Les macrophages de mucus dans la bronchite chronique sont résistants aux corticostéroïdes et dirigent la production épithéliale de mucine par TNFα

Andelid, Kristina; Andersson, Anna-Lena; Öst, Karolina; Vanfleteren, Lowie E.G.W.; Göransson, Melker

doi:10.1016/j.rmra.2019.11.196

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“…In this study, we aimed to investigate the nature of macrophage-epithelial signaling driving mucus hyper-production using a newly established mechanistic in vitro model and to compare the LPS and steroid responsiveness of clinically sampled macrophages isolated from sputum plugs from patients with COPD and chronic bronchitis to that of alveolar macrophages isolated from lung resection tissue. Some of the results of these studies have been previously reported in the form of abstracts [ 28 , 29 ].…”

Section: Introductionmentioning

confidence: 99%

Lung macrophages drive mucus production and steroid-resistant inflammation in chronic bronchitis

et al. 2021

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Background Patients 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. Methods In 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. Results We 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. Conclusions For 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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Section: Introductionmentioning

confidence: 99%