Wnt Signaling in Chronic Rhinosinusitis with Nasal Polyps

Abstract

The signaling pathways that sustain the disease process of chronic rhinosinusitis with nasal polyps (CRSwNP) remain poorly understood. We sought to determine the expression levels of Wnt signaling genes in CRSwNP and to study the role of the Wnt pathway in inflammation and epithelial remodeling in the nasal mucosa. Microarrays and real time-quantitative polymerase chain reaction comparing gene expression in matched NPs and inferior turbinates revealed that WNT2B, WNT3A, WNT4, WNT7A, WNT7B, and FZD2 were up-regulated and that FZD1, LRP5, LRP6, and WIF1 were down-regulated in NPs. Immunolabeling showed robust expression of Wnt ligands, nuclear β-catenin, and Axin-2 in NP tissue, suggesting that Wnt/β-catenin signaling is activated in NPs. We used primary human nasal epithelial cell (HNEpC) cultures to test the functional consequences of Wnt pathway activation. Monolayer HNEpCs treated with recombinant human WNT (rhWNT) 3A, but not with rhWNT4, had altered epithelial morphology and decreased adhesion, without loss of viability. We found that neither rhWNT3A nor rhWNT4 treatment induced proliferation. The expression and release of inflammatory cytokines IL-6 and granulocyte-macrophage colony-stimulating factor were increased after rhWNT3A exposure of HNEpCs. When differentiated at an air-liquid interface, rhWNT3A- and WNT agonist-, but not rhWNT4-treated HNEpCs, had abnormal epithelial architecture, failed to undergo motile ciliogenesis, and had defective noncanonical Wnt (planar cell polarity) signaling. On the basis of these results, we propose a model in which Wnt/β-catenin signaling sustains mucosal inflammation and leads to a spectrum of changes consistent with those seen during epithelial remodeling in NPs.

Nasal polyp fibroblasts modulate epithelial characteristics via Wnt signaling

“…A). These results corroborate previous literature of CHIR99021 driving epithelial elongation, and for the first time show CRSwNP‐hSNF‐derived epithelial elongation.…”

“…Differential expression of Wnt in fibroblasts derived from nasal polyps vs healthy sinonasal tissue is an intriguing finding that potentially sheds new light on dysregulated epithelial‐mesenchymal interactions in CRSwNP. The predilection toward WNT3A expression may indicate predominantly canonical Wnt pathway activation in CRSwNP, in agreement with previous reports evaluating Wnt expression in inferior turbinates compared to nasal polyp tissue . Furthermore, a high Wnt milieu generated pharmacologically or by co‐culture with CRSwNP‐hSNFs results in decreased ciliated epithelial cells and altered epithelial cell morphology.…”

“…While essential to the normal differentiation of ciliated airway epithelial cells, upregulated Wnt signaling in CRSwNP has been proposed to result in abnormal epithelial cell morphology and dysfunctional MCC . In the lung, Wnt derives from epithelial and subepithelial mesenchymal cell populations, including fibroblasts .…”

Modulation of Wnt signaling is essential for the differentiation of ciliated epithelial cells in human airways

“…Similar results have been described in chronic rhinosinusitis with nasal polyps. The canonical Wnt pathway is activated in nasal polyps and leads to the formation of an abnormal epithelium with compromised adherents junctions, absent ciliogenesis, and impaired PCP signaling [73]. We show here that stimulation of the canonical Wnt pathway by inhibition of GSK3b leads to similar features in human airway epithelial cells with increased expression of involucrin, a marker of squamous metaplasia [74], a decrease in the expression of E-cadherin, a maker for epithelial structure [75], and significant reduction of the ciliated cell population.…”

Noncanonical Wnt planar cell polarity signaling in lung development and disease

“…The requirement of PCP for MCC and barrier function, the two chief functions of the airway epithelium, as well as its regeneration, indicate that this pathway is a critical regulator of airway epithelial development and homeostasis. Not surprisingly, core PCP defects were found in a variety of chronic inflammatory airway diseases such as cystic fibrosis (CF), chronic rhinosinusitis (CRS), idiopathic pulmonary fibrosis (IPF) and asthma [12,[76][77][78]. See Table 3 for a list human nonmalignant respiratory diseases and associated PCP defects.…”