Dysregulation of the Wnt pathway in adult eosinophilic esophagitis

Abstract

Eosinophilic esophagitis (EoE) is a chronic inflammatory disease characterized pathologically by eosinophil infiltration. In addition to loss of barrier integrity, a dominant T Helper 2-associated immune response and strong allergic connection, the esophagus tissue undergoes dramatic changes, with frequent presence of mucosal rings, strictures, linear furrows, and trachealization. Although the inflammatory mechanisms behind this disease are being increasingly well understood, the structural features remain unexplained. We examined the expression of key members of the Wnt-signaling pathway in biopsies from patients with EoE. This pathway has been shown to be critically important in regulating cellular homeostasis, growth, and differentiation and to be dysregulated in several disease conditions. Biopsies from adult EoE patients were collected by endoscopy and mRNA extracted. After cDNA synthesis, the relative gene expression from key upstream (secreted frizzled-related protein 1) and downstream (c-myc and Cyclin D1) molecules in the Wnt pathway, as well as several Wnt pathway members (Wnt1, Axin1, low-density lipoprotein receptor-related protein 6, glycogen synthase kinase 3 beta, and β-catenin), were determined. Biopsies from patients with EoE displayed significantly higher expression of secreted frizzed-related protein 1 than controls, as well as reductions in Cyclin D1 and c-myc. In contrast, there were no differences in the Wnt pathway molecules. The levels of expression of Cyclin D1 and c-myc, as well as β-catenin, in EoE patients showed strong correlations with the frequency of esophageal eosinophils. Our findings suggest that although there are no changes in the overall levels of key Wnt pathway genes in adult EoE, there is evidence for dysregulation of upstream and downstream regulators of Wnt signaling. Importantly, the associations with eosinophilia suggest that these may participate in the pathogenesis of this disease and be markers of disease severity.

Shaping eosinophil identity in the tissue contexts of development, homeostasis, and disease

“…Activation of the Wnt, Hippo, Notch/Jagged, and Hedgehog developmental pathways is necessary for epithelial development and patterning and is strongly associated with epithelial remodeling. Importantly, EMT‐related morphogenetic ligands such as WNTs and Hedgehog proteins can be secreted by remodeling tissue and can directly engage eosinophils and other immune cells . Moreover, the mesenchymal compartment and myofibroblasts in particular have the ability to secrete multiple provisional ECM proteins with multiple regulatory effects on immune cells …”

“…Importantly, EMT-related morphogenetic ligands such as WNTs and Hedgehog proteins can be secreted by remodeling tissue and can directly engage eosinophils and other immune cells. [29][30][31] Moreover, the mesenchymal compartment and myofibroblasts in particular have the ability to secrete multiple provisional ECM proteins with multiple regulatory effects on immune cells. [32][33][34]…”

Epigenetic methylation in Eosinophilic Esophagitis: Molecular ageing and novel biomarkers for treatment response

“…Perhaps among the most interesting is cg17022577, a CpG site linked to WNT family member 4 ( WNT4 ). WNT4 has been shown to be upregulated in a wide range of diseases, including ulcerative colitis, 50,51 and with EoE disease severity in adults 52 . Two differentially methylated sites were located within UNC5B (unc‐5 netrin receptor B), a member of the netrin family of receptors and involved in pro‐ and anti‐apoptotic processes.…”

Impaired LRP6-TCF7L2 Activity Enhances Smooth Muscle Cell Plasticity and Causes Coronary Artery Disease

“…Increased eosinophil activation in patients with hypereosinophilia has been attributed to impaired Wnt signaling, measured by lower cyclin D1 and β-catenin levels. Interestingly, eotaxin has been shown to activate T cell infiltration, which may be another explanation for increased T cells in LRP6 R611C ; LDLR−/− vs., LDLR−/− lesions (Giannetti et al, 2014). Finally, increased T cell in LRP6 R611C ; LDLR−/− vs., LDLR−/− may have been contributed by increased IL-6, as IL-6 is known to promote T cell proliferation (Dienz and Rincon, 2009).…”