Thymic Epithelial Cells Were Preserved by Wnt4 Through FOXN1/DLL4-Mediated β-Catenin Signaling Pathway during Thymic Involution

Age-related thymic involution is a physiological process that occurs with aging and it is characterized by a decreased naive T cells output; this decreased output greatly reduces immune system function and increases the risk of pathogen infection, tumor, and autoimmune disease development. Thymic epithelial cells (TECs) constitute the major component of the thymic microenvironment and support the development and maturation of thymocytes. Wnt4 has been reported to be associated with thymic involution. However, the mechanism underlying the role of Wnt4 in this process is not clear. In this study, when Wnt4 was overexpressed, cell proliferation, migration, and epithelial-mesenchymal transition (EMT) in TECs was promoted but cell apoptosis was suppressed. However, knockdown of Wnt4 reversed these effects. Additionally, Wnt4 was shown to positively regulate the expression of FOXN1 in TECs. Furthermore, the canonical β-catenin signaling pathway was activated by Wnt4 in TECs. Moreover, FOXN1, which is a downstream member of this pathway, was shown to regulate Delta like canonical Notch ligand 4 (DLL4), a ligand of Notch signaling which controls thymic T cell lineage commitment. When FOXN1 was overexpressed, the proliferation and migration of TECs were increased, and cell apoptosis was inhibited. Knockdown of FOXN1 reversed these effects. In summary, our data demonstrate that Wnt4 regulates the proliferation, migration, EMT and apoptosis of TECs through FOXN1 and that these effects are mediated by the canonical β-catenin signaling. And DLL4 might play important role in this process. These finding may provide new therapeutic targets for delaying or improving age-related thymic involution.