IL-4R? expression by airway epithelium and smooth muscle accounts for nearly all airway hyperresponsiveness in murine allergic airway disease.

ABSTRACT: Airway hyperresponsiveness (AHR) often defines asthma. Murine allergic airway disease (AAD), like human eosinophilic asthma, is characterized by AHR, eosinophilia, goblet cell metaplasia (GCM), smooth muscle hypercontractility, and increased production of IL-4 and IL-13-cytokines that induce these characteristics by binding to the IL-4R? chain. We evaluated the epithelial and smooth muscle IL-4R?-dependent contributions to AHR of BALB/c mice that possessed 0-2 functional IL-4R? alleles and had airway disease induced by house dust mite extract (HDM) or exogenous IL-13. Two functional IL-4R? alleles were required for maximal AHR, while only one functional allele was required for maximal GCM and systemic IL-4/IL-13 levels. Deletion of IL-4R? from both smooth muscle and epithelial cells inhibited AHR >83% in mice with two functional IL-4R? alleles. In mice with one functional IL-4R? allele, selective epithelial cell IL-4R? deletion maximally inhibited AHR, while selective smooth muscle IL-4R? deletion decreased IL-13-induced, but not HDM-induced, AHR. Less IL-4R? signaling is required to maximize the epithelial cell contribution to AHR compared to the smooth muscle contribution to AHR. In addition, epithelial cell responses to IL-4/IL-13 can increase the IL-4R?-dependent smooth muscle contribution to AHR. These findings carry increasing relevance as IL-4R?-targeted therapy is administered to human asthmatics.

SUBMITTER: McKnight CG 

PROVIDER: S-EPMC7641252 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature