Eosinophil IL-5Rα/JAK2/STAT5 Signaling Contributes to Epithelial-Mesenchymal Transition in Eosinophilic Chronic Rhinosinusitis with Nasal Polyps.

Background and Objectives: Eosinophilic chronic rhinosinusitis with nasal polyps (ECRSwNP) is characterized by type 2 inflammation, marked eosinophil infiltration, and enhanced epithelial-mesenchymal transition (EMT). Although interleukin-5 (IL-5) is central to eosinophil differentiation and activation, its role in EMT in human nasal epithelial cells (HNECs) remains unclear. This study aimed to elucidate the contribution of IL-5Rα/Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) signaling in eosinophils in EMT in ECRSwNP. Materials and Methods: Nasal mucosal tissues from control and ECRSwNP or non-ECRSwNP group patients (n = 12 each) were analyzed for type 2 cytokine, EMT marker, and IL-5Rα/JAK2/STAT5 axis component levels using Western blotting, immunohistochemistry, and quantitative real-time polymerase chain reaction. HL-60 cells were differentiated into eosinophil-like cells using butyric acid and stimulated with IL-5, and HNECs were co-cultured with undifferentiated, differentiated, or IL-5-activated differentiated HL-60 cells. EMT induction and migration were assessed using immunofluorescence, wound-healing assays, and Western blotting. IL-5RA, JAK2, or STAT5 was silenced using small interfering RNA to determine pathway dependency. Results: ECRSwNP tissues showed elevated type 2 cytokine and EMT marker expression and enhanced IL-5Rα/JAK2/STAT5 pathway activation. Co-culture with IL-5-activated differentiated HL-60 cells induced EMT in HNECs, evidenced by decreased E-cadherin and zonula occludens-1, increased N-cadherin and vimentin levels, and enhanced migration. Moreover, silencing IL-5RA, JAK2, or STAT5 significantly attenuated these effects. Conclusions: IL-5-activated IL-5Rα/JAK2/STAT5 signaling in eosinophils may contribute to EMT in HNECs. Thus, this pathway could be a potential therapeutic target for tissue remodeling and polyp formation in type 2 chronic rhinosinusitis.