RAGE mediates β-catenin stabilization via activation of the Src/p-Cav-1 axis in a chemical-induced asthma model.

We previously demonstrated receptor for advanced glycation end products (RAGE) was required for β-catenin stabilization in a toluene diisocyanate (TDI)-induced asthma model, suggesting it plays an important role in TDI-induced airway inflammation. The aim of this study was to examine whether RAGE mediates β-catenin stabilization via activation of the Src/p-Cav-1 axis in TDI-induced asthma model. To generate a chemical-induced asthma model, male BALB/c mice were sensitized and challenged with TDI. Before each challenge, FPS-ZM1 (RAGE inhibitor) and PP2 (Src inhibitor) was given via intraperitoneal injection. In the TDI-exposed mice, airway reactivity, airway inflammation, goblet cell metaplasia, and the release of Th2 cytokines and IgE increased significantly. The level of membrane β-catenin decreased but was increased in the cytoplasm. Increased expression of RAGE, p-Src, and p-Cav-1 was also detected in TDI-exposed lungs. However, all these changes were inhibited by FPS-ZM1 and PP2. In TDI-HSA stimulated human airway epithelial (16HBE) cells, the expression of p-Src and p-Cav-1, and the abnormal distribution of β-catenin were significantly increased, and then inhibited in RAGE knockdown cells. Similarly, PP2 or non-phosphorylatable Cav-1 mutant (Y14F-Cav-1) treated 16HBE cells had the same effect on the distribution of β-catenin. In addition, blockage of RAGE signaling and phosphorylation of Cav-1 eliminated the translocation of β-catenin from cytomembrane to cytoplasm. Our results showed that RAGE modulates β-catenin aberrant distribution via activation of Src/p-Cav-1 in a chemical-induced asthma model.