Multi-omics links IL-6 trans-signalling with neutrophil extracellular trap formation and Haemophilus infection in COPD

BackgroundIL-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.ObjectiveOur aim was to identify and characterize COPD patients with increased airway IL-6TS and to elucidate the biological drivers of IL-6TS pathway activation.MethodsWe used an IL-6TS-specific sputum biomarker profile (sIL-6R, IL-6, IL-1β, IL-8, MIP-1β) to stratify sputum data from patients with COPD (n=74; 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.ResultsHierarchical clustering revealed an IL-6TS-high subset (n=24) of COPD patients, which shared phenotypic traits with an IL-6TS-high subset previously identified in asthma. The subset was characterized by increased sputum cell counts (p=0.0001), persistent sputum neutrophilia (p=0.0004), reduced quality of life (CRQ total score; p=0.008), and increased levels of pro-inflammatory mediators and MMPs 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 soluble IL-6 receptor (sIL-6R) levels. This was supported by a significant positive correlation between sIL-6R and NETosis markers in bronchoalveolar lavage fluid from COPD patients.ConclusionIL-6TS pathway activation due to chronic colonization with Haemophilus may be an important disease driver in a subset of COPD patients.