PT  - JOURNAL ARTICLE
AU  - Sofia Winslow
AU  - Lina Odqvist
AU  - Sarah Diver
AU  - Rebecca Riise
AU  - Suado Abdillahi
AU  - Cecilia Wingren
AU  - Helena Lindmark
AU  - Annika Wellner
AU  - Sofia Lundin
AU  - Linda Yrlid
AU  - Elisabeth Ax
AU  - Ratko Djukanovic
AU  - Sriram Sridhar
AU  - Andrew Higham
AU  - Dave Singh
AU  - Thomas Southworth
AU  - Christopher E. Brightling
AU  - Henric K. Olsson
AU  - Zala Jevnikar
TI  - Multi-omics links IL-6 trans-signalling with neutrophil extracellular trap formation and <em>Haemophilus</em> infection in COPD
AID  - 10.1183/13993003.03312-2020
DP  - 2021 Oct 01
TA  - European Respiratory Journal
PG  - 2003312
VI  - 58
IP  - 4
4099  - http://erj.ersjournals.com/content/58/4/2003312.short
4100  - http://erj.ersjournals.com/content/58/4/2003312.full
SO  - Eur Respir J2021 Oct 01; 58
AB  - 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, IL-1β, IL-8, macrophage inflammatory protein-1β) 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.Lung IL-6 trans-signalling driven by Haemophilus influenzae-induced NETosis is a pathological feature of COPD patients with chronic Haemophilus infection, stable neutrophilic inflammation and uncontrolled disease https://bit.ly/30vhgD5