrophage samples were analyzed; three from each timepoint (postnatal day 0, 3, 10, and 42) for both wildtype and Scnn1b-transgenic mice grown in specific-pathogen-free facilities and from postnatal day 42 wildtype and Scnn1b-transgenic mice maintained in a germ-free facility. In our manuscript, we were most interested in changes between WT and Scnn1b-Tg mice, however, the data can also be used to evaluate changes in gene expression across time (postnatal day 0, 3, 10, and 42). This data can also be used to evaluate the differences in macrophage biology at postnatal day 42 when mice are grown in specific-pathogen-free versus germ-free environments.

Project description:Scnn1b-Tg mice overexpress the beta subunit of the epithelial sodium channel (Scnn1b) in airway Club cells. The general phenotype of these mice is described in three published manuscripts (Mall et al. 2004, Nature Medicine, 10(5):487-93; Mall et al. 2008, Am J Respir Crit Care Med. 177(7):730-42; Livraghi-Butrico et al. 2012, Physiol. Genomics 44(8):470-84; and Livraghi-Butrico et al. 2012, Mucosal Immunology 5(4):397-408). Briefly, overexpression of the Scnn1b transgene in airway Club cells leads to hyperabsorption of sodium from the airway surface liquid, which causes airway surface liquid and mucus dehydration, resulting in reduced mucus clearance and airway mucus obstruction. The data provided here represents mRNA expression data from dissected whole trachea (distal and proximal ends were cut 3-4 cartilage rings below the larynx and just above the bifurcation, respectively) from male WT and Scnn1b-Tg littermates (C57Bl/6N Tac background) at 4 time points [postnatal days (PND) 0, 3, 10, and 42]. Histologically, PND 0 trachea are normal, a tracheal mucus plug/obstruction develops around PND 3 and typically recedes to the intrapulmonary airways after PND 10, and the trachea is again histologically normal by PND 42. The data from the WT mice provides a global look at mRNA post-natal developmental changes, while the data from the Scnn1b-Tg line provides mRNA data that allows differential gene expression due to airway mucus obstruction to be queried. The data presented for the trachea is part of a larger body of work evaluating gene expression in whole lung, trachea, and purified macrophages. 24 Total tracheal samples were analyzed; three from each timepoint. In our manuscript, we were most interested in changes between WT and Scnn1b-Tg mice, however, the data can also be used to evaluate changes in gene expression across time (PND 0, 3, 10, and 42). It should be noted that a significant difference in RNA expression quality parameters was noted for the 10 day trachea data.