TRPV4-Mediated Epithelial Junction Disruption in Allergic Rhinitis Triggered by House Dust Mites

Abstract

Background Epithelial barrier disruption is a crucial feature of allergic rhinitis (AR). Previous reports have indicated the role of transient receptor potential vanilloid (TRPV) 4 in regulating the intercellular junctions in various cells. However, the role of TRPV4 and its regulation by T helper 2 cell cytokines in the epithelial cells of patients with AR remains unclear. Objective We aimed to elucidate the expression of TRPV4 in nasal epithelial cells and its cytokine-induced regulation, and to reveal its role in house dust mite-induced junction disruption in AR. Methods The expression of TRPV4 in nasal epithelial cells was measured using real-time polymerase chain reaction, western blot, and immunohistochemical assays, and the expression levels were compared between the patients with AR and healthy controls. Altered expression of TRPV4 was induced in cultured nasal epithelial cells by stimulation of interleukin (IL) 4, IL-13, and tumor necrosis factor alpha. In addition, expression of E-cadherin and zonula occludens 1 was induced in Der p 1-stimulated epithelial cells by treatment with either a TRPV4 agonist (GSK1016790A) or a TRPV4 antagonist (RN1734). Results TRPV4 expression was increased in epithelial cells harvested from the affected turbinates compared to those from the normal turbinates. The stimulation of cultured epithelial cells with IL-4 and IL-13 resulted in TRPV4 upregulation. Additionally, E-cadherin and zonula occludens 1 expression levels decreased in the cultured epithelial cells treated with GSK1016790A after stimulation with Der p 1, whereas Der p 1 stimulation alone showed no effect on junctional protein expression. Conclusions Increased TRPV4 expression occurred in epithelial cells harvested from patients with AR and epithelial cells stimulated by Th2 cytokines. Decreased junctional protein expression in epithelial cells after the stimulation by house dust mite allergen with TRPV4 agonist indicates a possible role of TRPV4 in the pathogenesis of allergen-induced epithelial barrier disruption in AR.

Nasal Epithelial Barrier Integrity and Tight Junctions Disruption in Allergic Rhinitis: Overview and Pathogenic Insights

“…Hence, barrier function in AR might be disrupted by increased expression or activity of epithelial TRPV1. Moreover, increased TRPV4 expression was shown in epithelial cells of AR patients compared with normal controls and in cultured epithelial cells stimulated by Th2 cytokines (IL-4 and IL-13) (119). Decreased E-cadherin and ZO-1 expression was demonstrated in epithelial cells of AR patients exposed to HDM allergen and TRPV4 agonist (GSK1016790A), suggesting possible roles of TRPV4 in the pathogenesis of allergen-induced epithelial barrier disruption in AR (119).…”

Transient Receptor Potential (TRP) Channels in Airway Toxicity and Disease: An Update

“…TRPV4-deficient mice were protected from airway remodeling in a house dust mite (HDM) model, which is more relevant to the human situation than OVA challenge [ 77 ]. Moreover, in allergic rhinitis caused by HDM, the up-regulation of TRPV4 proteins in nasal cells was demonstrated, which resulted in epithelial barrier disruption [ 78 ]. TRPV4 is also expressed in human airway smooth muscle cells (see Figure 1 ), and specific agonists induce the release of ATP in non-atopic, immunoglobulin E-independent asthma patients [ 79 ].…”

Ca2+ Signaling by TRPV4 Channels in Respiratory Function and Disease

“…TRPV4deficient mice were however protected from airway remodeling in a house dust mite (HDM) model, which is more relevant to the human situation [80]. In nasal cells of patients with allergic rhinitis (AR) caused by HDM, TRPV4 proteins were up-regulated and GSK1016790A as TRPV4 channel activator decreased expression of the cell junctional proteins E-cadherin and Zona occludens 1, which may be responsible for epithelial barrier disruption [81]. TRPV4 agonists induced the release of ATP from human airway smooth muscle cells (HASMC) of non-atopic, immunoglobulin E-independent, asthma patients.…”