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Oxidised IL-33 driv...
Oxidised IL-33 drives COPD epithelial pathogenesis via ST2-independent RAGE/EGFR signalling complex
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- Strickson, Sam (author)
- AstraZeneca, UK
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- Houslay, Kirsty F. (author)
- AstraZeneca, UK
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- Negri, Victor A. (author)
- AstraZeneca, UK
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show more...
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- Ohne, Yoichiro (author)
- AstraZeneca, UK
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- Ottosson, Tomas (author)
- AstraZeneca, Sweden
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- Dodd, Roger B. (author)
- AstraZeneca, UK
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- Huntington, Catherine Chaillan (author)
- AstraZeneca, UK
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- Baker, Tina (author)
- AstraZeneca, UK
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- Li, Jingjing (author)
- AstraZeneca, UK
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- Stephenson, Katherine E. (author)
- AstraZeneca, UK
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- O’Connor, Andy J. (author)
- AstraZeneca, UK
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- Sagawe, J. Sophie (author)
- AstraZeneca, UK
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- Killick, Helen (author)
- AstraZeneca, UK
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- Moore, Tom (author)
- AstraZeneca, UK
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- Rees, D. Gareth (author)
- AstraZeneca, UK
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- Koch, Sofia (author)
- AstraZeneca, UK
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- Sanden, Caroline (author)
- Lund University,Lunds universitet,Luftvägsinflammation,Forskargrupper vid Lunds universitet,Airway Inflammation and Immunology,Lund University Research Groups,Medetect AB
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- Wang, Yixin (author)
- AstraZeneca, Sweden
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- Gubbins, Elise (author)
- AstraZeneca, UK
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- Ghaedi, Mahboobe (author)
- AstraZeneca, UK
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- Kolbeck, Roland (author)
- AstraZeneca, UK
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- Saumyaa, Saumyaa (author)
- AstraZeneca, Sweden
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- Erjefält, Jonas S. (author)
- Lund University,Lunds universitet,Luftvägsinflammation,Forskargrupper vid Lunds universitet,DCD transplantation av lungor,Airway Inflammation and Immunology,Lund University Research Groups,DCD transplantation of lungs,Skåne University Hospital
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- Sims, Gary P. (author)
- AstraZeneca, UK
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- Humbles, Alison A. (author)
- AstraZeneca, UK
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- Scott, Ian C. (author)
- AstraZeneca, UK
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- Ros, Xavier Romero (author)
- AstraZeneca, UK
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- Cohen, E. Suzanne (author)
- AstraZeneca, UK
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(creator_code:org_t)
- 2023
- 2023
- English.
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In: European Respiratory Journal. - 0903-1936. ; 62:3
- Related links:
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http://dx.doi.org/10... (free)
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Subject headings
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- 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-33ox) is thought to limit its activity. We investigated whether IL-33ox 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-33ox. Transcriptomic changes occurring in healthy ALI cultures treated with IL-33ox 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-33ox 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-33ox increased the proportion of mucus-producing cells and reduced epithelial defence functions, mimicking pathogenic traits of COPD. Neutralisation of the IL-33ox pathway reversed these deleterious traits in COPD epithelia. Gene signatures defining the pathogenic effects of IL-33ox 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 mucoobstructive features in COPD.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Lungmedicin och allergi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Respiratory Medicine and Allergy (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Strickson, Sam
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Houslay, Kirsty ...
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Negri, Victor A.
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Ohne, Yoichiro
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Ottosson, Tomas
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Dodd, Roger B.
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show more...
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Huntington, Cath ...
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Baker, Tina
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Li, Jingjing
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Stephenson, Kath ...
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O’Connor, Andy J ...
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Sagawe, J. Sophi ...
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Killick, Helen
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Moore, Tom
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Rees, D. Gareth
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Koch, Sofia
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Sanden, Caroline
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Wang, Yixin
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Gubbins, Elise
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Ghaedi, Mahboobe
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Kolbeck, Roland
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Saumyaa, Saumyaa
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Erjefält, Jonas ...
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Sims, Gary P.
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Humbles, Alison ...
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Scott, Ian C.
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Ros, Xavier Rome ...
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Cohen, E. Suzann ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Respiratory Medi ...
- Articles in the publication
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European Respira ...
- By the university
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Lund University