Integrins αvβ5 and αvβ6 Mediate IL-4-induced Collective Migration in Human Airway Epithelial Cells

Abstract

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 allergicairwayinflammation and remodeling. Given thatcollectivecellmigrationinvolves cell-cell and cell-extracellular matrix adhesions, and given that IL-4 inducesepithelialbarrier dysfunction and decreases cell-extracellular matrix adhesions, we hypothesized that IL-4 may inducecollectivemigrationin the well-differentiated primaryhumannasalepithelialcells(HNECs). Well-differentiated HNECs were treated with IL-4, and the effects of IL-4 on cellmigrationwere 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 inducedcollectiveepithelialmigrationand cell shape changes driven by actin cytoskeleton reorganization. In addition, the effect of IL-4 oncollectiveHNECmigrationwas reversed by pharmacologic and genetic inhibition of the αv-integrin-activating enzyme furin, and function-blocking antibodies for αvβ5or αvβ6. In IL-4-stimulatedcells, both anti-αvβ5and anti-αvβ6inhibited the phosphorylation of focal adhesion kinase. Furthermore, both β5- and β6-integrins were enriched in basalcellsin the injuredairwayepithelium with allergic rhinitis. These findings suggest that αvβ5and αvβ6serve as critical mechanoreceptors inIL-4-inducedcollectiveHNECmigrationthrough the focal adhesion kinase signaling pathway. These results have implications for targeting treatment of exacerbation of respiratory allergic diseases.