دورية أكاديمية
Oxidised IL-33 drives COPD epithelial pathogenesis via ST2-independent RAGE/EGFR signalling complex.
| العنوان: | Oxidised IL-33 drives COPD epithelial pathogenesis via ST2-independent RAGE/EGFR signalling complex. |
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| المؤلفون: | Strickson S; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.; These authors contributed equally to this work., Houslay KF; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.; These authors contributed equally to this work., Negri VA; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Ohne Y; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA., Ottosson T; Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden., Dodd RB; Biologics Engineering, R&D, AstraZeneca, Cambridge, UK., Huntington CC; Biologics Engineering, R&D, AstraZeneca, Cambridge, UK., Baker T; Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Li J; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Stephenson KE; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., O'Connor AJ; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Sagawe JS; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Killick H; Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Moore T; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Rees DG; Biologics Engineering, R&D, AstraZeneca, Cambridge, UK., Koch S; Imaging & Data Analytics, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Cambridge, UK., Sanden C; Experimental Medical Sciences, Lund University, Lund, Sweden.; Medetect AB, Lund, Sweden., Wang Y; Imaging & Data Analytics, Clinical Pharmacology and Safety Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Gubbins E; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Ghaedi M; Bioscience COPD/IPF, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA., Kolbeck R; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.; Current: Spirovant Sciences, Philadelphia, PA, USA., Saumyaa S; Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden., Erjefält JS; Experimental Medical Sciences, Lund University, Lund, Sweden.; Allergology and Respiratory Medicine, Lund University, Skåne University Hospital, Lund, Sweden., Sims GP; Bioscience Immunology, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA., Humbles AA; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.; Current: Roche Pharma Research & Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland., Scott IC; Translational Science and Experimental Medicine, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Romero Ros X; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK.; These authors contributed equally to this work., Cohen ES; Bioscience Asthma and Skin Immunity, Research and Early Development, Respiratory & Immunology, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK suzanne.cohen@astrazeneca.com.; These authors contributed equally to this work. |
| المصدر: | The European respiratory journal [Eur Respir J] 2023 Sep 28; Vol. 62 (3). Date of Electronic Publication: 2023 Sep 28 (Print Publication: 2023). |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: European Respiratory Society Country of Publication: England NLM ID: 8803460 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1399-3003 (Electronic) Linking ISSN: 09031936 NLM ISO Abbreviation: Eur Respir J Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Sheffield, United Kingdom : European Respiratory Society Original Publication: Copenhagen : Published jointly by the Society and Munksgaard, 1988- |
| مواضيع طبية MeSH: | Interleukin-33*/genetics , Interleukin-33*/metabolism , Pulmonary Disease, Chronic Obstructive*/genetics , Pulmonary Disease, Chronic Obstructive*/metabolism , Pulmonary Disease, Chronic Obstructive*/pathology, Humans ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; ErbB Receptors ; Interleukin-1 Receptor-Like 1 Protein ; Oxidation-Reduction ; Receptor for Advanced Glycation End Products/metabolism |
| مستخلص: | Background: Epithelial damage, repair and remodelling are critical features of chronic airway diseases including chronic obstructive pulmonary disease (COPD). Interleukin (IL)-33 released from damaged airway epithelia causes inflammation via its receptor, serum stimulation-2 (ST2). Oxidation of IL-33 to a non-ST2-binding form (IL-33 ox ) is thought to limit its activity. We investigated whether IL-33 ox has functional activities that are independent of ST2 in the airway epithelium. Methods: In vitro epithelial damage assays and three-dimensional, air-liquid interface (ALI) cell culture models of healthy and COPD epithelia were used to elucidate the functional role of IL-33 ox . Transcriptomic changes occurring in healthy ALI cultures treated with IL-33 ox and COPD ALI cultures treated with an IL-33-neutralising antibody were assessed with bulk and single-cell RNA sequencing analysis. Results: We demonstrate that IL-33 ox forms a complex with receptor for advanced glycation end products (RAGE) and epidermal growth factor receptor (EGFR) expressed on airway epithelium. Activation of this alternative, ST2-independent pathway impaired epithelial wound closure and induced airway epithelial remodelling in vitro . IL-33 ox increased the proportion of mucus-producing cells and reduced epithelial defence functions, mimicking pathogenic traits of COPD. Neutralisation of the IL-33 ox pathway reversed these deleterious traits in COPD epithelia. Gene signatures defining the pathogenic effects of IL-33 ox were enriched in airway epithelia from patients with severe COPD. Conclusions: Our study reveals for the first time that IL-33, RAGE and EGFR act together in an ST2-independent pathway in the airway epithelium and govern abnormal epithelial remodelling and muco-obstructive features in COPD. Competing Interests: Conflict of interest: S. Strickson, V.A. Negri, Y. Ohne, T. Ottosson, R.B. Dodd, C.C. Huntington, T. Baker, J. Li, K.E. Stephenson, A.J. O'Connor, J.S. Sagawe, H. Killick, D.G. Rees, S. Koch, Y. Wang, M. Ghaedi, S. Saumyaa, G.P. Sims, I.C. Scott, X. Romero Ros and E.S. Cohen are employees of AstraZeneca and may hold stock or stock options in AstraZeneca. K.F. Houslay, T. Moore, E. Gubbins, R. Kolbeck and A.A. Humbles are former employees of AstraZeneca and may hold stock or stock options in AstraZeneca. C. Sanden has nothing to disclose. J.S. Erjefält is a founder and board member of Medetect AB. (Copyright ©The authors 2023.) |
| التعليقات: | Comment in: Eur Respir J. 2023 Sep 28;62(3):. (PMID: 37770091) |
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| المشرفين على المادة: | EC 2.7.10.1 (EGFR protein, human) EC 2.7.10.1 (ErbB Receptors) 0 (IL1RL1 protein, human) 0 (IL33 protein, human) 0 (Interleukin-1 Receptor-Like 1 Protein) 0 (Interleukin-33) 0 (Receptor for Advanced Glycation End Products) 0 (AGER protein, human) |
| تواريخ الأحداث: | Date Created: 20230713 Date Completed: 20231011 Latest Revision: 20231011 |
| رمز التحديث: | 20231012 |
| مُعرف محوري في PubMed: | PMC10533947 |
| DOI: | 10.1183/13993003.02210-2022 |
| PMID: | 37442582 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1399-3003 |
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| DOI: | 10.1183/13993003.02210-2022 |