TY - JOUR T1 - Cross-talk of inflammatory mediators and airway epithelium reveals the cystic fibrosis transmembrane conductance regulator as a major target JF - ERJ Open Research JO - erjor DO - 10.1183/23120541.00247-2021 VL - 7 IS - 4 SP - 00247-2021 AU - Filipa B. Simões AU - Arthur Kmit AU - Margarida D. Amaral Y1 - 2021/10/01 UR - http://openres.ersjournals.com/content/7/4/00247-2021.abstract N2 - Airway inflammation, mucus hyperproduction and epithelial remodelling are hallmarks of many chronic airway diseases, including asthma, COPD and cystic fibrosis. While several cytokines are dysregulated in these diseases, most studies focus on the response of airways to interleukin (IL)-4 and IL-13, which have been shown to induce mucus hyperproduction and shift the airway epithelium towards a hypersecretory phenotype.We hypothesised that other cytokines might induce the expression of chloride (Cl−) channels/transporters, and regulate epithelial differentiation and mucus production. To this end, fully differentiated human airway basal cells (BCi-NS1.1) were treated with cytokines identified as dysregulated in those diseases, namely IL-8, IL-1β, IL-4, IL-17A, IL-10 and IL-22, and tumour necrosis factor-α.Our results show that the cystic fibrosis transmembrane conductance regulator (CFTR) is the main Cl− channel modulated by inflammation, in contrast to transmembrane protein 16A (TMEM16A), whose levels only changed with IL-4. Furthermore, we identified novel roles for IL-10 and IL-22 by influencing epithelial differentiation towards ciliated cells and away from pulmonary ionocytes. In contrast, IL-1β and IL-4 reduced the number of ciliated cells while increasing club cells. Interestingly, while IL-1β, IL-4 and IL-10 upregulated CFTR expression, IL-4 was the only cytokine that increased both its function and the number of CFTR-expressing club cells, suggesting that this cell type may be the main contributor for CFTR function. Additionally, all cytokines assessed increased mucus production through a differential upregulation of MUC5AC and MUC5B transcript levels.This study reveals a novel insight into differentiation resulting from the cross-talk of inflammatory mediators and airway epithelial cells, which is particularly relevant for chronic airway diseases.Disease-specific inflammatory cytokines induce airway mucus hyperproduction and changes in chloride channels/transporters, and modulate epithelial differentiation https://bit.ly/2WaeV1z ER -