Interleukin-13 Alters Tight Junction Proteins Expression Thereby Compromising Barrier Function and Dampens Rhinovirus Induced Immune Responses in Nasal Epithelium

Abstract

Tight junctions (TJs) are intercellular structures which are essential for epithelial barrier function and play an important role in antimicrobial defense. Epithelium dysfunction and type-2-skewed inflammation are two main pathological phenomena of chronic rhinosinusitis with nasal polyps (CRSwNP). However, the effect of pro-inflammatory type-2 cytokine IL-13 on TJs in CRSwNP is poorly understood. Nasal biopsies of CRSwNP patients and in vitro IL-13-matured human nasal epithelial cells (hNECs) were used to analyze epithelial markers and TJ proteins. Epithelium permeability, transepithelial electrical resistance (TEER), expression of TJs were quantified for IL-13-matured hNECs and that with RV infection. The expression of occludin, claudin-3, and ZO-1 were significantly decreased in CRSwNP biopsies and in hNECs after IL-13 treatment. IL-13 treatment increased epithelium permeability, decreased TEER and altered hNECs composition resulting in lesser ciliated cells and mucus over-secretion. Interestingly, claudin-3 is selectively expressed on ciliated cells. While RV infection induced minimal changes to TJs, the IL-13-matured hNECs has reduced capacity for upregulation of IFN-λ1 and CXCL10 but further increased the expression of TSLP upon RV infection. These findings suggested that IL-13-mediated dysfunction of TJs and compromised epithelial barrier. IL-13-induced cilia loss conferred lowered viral replication and impaired antiviral responses of nasal epithelium against RV infection.

Viral PB1-F2 and host IFN-γ guide ILC2 and T cell activity during influenza virus infection

“…IL-13 increases mucus secretion, goblet cell hyperplasia and AHR, which are typically detrimental, although some investigators have reported beneficial effects in parasitic infections ( 48 , 49 ). In influenza infection, IL-13 can compromise the epithelial barrier ( 50 , 51 ) and predispose to a more severe form of disease ( 52 ), as also seen in our study. Furthermore, continuous production of IL-13 by macrophages following lung inflammation can result in chronic lung disease ( 53 ).…”

IL-4/IL-13 Axis in Allergic Rhinitis: Elevated Serum Cytokines Levels and Inverse Association With Tight Junction Molecules Expression

“…In terms of IL-13, overexpression of miR-143 in IL-13-stimulated nasal epithelial cells (NECs) from AR patients suppressed the production of IL-13-induced inflammatory cytokines, and miR-143 rendered these effects by directly targeting and repressing IL13RA1 transcript expression ( Teng et al, 2015 ). Treatment of human NECs with the cytokine suppressed the expression of TJ molecules including ZO-1 and CLDN3 ( Huang et al, 2020 ). Moreover, correlation analysis of our cohort of AR and non-allergic control groups showed that serum IL-4 and IL-13 levels were positively associated with IL13RA1 expresion.…”

The Antimicrobial Peptide Mastoparan X Protects Against Enterohemorrhagic Escherichia coli O157:H7 Infection, Inhibits Inflammation, and Enhances the Intestinal Epithelial Barrier

“…In addition, the intestinal epithelial barrier is the first barrier for preventing bacteria, antigens, and other toxic and harmful substances from entering the submucosa of the intestine and blood ( Han et al, 2015 ). The TJ structure is composed of TJ proteins, such as ZO-1, occludin, and claudins, which are an important part of the intestinal epithelial barrier and play important roles in intestinal epithelial cells ( Huang et al, 2020 ). Lin et al (2019) investigated the effect of the antimicrobial peptide gloverin A2 (BMGlvA2) on ETEC-induced intestinal barrier disruption in mice and found that it clearly improved the expression of the TJ protein ZO-1 in the intestine after ETEC infection.…”