Sofia Winslow1, Lina Odqvist2, Sarah Diver3, Rebecca Riise2, Suado Abdillahi2, Cecilia Wingren2, Helena Lindmark4, Annika Wellner5, Sofia Lundin1, Linda Yrlid2, Elisabeth Ax1,6, Ratko Djukanovic7, Sriram Sridhar8, Andrew Higham9, Dave Singh9, Thomas Southworth9, Christopher E Brightling3, Henric K Olsson1, Zala Jevnikar1. 1. Translational Science and Experimental Medicine, Early Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. 2. Bioscience COPD/IPF, Early Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. 3. Department of Respiratory Science, Institute for Lung Health, NIHR Leicester Biomedical Research Centre, University of Leicester and University Hospitals of Leicester NHS Trust, Leicester, UK. 4. Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. 5. Medicinal Chemistry, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden. 6. Krefting Research Centre, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 7. NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences and Human Development and Health, University of Southampton, Southampton, UK. 8. Oncology Bioinformatics, Translational Science, Early Oncology, Oncology R&D, AstraZeneca, Gaithersburg, MD, USA. 9. The University of Manchester Division of Infection, Immunity and Respiratory Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester and University Hospital of South Manchester, NHS Foundation Trust, Manchester, UK.
Abstract
BACKGROUND: 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 characterize 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 (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. RESULTS: Hierarchical 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. CONCLUSION: IL-6TS pathway activation due to chronic colonization with Haemophilus may be an important disease driver in a subset of COPD patients.
BACKGROUND: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 characterize COPDpatients 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 (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. RESULTS: Hierarchical clustering revealed an IL-6TS-high subset (n=24) of COPDpatients, 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 COPDpatients 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 COPDpatients. CONCLUSION: IL-6TS pathway activation due to chronic colonization with Haemophilus may be an important disease driver in a subset of COPDpatients.