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

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.

ScRNA-seq expression ofIFI27andAPOC2identifies four alveolar macrophage superclusters in healthy BALF

“…They derive from prenatal monocytes, self-renew, and have shown remarkable plasticity by altering their transcriptome in response to the environmental changes ( Janssen et al, 2011 ; Jakubzick et al, 2013 ; Yona et al, 2013 ; Misharin et al, 2017 ; Mould et al, 2019 ; Aegerter et al, 2020 ; Arafa et al, 2022 ). Their transcriptional profile is altered in various inflammatory lung diseases, including asthma ( Fricker & Gibson, 2017 ; Hetzel et al, 2021 ), chronic obstructive pulmonary disease ( O’Beirne et al, 2020 ), cystic fibrosis ( McFarland & Rosenberg, 2009 ), and cancer ( Deriy et al, 2009 ; Bonfield, 2015 ; Bruscia & Bonfield, 2016 ; Casanova-Acebes, 2021 ; Hey et al, 2021 ; Li et al, 2021 ). Therefore, enhancing our current understanding of the normal cellular composition and functional diversity of AM subtypes will help characterize disease-related transcriptional changes more precisely and assess targeting specifically a given AM subtype to restore immune balance.…”

High-resolution transcriptomic and epigenetic profiling identifies novel regulators of COPD phenotypes in human lung fibroblasts

“…Smoking is the most prominent risk factor for COPD, and its impact on epigenetic landscape remodeling is well established (Belinsky et al 2002;Chen et al 2013;Zeilinger et al 2013;Wan et al 2015). Earlier studies also provided strong evidence for the association of dysregulated DNA methylation and COPD in blood (Qiu et al 2012;Busch et al 2016;Carmona et al 2018), sputum (Sood et al 2010), oral mucosa (Wan et al 2015), lung tissue (Sood et al 2010;Yoo et al 2015;Morrow et al 2016;Sundar et al 2017), bronchial brushings (Vucic et al 2014), fibroblasts (Clifford et al 2018) and macrophages from a mouse model of muco-obstructive disease (Hey et al 2021). Notably, DNA methylation changes were associated with altered expression of genes and pathways important to COPD pathology.…”

ScRNA-seq Expression ofIFI27andAPOC2Identifies Four Alveolar Macrophage Superclusters in Healthy BALF

“…They derive from prenatal monocytes, self-renew, and have shown remarkable plasticity by altering their transcriptome in response to the environmental changes (3,(5)(6)(7)(8). Their transcriptional profile is altered in various inflammatory lung diseases, including asthma (2,9), chronic obstructive pulmonary disease (10), cystic fibrosis (CF) (11), and cancer (12)(13)(14)(15)(16)(17). Therefore, enhancing our current understanding of the normal cellular composition and functional diversity of AM subtypes will help characterize disease-related transcriptional changes more precisely and assess targeting specifically a given AM subtype to restore immune balance.…”