Previous studies have shown that IL-25 levels are increased in patients with asthma with fixed airflow limitation (FAL). However, the mechanism by which IL-25 contributes to airway remodeling and FAL remains unclear. Here, we hypothesized that IL-25 facilitates pro-fibrotic phenotypic changes in bronchial epithelial cells (BECs) and circulating fibrocytes (CFs), orchestrates pathological crosstalk from BECs to CFs, and thereby contributes to airway remodeling and FAL.
Fibrocytes from asthmatic patients with FAL and chronic asthma murine models were detected using flow cytometry, multiplex staining and multispectral imaging analysis. The effect of IL-25 on BECs and CFs and on the crosstalk between BECs and CFs was determined using cell culture and co-culture systems.
We found that asthmatic patients with FAL had higher numbers of IL-25 receptor (i.e., IL-17RB)-CFs, which were negatively correlated with forced expiratory volume in 1 s/forced vital capacity (FEV/FVC). The number of airway IL-17RB-fibrocytes was significantly increased in ovalbumin (OVA)- and IL-25-induced asthmatic mice versus the control subjects. BECs stimulated with IL-25 exhibited an epithelial-mesenchymal transition (EMT)-like phenotypic changes. CFs stimulated with IL-25 produced high levels of extracellular matrix (ECM) proteins and connective tissue growth factors (CTGF). These profibrotic effects of IL-25 were partially blocked by the PI3K-AKT inhibitor LY294002. In the cell co-culture system, OVA-challenged BECs facilitated the migration and expression of ECM proteins and CTGF in CFs, which were markedly blocked using an anti-IL-17RB antibody.
These results suggest that IL-25 may serve as a potential therapeutic target for asthmatic patients with FAL.

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