Asthma is an airway inflammatory disease characterized by epithelial barrier dysfunction and airway remodeling. Interleukin‐13 (IL‐13) is a pleiotropic cytokine shown to contribute to features of airway remodeling. We have previously demonstrated that IL‐13 is an important mediator of normal airway epithelial repair and health. The role of IL‐13 signaling via its receptor subunits (IL‐13Rα1/IL‐4Rα and IL‐13Rα2) in airway epithelial repair and restoration of intact barrier function is not well understood and was investigated in this study using in vitro models. The blocking of IL‐13 signaling via IL‐13Rα2 significantly reduced airway epithelial repair by 24 h post‐mechanical wounding in 1HAEo− cells. Expression and release of repair‐mediating growth factor, heparin‐binding epidermal growth factor (EGF)‐like growth factor (HB‐EGF), and subsequent activation of EGF receptor (EGFR) were also significantly reduced in response to wounding when IL‐13Rα2 was blocked. Our data support that IL‐13 signals via IL‐13Rα2 to mediate normal airway epithelial repair via HB‐EGF‐dependent activation of EGFR. In human donor lung tissues, we observed that airway epithelium of asthmatics expressed significantly decreased levels of IL‐13Rα2 and increased levels of IL‐13Rα1 compared with nonasthmatics. Dysregulated expression of IL‐13 receptor subunits in the airways of asthmatics may thus contribute to the epithelial barrier dysfunction observed in asthma.—Yang, S. J., Allahverdian, S., Saunders, A. D. R., Liu, E., Dorscheid, D. R. IL‐13 signaling through IL‐13 receptor α2 mediates airway epithelial wound repair. FASEB J. 33, 3746–3757 (2019). http://www.fasebj.org

Rationale:The airway epithelium serves as a defense barrier and suffers frequent injury as a result, requiring repair coordinate with inflammation. Interleukin-13 (IL-13) is known to be a key cytokine in mediating inflammatory and remodelling processes in asthma. The actions of IL-13 are mediated by IL-13 receptor α1 (IL-13Rα1) and IL-13 receptor α2 (IL-13Rα2). Our lab has demonstrated that IL-13 is critical to normal airway epithelial repair via signaling the release of HB-EGF and activation of EGF-R. Appropriate control of inflammatory and repair processes is tightly regulated by the balance of IL-13Rα1 and IL-13Rα2 expression and function in response to injury. In this current investigation we studied the expression of IL-13Rα1 and IL-13Rα2 in normal and asthmatic airways. We hypothesize that the expression of IL-13 receptors is dysregulated in the asthmatic airway epithelium and contributes to the inappropriate IL-13 response observed in asthma. Methods: Expressions of IL-13Rα1 and IL-13Rα2 in sections from normal and asthmatic lung tissue and differentiated air-liquid interface (ALI) cultures of primary normal and asthmatic airway epithelial cells (AEC) were determined via immunohistochemistry and quantified using ImagePro Plus via colour segmentation. Primary airway epithelial cells from normal and asthmatic donors were cultured in monolayers and subjected to mechanical wounding and IL-13 stimulation over a time course of 24 hours. The cultures were then lysed IL-13 for protein and RNA extraction and Rα1 and IL-13Rα2 levels were detected via Western blotting and qRT-PCR respectively.Results: Immunohistochemical detection demonstrated that asthmatic airways, specifically in the epithelium, expressed significantly (p<0.05) higher levels of IL-13Rα1 compared to normal donors. Asthmatic airways also do not express significant levels of IL-13Rα2 and exhibit epithelial abnormalities. Cultured monolayer AEC from asthmatic donors continue to secrete IL-13 in excess relative to normal AEC. In addition to dysregulated IL-13 release, these cells demonstrate abnormal IL-13Rα2 expression and function with markedly impaired repair.