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The role of interleukin-13 receptors in airway epithelial wound repair

University of British Columbia

The normal airway epithelium serves as a physical and immune barrier against environmental challenges and effectively repairs frequent injuries. Asthma is characterized by excessive and persistent airway epithelial damage and shedding, and barrier dysfunction. Interleukin-13 (IL)-13 is known to be a key cytokine in driving inflammatory and remodelling processes in asthma. Our laboratory demonstrated that IL-13 is a critical mediator of normal airway epithelial repair. Actions of IL-13 are mediated by IL-13 receptor α1 (IL-13Rα1)/IL-4 receptor alpha subunit (IL-4Rα) and IL-13 receptor α2 (IL-13Rα2). The understanding of IL-13 biology was previously ligand centric and focused on airway remodeling effects induced by IL-13-IL-13Rα1/IL-4Rα signalling via STAT6 activation. IL-13Rα2 was viewed as a high-affinity decoy receptor with a soluble form that binds IL-13 and inhibits signalling. Here, we present an updated paradigm, where balanced expression and appropriate regulation of IL-13 receptor subunits play major roles in epithelial repair and inflammatory responses. Our goal was to characterize the critical role of IL-13 receptor subunits and subsequent signalling pathways in modulating normal repair processes and maintaining airway epithelial barrier function. Using in vitro models of airway epithelial wound repair, we identified a novel signalling role for IL-13Rα2 in contrast to its established action as a decoy receptor. IL-13 signals via IL-13Rα2/IL-4Rα subunit to induce heparin-binding EGF-like factor (HB-EGF)-dependent activation of epidermal growth factor receptor (EGFR) and subsequent repair. IL-13 receptor subunit expression is dynamically altered in response to injury, particularly membranous IL-13Rα2 and IL-4Rα subunit positive airway epithelial cells (AEC) and colocalization of IL-13Rα2 and IL-4Rα subunit in AEC are both upregulated post-mechanical wounding. We demonstrated that IL-13Rα1 play a complex regulatory role in IL-13-IL-13Rα2 downstream signalling pathways and anti-inflammatory responses. In donor lung tissue, the airway epithelium of asthmatics expressed significantly decreased levels of IL-13Rα2 and increased levels of IL-13Rα1 compared with non-asthmatics. Dysregulated expression of IL-13 receptor subunits in airways of asthmatics may contribute to the epithelial barrier dysfunction observed in asthma. IL-13 receptor biology expanded by our work will aid in the development of novel therapeutics and relevant phenotyping assays for existing and novel therapies targeting the IL-13 and IL-4 pathways.

Text

2022-04-30

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/72094

Experimental Medicine

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/