IL-33 Expression Is Lower in Current Smokers at both Transcriptomic and Protein Levels
American Journal of Respiratory and Critical Care Medicine, vol. 208, pp. 1075–1087
Abstract
Abstract Rationale IL-33 is a proinflammatory cytokine thought to play a role in the pathogenesis of asthma and chronic obstructive pulmonary disease (COPD). A recent clinical trial using an anti–IL-33 antibody showed a reduction in exacerbation and improved lung function in ex-smokers but not current smokers with COPD. Objectives This study aimed to understand the effects of smoking status on IL-33. Methods We investigated the association of smoking status with the level of gene expression of IL-33 in the airways in eight independent transcriptomic studies of lung airways. Additionally, we performed Western blot analysis and immunohistochemistry for IL-33 in lung tissue to assess protein levels. Measurements and Main Results Across the bulk RNA-sequencing datasets, IL-33 gene expression and its signaling pathway were significantly lower in current versus former or never-smokers and increased upon smoking cessation (P < 0.05). Single-cell sequencing showed that IL-33 is predominantly expressed in resting basal epithelial cells and decreases during the differentiation process triggered by smoke exposure. We also found a higher transitioning of this cellular subpopulation into a more differentiated cell type during chronic smoking, potentially driving the reduction of IL-33. Protein analysis demonstrated lower IL-33 levels in lung tissue from current versus former smokers with COPD and a lower proportion of IL-33–positive basal cells in current versus ex-smoking controls. Conclusions We provide strong evidence that cigarette smoke leads to an overall reduction in IL-33 expression in transcriptomic and protein level, and this may be due to the decrease in resting basal cells. Together, these findings may explain the clinical observation that a recent antibody-based anti–IL-33 treatment is more effective in former than current smokers with COPD.
Authors 31
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University of Technology Sydney · University of Groningen
Affiliation as printed
Department of Pulmonary Diseases, and
Groningen Research Institute for Asthma and COPD
Respiratory Bioinformatics and Molecular Biology, School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia
Department of Pulmonary Diseases, and; Groningen Research Institute for Asthma and COPD,; Respiratory Bioinformatics and Molecular Biology, School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia;
Groningen Research Institute for Asthma and COPD,
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University of Technology Sydney
Affiliation as printed
Respiratory Bioinformatics and Molecular Biology, School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia
University of Technology Sydney, 1994, Respiratory Bioinformatics and Molecular Biology (RBMB), School of Life Sciences, Faculty of Science, Sydney, New South Wales, Australia
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University of Technology Sydney · Centenary Institute
Affiliation as printed
Centre for Inflammation, Faculty of Science, Centenary Institute and University of Technology Sydney, Sydney, New South Wales, Australia
Respiratory Bioinformatics and Molecular Biology, School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia
Centre for Inflammation, Faculty of Science, Centenary Institute and University of Technology Sydney, Sydney, New South Wales, Australia;
Centre for Inflammation, Faculty of Science, Centenary Institute and University of Technology Sydney, Sydney, New South Wales, Australia;; Respiratory Bioinformatics and Molecular Biology, School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia;
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
Groningen Research Institute for Asthma and COPD
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands;
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands;; Groningen Research Institute for Asthma and COPD,
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
Groningen Research Institute for Asthma and COPD
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands;
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands;; Groningen Research Institute for Asthma and COPD,
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
Groningen Research Institute for Asthma and COPD
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands;
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands;; Groningen Research Institute for Asthma and COPD,
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
Groningen Research Institute for Asthma and COPD
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands;
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands;; Groningen Research Institute for Asthma and COPD,
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University of Technology Sydney · Centenary Institute
Affiliation as printed
Centre for Inflammation, Faculty of Science, Centenary Institute and University of Technology Sydney, Sydney, New South Wales, Australia
Centre for Inflammation, Faculty of Science, Centenary Institute and University of Technology Sydney, Sydney, New South Wales, Australia;
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University of Technology Sydney · Centenary Institute
Affiliation as printed
Centre for Inflammation, Faculty of Science, Centenary Institute and University of Technology Sydney, Sydney, New South Wales, Australia
Centre for Inflammation, Faculty of Science, Centenary Institute and University of Technology Sydney, Sydney, New South Wales, Australia;
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Affiliation as printed
Department of Pulmonary Diseases, and
Groningen Research Institute for Asthma and COPD
Department of Pulmonary Diseases, and; Groningen Research Institute for Asthma and COPD,
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
Department of Pulmonary Diseases, and
Groningen Research Institute for Asthma and COPD
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands;
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands;; Department of Pulmonary Diseases, and; Groningen Research Institute for Asthma and COPD,
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Inserm · Université Paris Sciences et Lettres · Centre de Bio-Informatique · École Nationale Supérieure des Mines de Paris · Institut Curie
Affiliation as printed
Cancer and Genome: Bioinformatics, Biostatistics and Epidemiology of Complex Systems Institut Curie, Paris, France
Centre for Computational Biology, Mines ParisTech, Paris Sciences et Lettres Research University, Paris, France
Institut Nationale de la Santé et de la Recherche Médicale U900, Paris, France
Cancer and Genome: Bioinformatics, Biostatistics and Epidemiology of Complex Systems Institut Curie, Paris, France;
Centre for Computational Biology, Mines ParisTech, Paris Sciences et Lettres Research University, Paris, France;
Institut Nationale de la Santé et de la Recherche Médicale U900, Paris, France;
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Affiliation as printed
Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany;
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University of Cologne · Max Delbrück Center · University Hospital Cologne · Berlin Institute for the Foundations of Learning and Data
Affiliation as printed
Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
Berlin Institute for the Foundations of Learning and Data, Berlin, Germany
Institute for Computational Cancer Biology, Center for Integrated Oncology, Cancer Research Center Cologne Essen, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany
Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany;
Berlin Institute for the Foundations of Learning and Data, Berlin, Germany;
Institute for Computational Cancer Biology, Center for Integrated Oncology, Cancer Research Center Cologne Essen, Faculty of Medicine and University Hospital Cologne, University of Cologne, Germany;
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Affiliation as printed
National Heart & Lung Institute, Imperial College London, London, United Kingdom
National Heart & Lung Institute, Imperial College London, London, United Kingdom;
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Affiliation as printed
National Heart & Lung Institute, Imperial College London, London, United Kingdom
National Heart & Lung Institute, Imperial College London, London, United Kingdom;
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Leiden University Medical Center
Affiliation as printed
Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands;
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Leiden University Medical Center
Affiliation as printed
Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands
Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands;
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Affiliation as printed
Sanofi, Chilly-Mazarin, France
Sanofi, Chilly-Mazarin, France;
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Affiliation as printed
Sanofi, Chilly-Mazarin, France
Sanofi, Chilly-Mazarin, France;
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Affiliation as printed
Sanofi, Cambridge, Massachusetts
Sanofi, Cambridge, Massachusetts;
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Affiliation as printed
Sanofi, Cambridge, Massachusetts
Sanofi, Cambridge, Massachusetts;
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Affiliation as printed
Sanofi, Cambridge, Massachusetts
Sanofi, Cambridge, Massachusetts, United States
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Affiliation as printed
Regeneron Pharmaceuticals, Tarrytown, New York
Regeneron Pharmaceuticals Inc, 7845, Tarrytown, New York, United States
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Affiliation as printed
Regeneron Pharmaceuticals, Tarrytown, New York
Regeneron Pharmaceuticals, Tarrytown, New York;
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Affiliation as printed
Regeneron Pharmaceuticals, Tarrytown, New York
Regeneron Pharmaceuticals Inc, 7845, Tarrytown, New York, United States
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Hunter Medical Research Institute · University of Newcastle Australia
Affiliation as printed
Centre for Asthma & Respiratory Disease, The University of Newcastle, Newcastle, New South Wales, Australia; and
Hunter Medical Research Institute, Vaccines, Infection, Viruses & Asthma Newcastle, New South Wales, Australia
Hunter Medical Research Institute, Vaccines, Infection, Viruses & Asthma, Newcastle, New South Wales, Australia; The University of Newcastle, Centre for Asthma & Respiratory Disease, Newcastle, New South Wales, Australia
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Affiliation as printed
Department of Pulmonary Diseases, and
Groningen Research Institute for Asthma and COPD
Department of Pulmonary Diseases, and; Groningen Research Institute for Asthma and COPD,
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
Groningen Research Institute for Asthma and COPD
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands;
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands;; Groningen Research Institute for Asthma and COPD,
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands
Groningen Research Institute for Asthma and COPD
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands;
Department of Pathology & Medical Biology, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands;; Groningen Research Institute for Asthma and COPD,
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Affiliation as printed
Department of Pulmonary Diseases, and
Groningen Research Institute for Asthma and COPD
Department of Pulmonary Diseases, and; Groningen Research Institute for Asthma and COPD,
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