Air pollution exposure leads to various inflammatory diseases in the human respiratory system. Chronic rhinosinusitis is an inflammatory disease caused by viruses, bacteria, or air pollutants. However, the underlying molecular mechanisms through which air particulate matter (PM) causes inflammation and disease remain unclear. In this article, we report that the induction of exosomal microRNAs (miRNAs) from human nasal epithelial cells upon airborne PM exposure promotes proinflammatory M1 macrophage polarization via downregulated RORa expression. Exposure of human nasal epithelial cells to PM results in inflammation-related miRNA expression, and more miRNA is secreted through exosomes delivered to macrophages. Among these, miRNA-19a and miRNA-614 directly bind to the 39-untranslated region of RORa mRNA and downregulate RORa expression, which leads to inflammation due to inflammatory cytokine upregulation and induces macrophages to a proinflammatory M1-like state. Finally, we showed enhanced expression of miRNA-19a and miRNA-614 but reduced RORa expression in a chronic rhinosinusitis patient tissue compared with the normal. Altogether, our results suggest that PM-induced exosomal miRNAs might play a crucial role in the proinflammatory mucosal microenvironment and macrophage polarization through the regulation of RORa expression.
Recent studies on the pathophysiology of irritable bowel syndrome (IBS) have focused on the role of mast cells (MCs) in intestinal mucosal immunity. A link between allergic airway diseases (AADs) and IBS has been suggested because both diseases have similar pathophysiology. We aimed to investigate whether the induction of AAD in mice could lead to inflammation of the colonic mucosa, similar to IBS. We also evaluated whether this inflammatory response could be suppressed by administering a therapeutic agent. Mice were divided into three groups: control, AAD-induced, and salbutamol-treated. An AAD mouse model was established by intraperitoneal injection and nasal challenge with ovalbumin. Mice with AAD were intranasally administered salbutamol. Analyses of cytokine levels, MC count, and tryptase levels in the intestinal mucosa were performed to compare the changes in inflammatory responses among the three groups. Inflammation was observed in the intestinal mucosa of mice in the AAD group. This inflammation in AAD mice was suppressed after salbutamol treatment. Our study demonstrates that AAD induces an inflammatory response similar to that in IBS, suggesting a possible association between IBS and AADs. In patients with IBS with such allergic components, salbutamol may have the potential to alleviate the inflammatory response.
BackgroundExposure to air particulate matter (PM) is associated with various diseases in the human respiratory system. To date, most in vitro studies showing cellular responses to PM have been performed in cell culture using a single cell type. There are few studies considering how multicellular networks communicate in a tissue microenvironment when responding to the presence of PM. Here, an in vitro three-dimensional (3D) respiratory mucosa-on-a-chip, composed of human nasal epithelial cells, fibroblasts, and endothelial cells, is used to recapitulate and better understand the effects of urban particulate matter (UPM) on human respiratory mucosa.ResultsWe hypothesized that the first cells to contact with UPM, the nasal epithelial cells, would respond similar to the tissue microenvironment, and the 3D respiratory mucosa model would be a suitable platform to capture these events. First, whole transcriptome analysis revealed that UPM induced gene expression alterations in inflammatory and adhesion-related genes in human nasal epithelial cells. Next, we developed an in vitro 3D respiratory mucosa model composed of human nasal epithelial cells, fibroblasts, and endothelial cells and demonstrated that the model is structurally and functionally compatible with the respiratory mucosa. Finally, we used our model to expose human nasal epithelial cells to UPM, which led to a disruption in the integrity of the respiratory mucosa by decreasing the expression of zonula occludens-1 in both the epithelium and endothelium, while also reducing vascular endothelial cadherin expression in the endothelium.ConclusionsWe demonstrate the potential of the 3D respiratory mucosa model as a valuable tool for the simultaneous evaluation of multicellular responses caused by external stimuli in the human respiratory mucosa. We believe that the evaluation strategy proposed in the study will move us toward a better understanding of the detailed molecular mechanisms associated with pathological changes in the human respiratory system.
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.
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