Function-specific IL-17A and dexamethasone interactions in primary human airway epithelial cells

Abstract

Asthmatics have elevated levels of IL-17A compared to healthy controls. IL-17A 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. Differentiated primary human airway epithelial cells (hAECs) were exposed to IL-17A in the absence or presence of dexamethasone. 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. 2861 genes were differentially expressed by IL-17A (Padj < 0.05), of which the majority was not sensitive to dexamethasone (< 50% inhibition). IL-17A did inhibit canonical corticosteroid genes, such as HSD11B2 and FKBP5 (p < 0.05). Inflammatory and goblet cell metaplasia markers, cytokine secretion and mucus production were all induced by IL-17A, and these effects were not prevented by dexamethasone. Dexamethasone did reverse IL-17A-stimulated epithelial barrier disruption, and this was associated with gene expression changes related to cilia function and development. We conclude that IL-17A induces function-specific corticosteroid-insensitivity. Whereas inflammatory response genes and mucus production in primary hAECs in response to IL-17A were corticosteroid-insensitive, corticosteroids were able to reverse IL-17A-induced epithelial barrier disruption.

Molecular mechanism of interleukin-17A regulating airway epithelial cell ferroptosis based on allergic asthma airway inflammation

“…Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed with ‘enrichKEGG’ in the ‘clusterProfiler’ R package using the gene expression profile prepared above. The GSE198683 dataset was analyzed using the online GEO2R function [ 27 ].…”

Th17 Cells, Glucocorticoid Resistance, and Depression

“…By itself, IL-17A inhibits the expression of canonical corticosteroid genes, such as HSD11B2 and FKBP5 [168]. Dexamethasone does not prevent the secretion of IL-17Ainduced pro-inflammatory cytokines (TNF, IL-1b, IL-6) by primary human airway epithelial cells, inducing specific cell insensitivity to dexamethasone and the development of steroidresistant neutrophilic airway inflammation [168,169], and in some cases, even increasing IL-17A production [170] and exacerbating inflammation [171]. Stimulation of epithelial cells by IL-17A leads to a shift towards the pro-inflammatory phenotype, which is also not prevented by dexamethasone [172,173].…”

Characterization of immunomodulatory factors and cells in bronchoalveolar lavage fluid for immune checkpoint inhibitor-related pneumonitis

“…In human fibroblast MRC5 cells, IL-17 increased type I collagen production, upregulated glucocorticoid receptor β (GR-β) expression, and impaired the inhibitory effect of glucocorticoids on type I collagen and extracellular matrix production in pulmonary fibrosis (Lo et al 2022). A recent study showed that IL-17A does inhibited typical corticosteroid genes, such as HSD11B2 and FKBP5 (Rahmawati et al 2022). These findings suggest that IL-17A may be associated with corticosteroid insensitivity in interstitial lung disease.…”