Neutrophil extracellular traps are associated with disease severity and microbiota diversity in patients with chronic obstructive pulmonary disease Alison.

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Presentation transcript:

Neutrophil extracellular traps are associated with disease severity and microbiota diversity in patients with chronic obstructive pulmonary disease Alison J. Dicker, PhD, Megan L. Crichton, MFM, Eleanor G. Pumphrey, Andrew J. Cassidy, PhD, Guillermo Suarez-Cuartin, MD, Oriol Sibila, MD, Elizabeth Furrie, PhD, Christopher J. Fong, Wasyla Ibrahim, Gill Brady, BSc, Gisli G. Einarsson, PhD, J. Stuart Elborn, MD, Stuart Schembri, MD, Sara E. Marshall, PhD, Colin N.A. Palmer, PhD, James D. Chalmers, PhD Journal of Allergy and Clinical Immunology Volume 141, Issue 1, Pages 117-127 (January 2018) DOI: 10.1016/j.jaci.2017.04.022 Copyright © 2017 The Authors Terms and Conditions

Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10 Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10.1016/j.jaci.2017.04.022) Copyright © 2017 The Authors Terms and Conditions

Fig 1 Histone-elastase complex concentrations in soluble sputum of patients with COPD are associated with clinical markers of COPD disease severity. A, NET concentration in stable samples compared with GOLD score (n = 99). B, NET concentration compared with number of exacerbations reported by study patients in previous year (n = 99). C, NET concentration in stable samples compared with percent predicted FEV1 (n = 99). D, NET concentration in stable samples compared with CAT score (n = 99). Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10.1016/j.jaci.2017.04.022) Copyright © 2017 The Authors Terms and Conditions

Fig 2 Sputum biomarkers and severity of COPD. A, Sputum MPO activity is associated with GOLD stage and exacerbation frequency (n = 99). B, Sputum cfDNA is not significantly associated with GOLD stage or exacerbations (n = 99). C, Neutrophil elastase activity is associated with GOLD stage but not significantly with exacerbation frequency (n = 99). Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10.1016/j.jaci.2017.04.022) Copyright © 2017 The Authors Terms and Conditions

Fig 3 Microbiota composition and NET formation in patients with stable COPD. In the above figure, each bar represents an individual patient. A, Microbiomes of patients with COPD when clinically stable, with 14 of the most commonly identified genera per patient highlighted. Each patient is only represented once. B, Correlation of SWDI values of all stable samples against NET complexes (n = 89). C, NET formation in stable soluble sputum samples stratified by percentage of Haemophilus species OTUs present (n = 82). Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10.1016/j.jaci.2017.04.022) Copyright © 2017 The Authors Terms and Conditions

Fig 4 Changes in microbiota and NET formation at COPD exacerbation. A, Individual microbiome profiles of all exacerbation samples (n = 37 from 24 separate exacerbation events), with corresponding start and end exacerbation samples adjacent to each other. Exacerbation number denotes start of exacerbation sample, with end of exacerbation sample positioned to its right. Some patients were unable to produce sputum at both visits. B, Examples of longitudinal changes in microbiomes over time, showing 2 individual patients. EndEx, Ten days after exacerbation treatment once clinical recovery has occurred; StartEx, onset of exacerbation before treatment. C, Haemophilus species OTU dominance at exacerbation is associated with significantly higher NET formation (n = 24). D, Based on blood eosinophilia,26 NET concentrations were increased in patients with noneosinophilic exacerbations and not in those with eosinophilic exacerbations (n = 24). Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10.1016/j.jaci.2017.04.022) Copyright © 2017 The Authors Terms and Conditions

Fig 5 Platelet-neutrophil aggregates are present in airways of patients with COPD. A, Neutrophils were gated based on CD16 and side scatter (top left), the quadrants for positive and negative CD41a were set (bottom left) in the isotype control, and these gates were applied to the test sample (right panels). The example shows positive staining for the platelet marker CD41a-PE. B, No relationship between DNA-elastase complexes and soluble CD40 ligand, a marker of platelet activation (n = 72). C, No relationship between sputum NET concentrations and CXCL8 levels in sputum (n = 72). PE, Phycoerythrin; PerCP, peridinin-chlorophyll-protein complex. Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10.1016/j.jaci.2017.04.022) Copyright © 2017 The Authors Terms and Conditions

Fig 6 Direct relationship between sputum DNA-elastase complexes and ex vivo phagocytosis assessed by using flow cytometry. A, Representative image of phagocytosis flow cytometry showing isotype control (top image) used to set gates for test sample (bottom image); test sample results were normalized by using isotype control to account for background fluorescence. B, Phagocytosis of fluorescein isothiocyanate–labeled P aeruginosa was evaluated by the percentage of positive cells and mean fluorescence, which quantifies the number of fluorescent bacteria ingested per cell (n = 40). C, Dose-dependent inhibition of phagocytosis of fluorescein isothiocyanate–labeled E coli by healthy donor neutrophils in response to pretreatment for 30 minutes with fluticasone propionate, pooled soluble sputum (n = 7 donors with COPD), or supernatant from neutrophils induced to undergo NETosis by means of incubation for 4 hours with 20 nmol/L PMA (n = 4 replicates with different donors for each experiment). *P < .05. D, Individual soluble sputum from 24 patients with COPD used to pretreat healthy donor neutrophils, followed by phagocytosis of fluorescein isothiocyanate–labeled E coli for 30 minutes. Data show a direct relationship between the sputum DNA-elastase complex concentration and subsequent neutrophil phagocytosis, suggesting that samples with high NET concentrations inhibit phagocytosis. Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10.1016/j.jaci.2017.04.022) Copyright © 2017 The Authors Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10.1016/j.jaci.2017.04.022) Copyright © 2017 The Authors Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10.1016/j.jaci.2017.04.022) Copyright © 2017 The Authors Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10.1016/j.jaci.2017.04.022) Copyright © 2017 The Authors Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10.1016/j.jaci.2017.04.022) Copyright © 2017 The Authors Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10.1016/j.jaci.2017.04.022) Copyright © 2017 The Authors Terms and Conditions

Fig E6 Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10.1016/j.jaci.2017.04.022) Copyright © 2017 The Authors Terms and Conditions

Fig E7 Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10.1016/j.jaci.2017.04.022) Copyright © 2017 The Authors Terms and Conditions

Fig E8 Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10.1016/j.jaci.2017.04.022) Copyright © 2017 The Authors Terms and Conditions

Fig E9 Journal of Allergy and Clinical Immunology 2018 141, 117-127DOI: (10.1016/j.jaci.2017.04.022) Copyright © 2017 The Authors Terms and Conditions