Involvement of the epidermal growth factor receptor in IL‐13–mediated corticosteroid‐resistant airway inflammation

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 ClinicalRelevance: 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. K E Y W O R D S animal models, asthma, basic mechanisms, corticosteroid-refractory, epithelium, neutrophils | 673 DAVIES Et Al.

Integrated Analysis of microRNAs and Metabolomics in Rat’s Serum Reveals Multi-action Modes of Qingfei Paidu Decoction for COVID-19 Treatment

“…Involving regulation of immunity [154], in ammatory cytokines [154][155][156][157][158][159][160] [190][191][192], virus infection [193][194][195][196][197][198][199][200][201][202][203], especially SARS-CoV-2 [196,[198][199][200][201][204][205][206], multi-organ (especially pulmonary) brosis [207][208][209][210] phospholipase C, gamma 1 (Plcg1) [219,220], in ammatory cytokines [221,222], virus infection, e.g., H1N1, HBV [223][224][225] Note: SARS-CoV-2, severe acute respiratory syndrome coronavirus-2; HTLV, human T-cell leukemia virus; HCV, hepatitis C virus; DHBV, duck hepatitis B virus; HBV, hepatitis B virus; H1N1, In uenza A virus H1N1 2009.…”

Airway Epithelial Dysfunction in Asthma: Relevant to Epidermal Growth Factor Receptors and Airway Epithelial Cells

“…However, EGFR and IL-13 shares an inhibitory effect on transcription factor of FOXA2 which regulates mucus production [ 39 ]. A recent study using conditional transgenic mice expressing the IL13 transgene showed that mice expressing IL-13 exhibited airway hyperresponsiveness and neutrophilic airway inflammation which are inhibited by EGF inhibitor treatment [ 28 ]. Eosinophilic airway inflammation induced by expressing- IL13 gene was not improved by treating with an EGFR inhibitor alone, but the combination therapy of EGFR inhibitor and dexamethasone suppressed airway eosinophilia and neutrophilic inflammation.…”

“…Eosinophilic airway inflammation induced by expressing- IL13 gene was not improved by treating with an EGFR inhibitor alone, but the combination therapy of EGFR inhibitor and dexamethasone suppressed airway eosinophilia and neutrophilic inflammation. Along with transcriptomic analysis among cohorts, including severe asthma patients, the EGFR pathway makes considerable contributions to mucus metaplasia among asthmatics, as well as the IL-13 pathway [ 28 ].…”

“…Recently, ErbB3 expression has a potential association with a severe asthma phenotype. The transcriptome analyses among a multi-center study cohort including severe asthmatics has been reported in relation between the severe asthma phenotype and EGFR family expression [ 28 ]. A severe asthma phenotype with neutrophilic inflammation showed upregulated ERBB3 expression as well as for several EGFR ligands including HB-EGF, epiregulin, and EGF as shown in “IL-17 signature.” Further sub-phenotype analysis revealed that the “IL-13” phenotype and the “IL-17” phenotype had upregulated ERBB3 expression.…”

Why we should focus on adolescents and young adults

“…Corticosteroid‐unresponsive, mixed granulocytic inflammation in seen people with severe asthma 6 . Davies et al have looked at whether the pro‐allergic cytokine, IL‐13, can drive this situation 7 . Using in vivo and in vitro models, they have identified epidermal growth factor receptor as a mediator of IL‐13‐driven, corticosteroid‐unresponsive inflammation and bronchial hyperresponsiveness.…”