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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
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 (BHR) 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.
0954-7894
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.
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. (doi:10.1111/cea.13591).

Record type: Article

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 (BHR) 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.

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Davies_et_al-2020-Clinical_&_Experimental_Allergy - Accepted Manuscript
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Accepted/In Press date: 19 February 2020
e-pub ahead of print date: 24 February 2020

Identifiers

Local EPrints ID: 438322
URI: http://eprints.soton.ac.uk/id/eprint/438322
ISSN: 0954-7894
PURE UUID: d978bed3-0f0a-4071-be11-4dc6a1ce7dea
ORCID for Elizabeth R. Davies: ORCID iD orcid.org/0000-0002-8629-8324
ORCID for Ratko Djukanovic: ORCID iD orcid.org/0000-0001-6039-5612
ORCID for Donna E. Davies: ORCID iD orcid.org/0000-0002-5117-2991
ORCID for Hans Michael Haitchi: ORCID iD orcid.org/0000-0001-8603-302X

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Date deposited: 05 Mar 2020 17:30
Last modified: 26 Nov 2021 06:15

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Contributors

Author: Jeanne Marie Perotin
Author: Joanne Kelly
Author: Donna E. Davies ORCID iD

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