Inhibition of IL-4Rα in bronchial epithelial cells reduces CCL26 and TSLP without affecting antiviral immune responses

<bold>Rationale</bold>: Anti-IL-4Rα monoclonal antibodies (mAb) enhance lung function and reduce annual exacerbations in severe asthma patients. Airway epithelial cells play a key role in releasing exacerbation factors. However, the contribution of innate immune responses linked to the airway epithelium in these clinical effects remains unclear. <bold>Objectives:</bold> We sought to understand the effect and mechanisms of blocking IL-4Rα on anti-viral, alarmin, and eosinophil chemoattractant responses in bronchial epithelial cells under T2 conditions with and without rhinoviral infection in vitro. <bold>Methods:</bold> Human bronchial cells from seven donors were grown at air–liquid interface (ALI). Differentiated cells were stimulated with IL-4 or IL-13 cytokines, treated with an IL-4Rα mAb for 24h, and then infected with rhinovirus (RV) for 24h. Levels of anti-viral mediators, alarmins (TSLP), and CCL26 (eotaxin-3) were measured by RT-qPCR and ELISA. <bold>Results:</bold> IL-4 and IL-13 increased the CCL26 gene and protein expression in BECs (p<0.05). A IL-4Rα mAb decreased IL-4/IL-13-induced CCL26 levels (p<0.05), regardless of RV infection. IL-4/IL-13 did not affect RV-induced IFNB or IFNL1 gene responses. IL-4Rα inhibitor had no significant impact on RV-induced IFNB, IFNL1, or TSLP gene expression in BECs under IL-4/IL-13 conditions, except for reduced TSLP protein during IL-13 stimulation. <bold>Conclusions:</bold> IL-4Rα mAb treatment did not have any effect on epithelial anti-viral interferon response. However, blocking the T2- pathway resulted in down-modulation of CCL26 and TSLP indicating a possible positive treatment effect on preventing exacerbations by reduction of eosinophil chemotaxis and immune tolerance.