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

Sofia Winslow, Lina Odqvist, Sarah Diver, Rebecca Riise, Suado Abdillahi, Cecilia Wingren, Helena Lindmark, Annika Wellner, Sofia Lundin, Linda Yrlid, Elisabeth Ax, Ratko Djukanovic, Sriram Sridhar, Andrew Higham, Dave Singh, Thomas Southworth, Christopher E. Brightling, Henric K. Olsson, Zala Jevnikar
European Respiratory Journal 2021 58: 2003312; DOI: 10.1183/13993003.03312-2020
Sofia Winslow
1Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Lina Odqvist
2Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Sarah Diver
3Dept of Respiratory Science, Institute for Lung Health, NIHR Leicester Biomedical Research Centre, University of Leicester and University Hospitals of Leicester NHS Trust, Leicester, UK
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Rebecca Riise
2Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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  • ORCID record for Rebecca Riise
Suado Abdillahi
2Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Cecilia Wingren
2Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Helena Lindmark
4Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
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Annika Wellner
5Medicinal Chemistry, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Sofia Lundin
1Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Linda Yrlid
2Bioscience COPD/IPF, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Elisabeth Ax
1Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
6Krefting Research Centre, Institute of Medicine at the Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
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Ratko Djukanovic
7NIHR Southampton Respiratory Biomedical Research Unit, Clinical and Experimental Sciences and Human Development and Health, University of Southampton, Southampton, UK
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Sriram Sridhar
8Oncology Bioinformatics, Translational Science, Early Oncology, Oncology R&D, AstraZeneca, Gaithersburg, MD, USA
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Andrew Higham
9The 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
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Dave Singh
9The 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
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Thomas Southworth
9The 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
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Christopher E. Brightling
3Dept of Respiratory Science, Institute for Lung Health, NIHR Leicester Biomedical Research Centre, University of Leicester and University Hospitals of Leicester NHS Trust, Leicester, UK
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Henric K. Olsson
1Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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Zala Jevnikar
1Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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  • For correspondence: Zala.JevnikarRojnik@astrazeneca.com
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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, 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.

Abstract

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

Footnotes

  • This article has supplementary material available from erj.ersjournals.com

  • This article has an editorial commentary: https://doi.org/10.1183/13993003.02143-2021

  • Conflict of interest: S. Winslow is an employee and a share/stockholder of AstraZeneca.

  • Conflict of interest: L. Odqvist is an employee and a share/stockholder of AstraZeneca.

  • Conflict of interest: S. Diver has nothing to disclose.

  • Conflict of interest: R. Riise is an employee and a share/stockholder of AstraZeneca.

  • Conflict of interest: S. Abdillahi is an employee and a share/stockholder of AstraZeneca.

  • Conflict of interest: C. Wingren is an employee and a share/stockholder of AstraZeneca.

  • Conflict of interest: H. Lindmark is an employee and a share/stockholder of AstraZeneca.

  • Conflict of interest: A. Wellner is an employee and a share/stockholder of AstraZeneca.

  • Conflict of interest: S. Lundin is an employee and a share/stockholder of AstraZeneca.

  • Conflict of interest: L. Yrlid is an employee and a share/stockholder of AstraZeneca.

  • Conflict of interest: E. Ax is an employee and a share/stockholder of AstraZeneca.

  • Conflict of interest: R. Djukanovic reports personal fees for lectures and consultancy from TEVA and Novartis, personal fees for consultancy from Synairgen, personal fees for meeting participation from GlaxoSmithKline, outside the submitted work.

  • Conflict of interest: S. Sridhar is an employee and a share/stockholder of AstraZeneca.

  • Conflict of interest: A. Higham has nothing to disclose.

  • Conflict of interest: D. Singh reports personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, Genentech, GlaxoSmithKline, Glenmark, Gossamerbio, Menarini, Mundipharma, Novartis, Peptinnovate, Pfizer, Pulmatrix, Theravance, Verona, outside the submitted work.

  • Conflict of interest: T. Southworth has nothing to disclose.

  • Conflict of interest: C.E. Brightling reports personal fees from GSK, AstraZeneca/MedImmune, Boehringer Ingelheim, Novartis, Roche and Chiesi, outside the submitted work.

  • Conflict of interest: H.K. Olsson is an employee and a share/stockholder of AstraZeneca.

  • Conflict of interest: Z. Jevnikar is an employee and a share/stockholder of AstraZeneca.

  • Support statement: This study was funded by AstraZeneca. Employees from AstraZeneca participated in the study design, data collection, data analysis, data interpretation and the writing of the manuscript. AstraZeneca reviewed the publication, without influencing the opinions of the authors, to ensure medical and scientific accuracy and the protection of intellectual property. The corresponding author had access to all data and had the final responsibility for the decision to submit the manuscript for publication. The other funding bodies were not involved in any parts of the design, analysis or interpretation of the study. E. Ax was also supported by the Swedish Foundation for Strategic Research (SSF). C.E. Brightling was supported by MedImmune, Medical Research Council, National Institute for Health Research Leicester Biomedical Research Centre (UK) and AirPROM (FP7–270194). D. Singh was supported by the National Institute for Health Research (NIHR) Manchester Biomedical Research Centre (BRC), North West Lung Centre Charity, Manchester, UK and by AstraZeneca, Gaithersburg, MD, USA. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

  • Received August 28, 2020.
  • Accepted March 4, 2021.
  • Copyright ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org
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Multi-omics links IL-6 trans-signalling with neutrophil extracellular trap formation and Haemophilus infection in COPD
Sofia Winslow, Lina Odqvist, Sarah Diver, Rebecca Riise, Suado Abdillahi, Cecilia Wingren, Helena Lindmark, Annika Wellner, Sofia Lundin, Linda Yrlid, Elisabeth Ax, Ratko Djukanovic, Sriram Sridhar, Andrew Higham, Dave Singh, Thomas Southworth, Christopher E. Brightling, Henric K. Olsson, Zala Jevnikar
European Respiratory Journal Oct 2021, 58 (4) 2003312; DOI: 10.1183/13993003.03312-2020

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Multi-omics links IL-6 trans-signalling with neutrophil extracellular trap formation and Haemophilus infection in COPD
Sofia Winslow, Lina Odqvist, Sarah Diver, Rebecca Riise, Suado Abdillahi, Cecilia Wingren, Helena Lindmark, Annika Wellner, Sofia Lundin, Linda Yrlid, Elisabeth Ax, Ratko Djukanovic, Sriram Sridhar, Andrew Higham, Dave Singh, Thomas Southworth, Christopher E. Brightling, Henric K. Olsson, Zala Jevnikar
European Respiratory Journal Oct 2021, 58 (4) 2003312; DOI: 10.1183/13993003.03312-2020
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