Involvement of the epidermal growth factor receptor in IL-13 mediated, corticosteroid-resistant airway inflammation: EGFR and corticosteroid resistance
Involvement of the epidermal growth factor receptor in IL-13 mediated, corticosteroid-resistant airway inflammation: EGFR and corticosteroid resistance
Background: Effective treatment for severe asthma is a significant unmet need. While eosinophilic inflammation caused by type 2 cytokines is responsive to corticosteroid and biologic therapies, many severe asthmatics exhibit corticosteroid-unresponsive mixed granulocytic inflammation. Objective: Here, we tested the hypothesis that the pro-allergic cytokine, IL-13, can drive both corticosteroid-sensitive and corticosteroid-resistant responses. Results: By integration of in vivo and in vitro models of IL-13–driven inflammation, we identify a role for the epidermal growth factor receptor (EGFR/ERBB1) as a mediator of corticosteroid-unresponsive inflammation and bronchial hyperresponsiveness driven by IL-13. Topological data analysis using human epithelial transcriptomic data from the U-BIOPRED cohort identified severe asthma groups with features consistent with the presence of IL-13 and EGFR/ERBB activation, with involvement of distinct EGFR ligands. Our data suggest that IL–13 may play a dual role in severe asthma: on the one hand driving pathologic corticosteroid-refractory mixed granulocytic inflammation, but on the other hand underpinning beneficial epithelial repair responses, which may confound responses in clinical trials. Conclusion and Clinical Relevance: Detailed dissection of those molecular pathways that are downstream of IL-13 and utilize the ERBB receptor and ligand family to drive corticosteroid-refractory inflammation should enhance the development of new treatments that target this sub-phenotype(s) of severe asthma, where there is an unmet need.
animal models, asthma, basic mechanisms, corticosteroid-refractory, epithelium, neutrophils
672-686
Davies, Elizabeth R.
aff6b3f7-91e0-4fd3-9554-a9389024b63b
Perotin, Jeanne Marie
48f760d9-7f2c-4e46-b6f7-cd3b9094bc19
Kelly, Joanne
5950d431-bc7e-4bad-817b-77446fc7332e
Djukanovic, Ratko
d9a45ee7-6a80-4d84-a0ed-10962660a98d
Davies, Donna E.
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe
1 June 2020
Davies, Elizabeth R.
aff6b3f7-91e0-4fd3-9554-a9389024b63b
Perotin, Jeanne Marie
48f760d9-7f2c-4e46-b6f7-cd3b9094bc19
Kelly, Joanne
5950d431-bc7e-4bad-817b-77446fc7332e
Djukanovic, Ratko
d9a45ee7-6a80-4d84-a0ed-10962660a98d
Davies, Donna E.
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe
Davies, Elizabeth R., Perotin, Jeanne Marie, Kelly, Joanne, Djukanovic, Ratko, Davies, Donna E. and Haitchi, Hans Michael
(2020)
Involvement of the epidermal growth factor receptor in IL-13 mediated, corticosteroid-resistant airway inflammation: EGFR and corticosteroid resistance.
Clinical & Experimental Allergy, 50 (6), .
(doi:10.1111/cea.13591).
Abstract
Background: Effective treatment for severe asthma is a significant unmet need. While eosinophilic inflammation caused by type 2 cytokines is responsive to corticosteroid and biologic therapies, many severe asthmatics exhibit corticosteroid-unresponsive mixed granulocytic inflammation. Objective: Here, we tested the hypothesis that the pro-allergic cytokine, IL-13, can drive both corticosteroid-sensitive and corticosteroid-resistant responses. Results: By integration of in vivo and in vitro models of IL-13–driven inflammation, we identify a role for the epidermal growth factor receptor (EGFR/ERBB1) as a mediator of corticosteroid-unresponsive inflammation and bronchial hyperresponsiveness driven by IL-13. Topological data analysis using human epithelial transcriptomic data from the U-BIOPRED cohort identified severe asthma groups with features consistent with the presence of IL-13 and EGFR/ERBB activation, with involvement of distinct EGFR ligands. Our data suggest that IL–13 may play a dual role in severe asthma: on the one hand driving pathologic corticosteroid-refractory mixed granulocytic inflammation, but on the other hand underpinning beneficial epithelial repair responses, which may confound responses in clinical trials. Conclusion and Clinical Relevance: Detailed dissection of those molecular pathways that are downstream of IL-13 and utilize the ERBB receptor and ligand family to drive corticosteroid-refractory inflammation should enhance the development of new treatments that target this sub-phenotype(s) of severe asthma, where there is an unmet need.
Text
Davies_et_al-2020-Clinical_&_Experimental_Allergy
- Accepted Manuscript
More information
Accepted/In Press date: 19 February 2020
e-pub ahead of print date: 24 February 2020
Published date: 1 June 2020
Additional Information:
Funding Information:
We would like to thank Professor Jeffrey A. Whitsett and Cincinnati Children's Hospital Medical Center for the transgenic IL-13 mice. We want to thank the animal facility at the University of Southampton for husbandry of the mice. We also thank Professor Colin D. Bingle at the University of Sheffield for teaching JFCK how to extract murine tracheal epithelial cells (mTEC) and grow them in culture. This work was supported by a Medical Research Council UK Clinician Scientist Fellowship to HMH (G0802804), a grant from the Asthma, Allergy & Inflammation (AAIR) Charity to ERD & HMH and a Medical Research Foundation/Asthma UK grant to HMH and DED (MRFAUK-2015-322). JMP is funded by the European Respiratory Society (Fellowship LTRF 2017), Association R?gionale pour l'Aide aux Insuffisants Respiratoires de Champagne-Ardenne (ARAIRCHAR), Association Nationale de Formation Continue en Allergologie (ANAFORCAL), Association des Allergologues de Champagne-Ardenne (ASALCAR) and Association des Pneumologues de Champagne-Ardenne (APCA).
Publisher Copyright:
© 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd
Keywords:
animal models, asthma, basic mechanisms, corticosteroid-refractory, epithelium, neutrophils
Identifiers
Local EPrints ID: 438322
URI: http://eprints.soton.ac.uk/id/eprint/438322
ISSN: 0954-7894
PURE UUID: d978bed3-0f0a-4071-be11-4dc6a1ce7dea
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Date deposited: 05 Mar 2020 17:30
Last modified: 17 Mar 2024 05:22
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Author:
Jeanne Marie Perotin
Author:
Joanne Kelly
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