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Am J Respir Cell Mol Biol. 2019 Apr;60(4):420-433. doi: 10.1165/rcmb.2018-0081OC.

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

Author information

1
1 The Airway Mucus Institute and.
2
2 School of Mechanical Engineering, Yonsei University, Seoul, Korea.
3
3 Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York; and.
4
4 Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York.
5
5 Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea.

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 αv-integrin-activating enzyme furin, and function-blocking antibodies for αvβ5 or αvβ6. In IL-4-stimulated cells, both anti-αvβ5 and anti-αvβ6 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 αvβ5 and αvβ6 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.

KEYWORDS:

IL-4; collective cell migration; cultured human nasal epithelial cells; furin; integrin

PMID:
30359079
DOI:
10.1165/rcmb.2018-0081OC

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