A positive link between persistent cellular motion and a defective tight junction barrier allows increased antigenic penetration and contact between ligand-receptor pairs, leading to exacerbated allergic airway inflammation and remodeling. Given that collective cell migration involves cell-cell and cell-extracellular matrix adhesions, and given that IL-4 induces epithelial barrier dysfunction and decreases cell-extracellular matrix adhesions, we hypothesized that IL-4 may induce collective migration in the well-differentiated primary human nasal epithelial cells (HNECs). Well-differentiated HNECs were treated with IL-4, and the effects of IL-4 on cell migration were investigated using genetic and pharmacological approaches, live-cell imaging, a vertex model, and immunostaining. IL-4 disrupted the expression and localization of the tight junction proteins zonula occludens 1 and occludin, and it induced the cleavage and asymmetric distribution of E-cadherin in the HNEC layers. It also induced collective epithelial migration and cell shape changes driven by actin cytoskeleton reorganization. In addition, the effect of IL-4 on collective HNEC migration was reversed by pharmacologic and genetic inhibition of the α_v-integrin-activating enzyme furin, and function-blocking antibodies for α_vβ₅ or α_vβ₆. In IL-4-stimulated cells, both anti-α_vβ₅ and anti-α_vβ₆ inhibited the phosphorylation of focal adhesion kinase. Furthermore, both β₅- and β₆-integrins were enriched in basal cells in the injured airway epithelium with allergic rhinitis. These findings suggest that α_vβ₅ and α_vβ₆ serve as critical mechanoreceptors in IL-4-induced collective HNEC migration through the focal adhesion kinase signaling pathway. These results have implications for targeting treatment of exacerbation of respiratory allergic diseases.

	Year	Citations

About