Neurotensin receptor1 signaling promotes progression of epithelial-mesenchymal transition in mice with chronic rhinosinusitis through Wnt3a/β-catenin pathway

Chronic rhinosinusitis (CRS) is a multifactorial inflammatory disease characterized by high prevalence and morbidity.Epithelial-to-mesenchymal transition (EMT) is associated with the pathophysiology of chronic rhinosinusitis with nasal polyp (CRSwNP).Since Neurotensin Receptor 1 (NTSR1) signaling has been shown to regulate the EMT process in Other Diseases.In this study, we investigated the effect of NTSR1 on the EMT process in CRS, and explored whether these regulations could serve as potential drug targets.Our results demonstrated that NTS and NTSR1 expression was significantly elevated in CRS mice who were accompanied with mucosal thickening, goblet cell hyperplasia, glandular hyperplasia, and dense infiltration of inflammatory cells.Treatment with NTSR1 inhibitor SR48692 significantly improved the nasal symptoms and pathological conditions of sinus mucosa tissues in CRS mice.In addition, SR48692 treatment significantly downregulated the mRNA expression of Th2 cytokines (IL-4 and IL-5) and IL-17. Moreover, we observed that treatment with SR48692 significantly reduced the expression of a-SMA and vimentin, while increased that of E-cadherin, suggesting inhibition of EMT.Mechanistically, we further found that SR48692 could downregulate Wnt3a and β-catenin mRNA and protein levels impairing the Wnt/β-catenin pathway.Our results indicate that NTSR1 signaling promotes progression of EMT in mice with CRS may through Wnt3a/β-catenin pathway, underlining the promise of NTSR1 as a potential target for CRS therapy.

Chronic rhinosinusitis (CRS); Eosinophilic inflammation; Epithelial-mesenchymal transition; Neurotensin receptor1 (NTSR1); SR48692; Wnt/β-catenin signaling.