The IFN-\u03b3\u2013p38, ERK kinase axis exacerbates neutrophilic chronic rhinosinusitis by inducing the epithelial-to-mesenchymal transition

Mingyu Lee,Dong-Young Kim,Yong-Min Kim,Jong-Wan Park,Seung-Hyun Shin,Dae Woo Kim,Doo Hee Han,Hyun-Jik Kim,Roza Khalmuratova,Chae-Seo Rhee,Hyun-Woo Shin

doi:10.1038/s41385-019-0149-1

Abstract

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)-γ; 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-γ in CRS patients with marked neutrophil infiltration. We report that the IFN-γ level is upregulated in the tissues of these patients, particularly those with non-eosinophilic nasal polyps. The level of IFN-γ was significantly correlated with markers of the epithelial-to-mesenchymal transition (EMT). We further demonstrated that IFN-γ induced the EMT via the p38 and extracellular signal-regulated kinase (ERK) pathways in a manner distinct from the hypoxia-inducible factor (HIF)-1α, SMAD, and NF-κB 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-γ 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.

Highlights

Chronic rhinosinusitis (CRS) is a heterogeneous and multifactorial inflammatory disease of the paranasal sinuses and nasal cavities that affects 5–15% of the global population.[1]
Increased level of IFN-γ in patients with NE-nasal polyp (NP) A multiplex enzyme-linked immunosorbent assay (ELISA) was performed to determine whether the IFN-γ level increases during the development of CRS
Because the number of neutrophils in tissues from non-eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP) (NE-NP) patients was significantly higher than in tissue from eosinophilic CRSwNP (E-NP) patients,[10] we examined whether the majority of IFN-γ was produced by

Summary

Introduction

Chronic rhinosinusitis (CRS) is a heterogeneous and multifactorial inflammatory disease of the paranasal sinuses and nasal cavities that affects 5–15% of the global population.[1] Accompanying nasal polyps (NPs) are suggestive of a recalcitrant and recurrent clinical course.[2] Two NP phenotypes are known; these differ in terms of the presence of eosinophilia: eosinophilic CRSwNP (E-NP) and non-eosinophilic CRSwNP (NE-NP).[3] NPs are characterized as a Th2-dominant immunologic disease with pronounced eosinophilia and excessive expression of type 2 cytokines in western countries.[4] the differences between Western and Asian patients with CRS suggest that CRS endotypes differ according to patient ethnicity.[5,6] A recent report suggested that second-generation Asian patients with

Methods

Results

Conclusion