PT - JOURNAL ARTICLE AU - Filipa B. Simões AU - Arthur Kmit AU - Margarida D. Amaral TI - Cross-talk of inflammatory mediators and airway epithelium reveals CFTR as a major target AID - 10.1183/23120541.00247-2021 DP - 2021 Jan 01 TA - ERJ Open Research PG - 00247-2021 4099 - http://openres.ersjournals.com/content/early/2021/07/15/23120541.00247-2021.short 4100 - http://openres.ersjournals.com/content/early/2021/07/15/23120541.00247-2021.full AB - Airway inflammation, mucus hyperproduction and epithelial remodelling are hallmarks of many chronic airway diseases, including asthma, Chronic Obstructive Pulmonary Disease and Cystic Fibrosis. While several cytokines are dysregulated in these diseases, most studies focus on the response of airways to IL-4 and IL-13, which were 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, 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 interleukins-8, 1β, 4, 17A, 10, 22, and tumour necrosis factor-α (TNF-α).Our results show that CFTR is the main Cl− channel modulated by inflammation, in contrast to 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. Contrarily, 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.Altogether, 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.FootnotesThis manuscript has recently been accepted for publication in the ERJ Open Research. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJOR online. Please open or download the PDF to view this article.