Function-specific IL17A and Dexamethasone interactions in primary human airway epithelial cells

Background: Sputum, nasal and bronchial biopsies, and serum of asthmatics have elevated levels of IL17 compared to healthy controls. IL17A is likely to contribute to reduced corticosteroid sensitivity of human airway epithelium. Here, we aimed to investigate the mechanistic underpinnings of this reduced sensitivity in more detail. Methods: Primary human airway epithelial cells (hAECs) were differentiated at an air liquid interface (ALI) and exposed to IL17A (10 ng/ml) in the absence or presence of dexamethasone (Dex, 10 nM) for 14 days. Cells were then collected for RNA sequencing analysis or used for barrier function experiments. Mucus was collected for volume measurement and basal medium for cytokine analysis. Results: 2861 genes were differentially expressed by IL17A (Padj<0.05), of which 2184 genes (92.78%) were not sensitive to Dex (<50% inhibition). Moreover, IL17A inhibited induction of canonical steroid genes by Dex, such as HSD11B2 and FKBP5 (p<0.05). Inflammatory and goblet cell metaplasia markers, cytokine secretion and mucus production were all induced by IL17A, and these effects were not prevented by Dex. However, Dex reversed IL17A-stimulated epithelial disruption (p<0.05) and this was associated with gene expression changes related to cilia function and development. Conclusions: IL17A induces function-specific steroid-insensitivity. Whereas inflammatory response genes and mucus production in primary hAECs in response to IL-17A were steroid-insensitive, corticosteroids were able to reverse IL17A-induced epithelial barrier disruption. The results highlights the function-specific role of corticosteroid-insensitivity in airway epithelial cells.