The IFN-γ-p38, ERK kinase axis exacerbates neutrophilic chronic rhinosinusitis by inducing the epithelial-to-mesenchymal transition

Chronic rhinosinusitis (CRS) is a heterogeneous and multifactorial inflammatory disease characterized by involvement of diverse types of inflammatory cells. Asian CRS patients frequently show infiltration of neutrophils and an elevated level of interferon (IFN)-gamma; by contrast, western patients exhibit eosinophil infiltration and enhanced levels of Th2-related cytokines. Neutrophilia in tissues decreases sensitivity to corticosteroids, but the mechanisms underlying the progression of neutrophilic CRS are unclear. In this study, we investigated the role of IFN-gamma in CRS patients with marked neutrophil infiltration. We report that the IFN-gamma level is upregulated in the tissues of these patients, particularly those with non-eosinophilic nasal polyps. The level of IFN-gamma was significantly correlated with markers of the epithelial-to-mesenchymal transition (EMT). We further demonstrated that IFN-gamma induced the EMT via the p38 and extracellular signal-regulated kinase (ERK) pathways in a manner distinct from the hypoxiainducible factor (HIF)-1 alpha, SMAD, and NF-kappa B signaling pathways. In a murine nasal polyp (NP) model, blocking the p38 and ERK signaling pathways prevented NP formation and chemotactic cytokine secretion by neutrophils but not eosinophils. Taken together, our results suggest that IFN-gamma can induce the EMT in nasal epithelial cells, and thus blocking the p38 and ERK pathways could be an effective therapeutic strategy against neutrophil-dominant CRS.