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- Andelid, Kristina, 1953, et al.
(författare)
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Lung macrophages drive mucus production and steroid-resistant inflammation in chronic bronchitis
- 2021
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Ingår i: Respiratory research. - : Springer Science and Business Media LLC. - 1465-993X. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- 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 TNF alpha 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 TNF alpha-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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| 2. |
- Winslow, S., et al.
(författare)
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Multi-omics links IL-6 trans-signalling with neutrophil extracellular trap formation and Haemophilus infection in COPD
- 2021
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Ingår i: European Respiratory Journal. - : European Respiratory Society (ERS). - 0903-1936 .- 1399-3003. ; 58:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Interleukin (IL)-6 trans-signalling (IL-6TS) is emerging as a pathogenic mechanism in chronic respiratory diseases; however, the drivers of IL-6TS in the airways and the phenotypic characteristic of patients with increased IL-6TS pathway activation remain poorly understood. Objective: Our aim was to identify and characterise COPD patients with increased airway IL-6TS and to elucidate the biological drivers of IL-6TS pathway activation. Methods: We used an IL-6TS-specific sputum biomarker profile (soluble IL-6 receptor (sIL-6R), IL-6, IL1 beta, IL-8, macrophage inflammatory protein-1 beta) to stratify sputum data from patients with COPD (n=74; Biomarkers to Target Antibiotic and Systemic Corticosteroid Therapy in COPD Exacerbation (BEAT-COPD)) by hierarchical clustering. The IL-6TS signature was related to clinical characteristics and sputum microbiome profiles. The induction of neutrophil extracellular trap formation (NETosis) and IL-6TS by Haemophilus influenzae were studied in human neutrophils. Results: Hierarchical clustering revealed an IL-6TS-high subset (n=24) of COPD patients, who shared phenotypic traits with an IL-6TS-high subset previously identified in asthma. The subset was characterised by increased sputum cell counts (p=0.0001), persistent sputum neutrophilia (p=0.0004), reduced quality of life (Chronic Respiratory Questionnaire total score; p=0.008), and increased levels of pro-inflammatory mediators and matrix metalloproteinases in sputum. IL-6TS-high COPD patients showed an increase in Proteobacteria, with Haemophilus as the dominating genus. NETosis induced by H. influenzae was identified as a potential mechanism for increased sIL-6R levels. This was supported by a significant positive correlation between sIL-6R and NETosis markers in bronchoalveolar lavage fluid from COPD patients. Conclusion: IL-6TS pathway activation due to chronic colonisation with Haemophilus may be an important disease driver in a subset of COPD patients.
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