Regenerative Metaplastic Clones in COPD Lung Drive Inflammation and Fibrosis.
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ABSTRACT:
SUBMITTER: Rao W
PROVIDER: S-EPMC7294989 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Controlled recruitment of C-C Motif Chemokine Receptor 2 (CCR2)-positive monocytes into lung tissues is a crucial component of the host immune response to infections. Pathogenesis of cystic fibrosis (CF) lung remodeling, which ultimately leads to respiratory failure, is caused by chronic infections and neutrophilic inflammation, but the immune mechanisms are not fully understood. Here, we show that lung explants from CF patients with severe disease contain abundant CCR2-positive classical monocytes in the submucosal tissues of small airways and areas of tissue remodeling. Recapitulating human CF lung remodeling by repeatedly exposing CF mice to lipopolysaccharide (LPS), and by using genetic ablation or pharmacological inhibition of CCR2, we demonstrate that CCR2-dependent accumulation of classical monocytes and monocyte-derived macrophages drive lung neutrophilia, pathogenic Transforming Growth Factor Beta signaling and irreversible lung tissue scarring. Importantly, six weeks after cessation of LPS exposure, the lungs of CF mice still have elevated numbers of pro-inflammatory monocytes with higher expression of neutrophil chemoattractants, thus perpetuating recruitment of neutrophils and lung tissue damage. Lastly, we demonstrate that the increased accumulation of immune cells to inflamed lungs is driven by dysfunctional CF transmembrane conductance regulator (CFTR) expression in CCR2-positive cells. These studies identify uncontrolled recruitment of CCR2-positive cells as a key driver of lung remodeling, and as a novel therapeutic target for patients with CF for which lung hyper-inflammation and tissue damage remain an issue despite recent advances in CFTR-specific therapeutics. Keywords: monocytes; macrophages; neutrophils; chronic lung inflammation; lipopolysaccharide; recruitment; CC-motif chemokine receptor 2; transforming growth factor beta; lung remodeling; cystic fibrosis
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Project description:BackgroundPatients with chronic obstructive pulmonary disease (COPD) frequently suffer from chronic bronchitis (CB) and display steroid-resistant inflammation with increased sputum neutrophils and macrophages. Recently, a causal link between mucus hyper-concentration and disease progression of CB has been suggested.MethodsIn this study, we have evaluated the steroid sensitivity of purified, patient-derived sputum and alveolar macrophages and used a novel mechanistic cross-talk assay to examine how macrophages and bronchial epithelial cells cross-talk to regulate MUC5B production.ResultsWe demonstrate that sputum plug macrophages isolated from COPD patients with chronic bronchitis (COPD/CB) are chronically activated and only partially respond to ex vivo corticosteroid treatment compared to alveolar macrophages isolated from lung resections. Further, we show that pseudo-stratified bronchial epithelial cells grown in air-liquid-interface are inert to direct bacterial lipopolysaccharide stimulation and that macrophages are able to relay this signal and activate the CREB/AP-1 transcription factor complex and subsequent MUC5B expression in epithelial cells through a soluble mediator. Using recombinant protein and neutralizing antibodies, we identified a key role for TNFα in this cross-talk.ConclusionsFor the first time, we describe ex vivo pharmacology in purified human sputum macrophages isolated from chronic bronchitis COPD patients and identify a possible basis for the steroid resistance frequently seen in this population. Our data pinpoint a critical role for chronically activated sputum macrophages in perpetuating TNFα-dependent signals driving mucus hyper-production. Targeting the chronically activated mucus plug macrophage phenotype and interfering with aberrant macrophage-epithelial cross-talk may provide a novel strategy to resolve chronic inflammatory lung disease.
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