IL-19 induced by IL-13/IL-17A in the nasal epithelium of patients with chronic rhinosinusitis upregulates MMP-9 expression via ERK/NF-κB signaling pathway.

Xia Li,Jiancong Huang,Shuaixiang Li,Xiaoping Lai,Yue Li,Gehua Zhang,Zizhen Huang,Xiaohong Chen,Lihong Chang

doi:10.1002/clt2.12003

Abstract

BackgroundTissue remodeling is a crucial characteristic of chronic rhinosinusitis (CRS). Imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) is crucial for the pathologic tissue remodeling in CRS. Elevation of interleukin (IL)‐19 or MMP‐9 levels in patients with CRS had been proven in previous studies. Here, we aimed to investigate the role of IL‐19 in mediating MMP‐9 expression in CRS.MethodsNasal tissue samples were collected from 45 individuals having chronic rhinosinusitis with nasal polyps (CRSwNP), 24 CRS without nasal polyps (CRSsNP), and 17 controls. Expression of IL‐19, its receptors (IL‐20R1/IL‐20R2), and MMP‐9 were investigated using RT‐qPCR and Immunofluorescence (IF). Human nasal epithelial cells (HNECs) were stimulated by IL‐19; ERK phosphorylation, nuclear factor‐κB (NF‐κB) pathway activation, and MMP‐9 level were detected by RT‐qPCR, enzyme‐linked immunosorbent assay, western blot, and IF. We also explored the effect of type1/2/3 cytokines on IL‐19 production by RT‐qPCR, and western blot.ResultsExpression levels of IL‐19, its receptors (IL‐20R1/IL‐20R2), and MMP‐9 were increased in nasal tissues from individuals with CRSwNP compared to those with CRSsNP as well as the controls. IL‐19 significantly elevated the production of MMP‐9 in HNECs. Furthermore, IL‐19 could activate the ERK and NF‐κB pathways, accompanied by increased MMP‐9 production in HNECs. Conversely, both ERK and NF‐κB inhibitors significantly attenuated the role of IL‐19 in MMP‐9 production. siRNA knockdown of IL‐20R1 suppressed ERK and NF‐κB pathway activation, thereby decreasing MMP‐9 expression. IL‐13 and IL‐17A were found to stimulate IL‐19 production in HNECs.ConclusionIL‐19, promoted by IL‐13 and IL‐17A, contributes to the upregulation of secretion of the tissue remodeling factor MMP‐9 in patients with CRS.

Highlights

Chronic sinusitis (CRS) is a common disease, with prevalence of 8% in China and 12% in the United States.[1,2,3] It is a considerable public health concern as well as a socioeconomic burden.[4]
Despite the variation across subtypes of chronic rhinosinusitis with nasal polyps (CRSwNP), manifestation of tissue remodeling is similar, indicating different inflammatory cytokines to eventually lead to similar tissue remodeling pattern through common downstream factors or pathways in nasal polyps
Considering the co-localization of IL-19 and matrix metalloproteinases (MMPs)-9 in the mucosa of patients with chronic rhinosinusitis (CRS), we explored whether IL-19 could elevate MMP-9 secretion in Human nasal epithelial cells (HNECs)

Summary

Introduction

Chronic sinusitis (CRS) is a common disease, with prevalence of 8% in China and 12% in the United States.[1,2,3] It is a considerable public health concern as well as a socioeconomic burden.[4]. CRSwNP is characterized by stromal tissue edema with albumin deposition and pseudocyst formation.[5] CRSwNP is considered a heterogeneous disease, and based on the expression of different inflammatory cytokines in CRSwNP, it can be divided into different clusters. Clinical characteristics, such as treatment outcomes, asthma prevalence, and postoperative recurrence, are significantly different across the clusters.[6, 7] Despite the variation across subtypes of CRSwNP, manifestation of tissue remodeling is similar, indicating different inflammatory cytokines to eventually lead to similar tissue remodeling pattern through common downstream factors or pathways in nasal polyps. We aimed to investigate the role of IL-19 in mediating MMP-9 expression in CRS

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