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While eosinophilic inflammation caused by type 2 cytokines is responsive to corticosteroid and biologic therapies, many severe asthmatics exhibit corticosteroid\u2010unresponsive mixed granulocytic inflammation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objective<\/jats:title><jats:p>Here, we tested the hypothesis that the pro\u2010allergic cytokine, IL\u201013, can drive both corticosteroid\u2010sensitive and corticosteroid\u2010resistant responses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>By integration of in vivo and in vitro models of IL\u201013\u2013driven inflammation, we identify a role for the epidermal growth factor receptor (EGFR\/ERBB1) as a mediator of corticosteroid\u2010unresponsive inflammation and bronchial hyperresponsiveness driven by IL\u201013. Topological data analysis using human epithelial transcriptomic data from the U\u2010BIOPRED cohort identified severe asthma groups with features consistent with the presence of IL\u201013 and EGFR\/ERBB activation, with involvement of distinct EGFR ligands. Our data suggest that IL\u201313 may play a dual role in severe asthma: on the one hand driving pathologic corticosteroid\u2010refractory mixed granulocytic inflammation, but on the other hand underpinning beneficial epithelial repair responses, which may confound responses in clinical trials. <\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Clinical Relevance<\/jats:title><jats:p>Detailed dissection of those molecular pathways that are downstream of IL\u201013 and utilize the ERBB receptor and ligand family to drive corticosteroid\u2010refractory inflammation should enhance the development of new treatments that target this sub\u2010phenotype(s) of severe asthma, where there is an unmet need.<\/jats:p><\/jats:sec>","DOI":"10.1111\/cea.13591","type":"journal-article","created":{"date-parts":[[2020,2,25]],"date-time":"2020-02-25T06:16:51Z","timestamp":1582611411000},"page":"672-686","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Involvement of the epidermal growth factor receptor in IL\u201013\u2013mediated corticosteroid\u2010resistant airway inflammation"],"prefix":"10.1111","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8629-8324","authenticated-orcid":false,"given":"Elizabeth R.","family":"Davies","sequence":"first","affiliation":[{"name":"Brooke Laboratories Clinical and Experimental Sciences Faculty of Medicine University of Southampton Southampton 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