Abstract Rationale The airway epithelium forms a vital physical and immunological barrier against environmental insults. Following injury from infection, particulates, or allergens, rapid epithelial repair is essential to restore barrier integrity and resolve inflammation. This process involves coordinated epithelial migration, proliferation, and differentiation to reestablish structure and function. Interleukin-13 (IL-13) regulates these events through two receptors, IL-13Rα1 and IL-13Rα2, which activate distinct signaling cascades that maintain epithelial homeostasis. Imbalance between these pathways contributes to airway remodeling in asthma. While IL-13Rα1 mediates canonical JAK-STAT6 signaling, the downstream role of IL-13Rα2 in epithelial repair remains poorly understood. This study investigates IL-13Rα2-dependent MAPK and AP-1 (Fra-1, Fra-2) signaling and its crosstalk with IL-13Rα1 during epithelial wound repair. Methods Human airway epithelial cells (1HAEo−) were cultured as monolayers, serum-starved, and treated with IL-13 following selective neutralization of IL-13Rα1 or IL-13Rα2. Samples were collected at 15 min, 30 min, 1 h, 2 h, 24 h, and 48 h post-treatment. Protein lysates were analyzed by Western blotting for phosphorylated STAT6, ERK1/2, Fra-1, and Fra-2. Data were analyzed using two-way ANOVA with Tukey’s post hoc test. Results Compared with IL-13-stimulated controls, IL-13Rα1 neutralization had minimal effect on early STAT6 phosphorylation but significantly increased p-STAT6 expression at 48 h (p 0.05). Neutralization of IL-13Rα2 led to enhanced p-STAT6 activation at 0.5, 24, and 48 h (p 0.05), suggesting loss of inhibitory regulation. IL-13Rα1 blockade promoted early Fra-1 activation (0.25-0.5 h), followed by decline at 2 h (p 0.01), and increased Fra-2 at 1 h (p 0.05). In contrast, IL-13Rα2 neutralization had no significant effect on Fra-1 or Fra-2 expression. ERK1/2 phosphorylation decreased after IL-13Rα1 neutralization but fluctuated dynamically under IL-13Rα2 blockade, showing transient activation between 15 min and 24 h and suppression at 48 h (p 0.001). Conclusion IL-13Rα1 and IL-13Rα2 act as reciprocally regulating nodes within the IL-13 signaling network, maintaining balance between activation and resolution phases in airway epithelial cells. IL-13Rα2 functions as a negative feedback regulator, constraining STAT6 and ERK1/2 activation to promote repair, while IL-13Rα1 drives canonical signaling associated with inflammation and remodeling. Temporal separation between early and late signaling peaks indicates receptor crosstalk, where IL-13Rα1 mediates activation and IL-13Rα2 governs resolution via MAPK/AP-1 pathways (Fra-1, Fra-2). Together, these receptors maintain epithelial homeostasis between inflammation and repair. This abstract is funded by: RespNet
Tanveer et al. (Fri,) studied this question.