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.
Keywords: animal models; asthma; basic mechanisms; corticosteroid-refractory; epithelium; neutrophils.
© 2020 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.