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 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 vβ 5 or α vβ 6. In IL-4-stimulated cells, both anti-α vβ 5 and anti-α vβ 6 inhibited the phosphorylation of focal adhesion kinase. Furthermore, both β 5- and β 6-integrins were enriched in basal cells in the injured airway epithelium with allergic rhinitis. These findings suggest that α vβ 5 and α vβ 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.
Original language | English (US) |
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Pages (from-to) | 420-433 |
Number of pages | 14 |
Journal | American Journal of Respiratory Cell and Molecular Biology |
Volume | 60 |
Issue number | 4 |
DOIs | |
State | Published - Apr 1 2019 |
Keywords
- Collective cell migration
- Cultured human nasal epithelial cells
- Furin
- IL-4
- Integrin
ASJC Scopus subject areas
- Molecular Biology
- Pulmonary and Respiratory Medicine
- Clinical Biochemistry
- Cell Biology