Characteristics of IL-25 and allergen-induced airways fibrosis in a murine model of asthma

Background: IL-25 has been implicated in the pathogenesis of human asthma by inducing a Th2 cytokine response, but its possible role in the development of airways remodelling is less clear. Objectives: We aim to examine IL-259s effect on murine airway remodelling by intranasal application of IL-25 alone. Methods: Parallel comparison of “IL-25-driven asthma model” was done with the “classical” surrogate of OVA intranasal instillation into previously sensitised animals. Airway fibrotic biomarkers were analyzed by immunohistochemistry and ELISA assay. Additionally, proliferation assay and real-time PCR analysis were performed to assess IL-259s effects on primary human bronchial fibroblasts in vitro. Results: In Balb/c mice, intranasal instillation of IL-25 alone induced florid airways fibrosis, including increased laydown of ECM proteins such as collagen I, III, V and fibronectin, increased numbers of fibroblasts/myofibroblasts, a profibrotic imbalance in MMP/TIMP production and increased expression of profibrotic mediators including CTGF and TGF-β1. These changes broadly reproduced those seen with “classical” intranasal OVA challenge in OVA-sensitised animals. Furthermore, IL-25 induced proliferation and expression of collagen I and III and smooth muscle α-actin in primary human lung fibroblasts. Conclusions: We conclude that chronic exposure of the airways to IL-25 alone is sufficient to cause functionally relevant airways remodelling, with the corollary that targeting of IL-25 may attenuate bronchial remodelling and fibrosis in human asthmatics.