Integrins &agr;v&bgr;5 and &agr;v&bgr;6 Mediate IL‐4‐induced Collective Migration in Human Airway Epithelial Cells

Abstract

&NA; 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 &agr;v‐integrin‐activating enzyme furin, and function‐blocking antibodies for &agr;v&bgr;5 or &agr;v&bgr;6. In IL‐4‐stimulated cells, both anti‐&agr;v&bgr;5 and anti‐&agr;v&bgr;6 inhibited the phosphorylation of focal adhesion kinase. Furthermore, both &bgr;5‐ and &bgr;6‐integrins were enriched in basal cells in the injured airway epithelium with allergic rhinitis. These findings suggest that &agr;v&bgr;5 and &agr;v&bgr;6 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.