Asthma inflammatory phenotypes show differential microRNA expression in sputum Tania Maes, PhD, Francisco Avila Cobos, MSc, Florence Schleich, MD, PhD,

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Presentation transcript:

Asthma inflammatory phenotypes show differential microRNA expression in sputum Tania Maes, PhD, Francisco Avila Cobos, MSc, Florence Schleich, MD, PhD, Valentina Sorbello, PhD, Monique Henket, MLT, Katleen De Preter, PhD, Ken R. Bracke, PhD, Griet Conickx, Pharm, Claire Mesnil, PhD, Jo Vandesompele, PhD, Lies Lahousse, PhD, Fabrice Bureau, PhD, Pieter Mestdagh, PhD, Guy F. Joos, MD, PhD, Fabio L.M. Ricciardolo, MD, PhD, Guy G. Brusselle, MD, PhD, Renaud Louis, MD, PhD Journal of Allergy and Clinical Immunology Volume 137, Issue 5, Pages 1433-1446 (May 2016) DOI: 10.1016/j.jaci.2016.02.018 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Journal of Allergy and Clinical Immunology 2016 137, 1433-1446DOI: (10 Journal of Allergy and Clinical Immunology 2016 137, 1433-1446DOI: (10.1016/j.jaci.2016.02.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 miRNA profiling in the screening cohort. A and C, Volcano plots of the −log10-adjusted P values versus the log10 fold changes in miRNA expression between groups. The horizontal line represents the significance level of the false discovery rate–adjusted P values (P < .05 was considered significant), indicating all miRNAs above this line are differentially expressed. A log10 fold change of 0.3 indicates a 2-fold increase in miRNA expression. Fig 1, A, Healthy subjects (n = 10) compared with patients with severe asthma (n = 9); Fig 1, C, patients with neutrophilic asthma (n = 8) compared with healthy subjects (n = 10). B and D, Hierarchic clustering of the top 20 most differentially expressed miRNAs in sputum supernatants. Samples are based on asthma severity (Fig 1, B) or the inflammatory phenotype (Fig 1, D). The heat map was built by using Manhattan distance and the Ward method. Red indicates an expression level greater than the mean across all subjects, and blue indicates an expression level lower than the mean. Journal of Allergy and Clinical Immunology 2016 137, 1433-1446DOI: (10.1016/j.jaci.2016.02.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Validation cohort: normalized miRNA expression levels (log10-based) determined by using qRT-PCR. A, Expression of miRNAs according to asthma severity. The mild asthma category includes patients with mild-to-moderate asthma. B, Expression of miRNA according to inflammatory phenotype (eosinophilic asthma, ≥3% eosinophils and <76% neutrophils in sputum; neutrophilic asthma, ≥76% neutrophils and <3% eosinophils in sputum). *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2016 137, 1433-1446DOI: (10.1016/j.jaci.2016.02.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Validation cohort. A-C, Spearman correlation between the percentage of sputum neutrophils and expression of miR-629-3p (Fig 3, A), miR-223-3p (Fig 3, B), and miR-142-3p (Fig 3, C). D-F, Spearman correlation between the percentage of sputum macrophages and expression of miR-629-3p (Fig 3, D), miR-223-3p (Fig 3, E), and miR-142-3p (Fig 3, F). G-I, Spearman correlation between miRNA expression in sputum supernatants. Fig 3, A, miR-223-3p and miR-142-3p; Fig 3, B, miR-223-3p and miR-629-3p; and Fig 3, C, miR-142-3p and miR-629-3p. Journal of Allergy and Clinical Immunology 2016 137, 1433-1446DOI: (10.1016/j.jaci.2016.02.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Origin of miR-629-3p, miR-223-3p, and miR-142-3p in sputum. A-C and G-I, In situ localization of miRNA expression (blue color) in bronchial biopsy specimens. Fig 4, A and B, miR-629-3p expression in patients with severe asthma. Fig 4, C, No staining for miR-629-3p in healthy control subjects. Fig 4, G-H, miR-223-3p expression in patients with severe asthma. Fig 4, I, Faint staining for miR-223-3p in healthy control subjects. Tissue was counterstained with nuclear fast red. D-F and J-L, Localization of neutrophil elastase–positive cells (red color, indicated by black arrows) in bronchial biopsy specimens in corresponding regions of consecutive sections of Fig 4, A-C and G-I, respectively. Tissue was counterstained with hematoxylin (blue). Black stars represents regions where miR-223-3p and neutrophil elastase are colocalized. M and N, Expression of miR-223-3p (Fig 4, M) and miR-142-3p (Fig 4, N) in sorted cell subsets in sputum. Sputum cells (n = 2-5, depending on cell type) were sorted by means of flow cytometry. Macrophages were defined as CD45+CD14+SSChigh, monocytes as CD45+CD14+SSClow, and neutrophils as CD45+CD14−CD16+; see Fig E3 for the gating strategy. miRNA expression was normalized to snord95, snord96A, and snord68. Log10-based values are shown. Journal of Allergy and Clinical Immunology 2016 137, 1433-1446DOI: (10.1016/j.jaci.2016.02.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Bioinformatic workflow to discover the functional role of miR-629-3p, miR-223-3p, and miR-142-3p in asthmatic patients. KEGG, Kyoto Encyclopedia of Genes and Genomes. Journal of Allergy and Clinical Immunology 2016 137, 1433-1446DOI: (10.1016/j.jaci.2016.02.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 A and B, Spearman correlations between IL-1β (in picograms per milliliter) and miR-223-3p (Fig 6, A) and IL-1β (in picograms per milliliter) and miR-142-3p (Fig 6, B) in sputum supernatants of the validation cohort. C and E-J, mRNA expression of genes relevant to asthma and/or direct miRNA targets in HBECs transfected with mimics for miR-629-3p, miR-223-3p, and miR-142-3p or negative scrambled control (NegSCR; n = 4 per group). D, IL-8 protein levels in supernatants of HBECs transfected with mimics for miR-629-3p, miR-223-3p, and miR-142-3p (n = 4 per group). *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2016 137, 1433-1446DOI: (10.1016/j.jaci.2016.02.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2016 137, 1433-1446DOI: (10.1016/j.jaci.2016.02.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2016 137, 1433-1446DOI: (10.1016/j.jaci.2016.02.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2016 137, 1433-1446DOI: (10.1016/j.jaci.2016.02.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2016 137, 1433-1446DOI: (10.1016/j.jaci.2016.02.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2016 137, 1433-1446DOI: (10.1016/j.jaci.2016.02.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Journal of Allergy and Clinical Immunology 2016 137, 1433-1446DOI: (10.1016/j.jaci.2016.02.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions