IL-5 increases pro-fibrotic and pro-inflammatory signalling in severe asthmatic fibroblasts

Fibrosis is a hallmark feature of airway remodeling in asthma. However, the exact molecular mechanisms driving its development and progression remain inadequately understood. Interleukin-5 (IL-5) plays a potent role in the inflammatory response associated with eosinophils and asthma pathophysiology, but its direct impact on lung fibroblasts and contribution to fibrosis have yet to be fully explored. In our study, we investigated the pro-fibrotic effects of IL-5 on human lung fibroblasts derived from asthmatic and normal subjects. Following IL-5 stimulation, these fibroblasts were subjected to a series of experiments to assess IL-5’s impact on fibrosis. Our findings reveal that IL-5 triggers the release of several extracellular matrix (ECM) components, and disrupts the balance of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) . This imbalance further disrupts the MMP/TIMP ratio. Additionally, IL-5 stimulation promotes the release of pro-inflammatory and pro-fibrotic cytokines, Overall, these findings indicate a novel pro-fibrotic role of IL-5 through its direct action on lung fibroblasts, offering valuable insights into the therapeutic potential of targeting IL-5 to mitigate or possibly reverse airway remodeling in asthma. In order to investigate the impact of IL-5 stimulation on lung derived fibroblasts, and what functional characteristics were gained by these cells post stimulation, RNAseq and bioinformatics analysis were conducted in human lung derived fibroblasts with or without IL-5 Stimulation 3 primary cell lines isolated from human lungs representing three different severe asthmatic patients, 3 primary cell lines isolated from human lungs representing three different healthy subjects, both were stimulated with 0.5ng/ml of IL-5 for 6h Abberviations: N = Normal, D= Diseased, C= Unstimulated, T= Treated Targeted RNA-Seq using Ion AmpliSeq whole transcriptome human gene expression kit