{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T23:45:08Z","timestamp":1790293508011,"version":"4.1.0"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2019,4,1]],"date-time":"2019-04-01T00:00:00Z","timestamp":1554076800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>A positive link between persistent cellular motion and a defective tight junction barrier allows increased antigenic penetration and contact between ligand\u2013receptor pairs, leading to exacerbated allergic airway inflammation and remodeling. Given that collective cell migration involves cell\u2013cell and cell\u2013extracellular matrix adhesions, and given that IL-4 induces epithelial barrier dysfunction and decreases cell\u2013extracellular 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 \u03b1v-integrin\u2013activating enzyme furin, and function-blocking antibodies for \u03b1v\u03b25 or \u03b1v\u03b26. In IL-4\u2013stimulated cells, both anti-\u03b1v\u03b25 and anti-\u03b1v\u03b26 inhibited the phosphorylation of focal adhesion kinase. Furthermore, both \u03b25- and \u03b26-integrins were enriched in basal cells in the injured airway epithelium with allergic rhinitis. These findings suggest that \u03b1v\u03b25 and \u03b1v\u03b26 serve as critical mechanoreceptors in IL-4\u2013induced collective HNEC migration through the focal adhesion kinase signaling pathway. These results have implications for targeting treatment of exacerbation of respiratory allergic diseases.<\/jats:p>","DOI":"10.1165\/rcmb.2018-0081oc","type":"journal-article","created":{"date-parts":[[2018,10,25]],"date-time":"2018-10-25T15:49:54Z","timestamp":1540482594000},"page":"420-433","source":"Crossref","is-referenced-by-count":21,"title":["Integrins \u03b1v\u03b25 and \u03b1v\u03b26 Mediate IL-4\u2013induced Collective Migration in Human Airway Epithelial Cells"],"prefix":"10.1093","volume":"60","author":[{"given":"Sang-Nam","family":"Lee","sequence":"first","affiliation":[{"name":"The Airway Mucus Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Suk","family":"Ahn","sequence":"additional","affiliation":[{"name":"The Airway Mucus Institute and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seong Gyu","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Mechanical Engineering, Yonsei University, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyung-Suk","family":"Lee","sequence":"additional","affiliation":[{"name":"School of Mechanical Engineering, Yonsei University, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Augustine M. K.","family":"Choi","sequence":"additional","affiliation":[{"name":"Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medical College and New York-Presbyterian Hospital, New York, New York; and"},{"name":"Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joo-Heon","family":"Yoon","sequence":"additional","affiliation":[{"name":"The Airway Mucus Institute and"},{"name":"Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2019,4,1]]},"reference":[{"key":"2026012222071985700_bib1","doi-asserted-by":"crossref","first-page":"1752","DOI":"10.1016\/j.jaci.2017.04.010","article-title":"Etiology of epithelial barrier dysfunction in patients with type 2 inflammatory diseases","volume":"139","author":"Schleimer","year":"2017","journal-title":"J Allergy Clin Immunol"},{"key":"2026012222071985700_bib2","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1183\/09031936.00150305","article-title":"Allergen-induced airway remodelling","volume":"29","author":"Lloyd","year":"2007","journal-title":"Eur Respir J"},{"key":"2026012222071985700_bib3","doi-asserted-by":"crossref","first-page":"726","DOI":"10.1513\/pats.200605-126SF","article-title":"Airway epithelial repair, regeneration, and remodeling after injury in chronic obstructive pulmonary disease","volume":"3","author":"Puchelle","year":"2006","journal-title":"Proc Am Thorac Soc"},{"key":"2026012222071985700_bib4","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.ceb.2003.10.008","article-title":"Apicobasal polarization: epithelial form and function","volume":"15","author":"Gibson","year":"2003","journal-title":"Curr Opin Cell Biol"},{"key":"2026012222071985700_bib5","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/nature01440","article-title":"Segregation of receptor and ligand regulates activation of epithelial growth factor receptor","volume":"422","author":"Vermeer","year":"2003","journal-title":"Nature"},{"key":"2026012222071985700_bib6","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.diff.2013.02.005","article-title":"Collective migration and cell jamming","volume":"86","author":"Sadati","year":"2013","journal-title":"Differentiation"},{"key":"2026012222071985700_bib7","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.1016\/j.bpj.2016.05.019","article-title":"Cellular contraction and polarization drive collective cellular motion","volume":"110","author":"Notbohm","year":"2016","journal-title":"Biophys J"},{"key":"2026012222071985700_bib8","doi-asserted-by":"crossref","first-page":"6024","DOI":"10.1038\/srep06024","article-title":"FAK and paxillin dynamics at focal adhesions in the protrusions of migrating cells","volume":"4","author":"Hu","year":"2014","journal-title":"Sci Rep"},{"key":"2026012222071985700_bib9","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrm1549","article-title":"Focal adhesion kinase: in command and control of cell motility","volume":"6","author":"Mitra","year":"2005","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2026012222071985700_bib10","doi-asserted-by":"crossref","first-page":"714","DOI":"10.2174\/1566524015666150921105339","article-title":"Integrins as therapeutic targets for respiratory diseases","volume":"15","author":"Teoh","year":"2015","journal-title":"Curr Mol Med"},{"key":"2026012222071985700_bib11","first-page":"L256","article-title":"Expression of integrin cell adhesion receptors during human airway epithelial repair in vivo","volume":"273","author":"Pilewski","year":"1997","journal-title":"Am J Physiol"},{"key":"2026012222071985700_bib12","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.ceb.2006.08.011","article-title":"Integrin-regulated FAK-Src signaling in normal and cancer cells","volume":"18","author":"Mitra","year":"2006","journal-title":"Curr Opin Cell Biol"},{"key":"2026012222071985700_bib13","doi-asserted-by":"crossref","first-page":"3997","DOI":"10.1242\/jcs.175539","article-title":"Focal-adhesion-independent integrin-\u03b1v regulation of FAK and c-Myc is necessary for 3D skin formation and tumor invasion","volume":"128","author":"Duperret","year":"2015","journal-title":"J Cell Sci"},{"key":"2026012222071985700_bib14","doi-asserted-by":"crossref","first-page":"e54290","DOI":"10.1371\/journal.pone.0054290","article-title":"High-resolution analysis and functional mapping of cleavage sites and substrate proteins of furin in the human proteome","volume":"8","author":"Shiryaev","year":"2013","journal-title":"PLoS One"},{"key":"2026012222071985700_bib15","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/nrd3699","article-title":"The biology and therapeutic targeting of the proprotein convertases","volume":"11","author":"Seidah","year":"2012","journal-title":"Nat Rev Drug Discov"},{"key":"2026012222071985700_bib16","doi-asserted-by":"crossref","first-page":"2667","DOI":"10.1002\/term.2240","article-title":"Proprotein convertase inhibition promotes ciliated cell differentiation \u2013 a potential mechanism for the inhibition of Notch1 signalling by decanoyl-RVKR-chloromethylketone","volume":"11","author":"Lee","year":"2017","journal-title":"J Tissue Eng Regen Med"},{"key":"2026012222071985700_bib17","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1165\/rcmb.2014-0029OC","article-title":"Proprotein convertase 5\/6a is associated with bone morphogenetic protein-2-induced squamous cell differentiation","volume":"52","author":"Lee","year":"2015","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026012222071985700_bib18","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.jaci.2014.05.049","article-title":"Epithelial barrier function: at the front line of asthma immunology and allergic airway inflammation","volume":"134","author":"Georas","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"2026012222071985700_bib19","doi-asserted-by":"crossref","first-page":"1087","DOI":"10.1016\/j.jaci.2012.05.052","article-title":"Defective epithelial barrier in chronic rhinosinusitis: the regulation of tight junctions by IFN-\u03b3 and IL-4","volume":"130","author":"Soyka","year":"2012","journal-title":"J Allergy Clin Immunol"},{"key":"2026012222071985700_bib20","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1023\/B:JOCI.0000029111.27168.c6","article-title":"Th2 cytokines IL-4 and IL-13 downregulate paxillin expression in bronchial airway epithelial cells","volume":"24","author":"Ramirez-Icaza","year":"2004","journal-title":"J Clin Immunol"},{"key":"2026012222071985700_bib21","doi-asserted-by":"crossref","first-page":"L164","DOI":"10.1152\/ajplung.90453.2008","article-title":"Insulin receptor substrate-1\/2 mediates IL-4-induced migration of human airway epithelial cells","volume":"297","author":"White","year":"2009","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026012222071985700_bib22","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1242\/dev.041731","article-title":"Exploring the effects of mechanical feedback on epithelial topology","volume":"137","author":"Aegerter-Wilmsen","year":"2010","journal-title":"Development"},{"key":"2026012222071985700_bib23","doi-asserted-by":"crossref","first-page":"1040","DOI":"10.1038\/nmat4357","article-title":"Unjamming and cell shape in the asthmatic airway epithelium","volume":"14","author":"Park","year":"2015","journal-title":"Nat Mater"},{"key":"2026012222071985700_bib24","first-page":"021011","article-title":"Motility-driven glass and jamming transitions in biological tissues","volume":"6","author":"Bi","year":"2016","journal-title":"Phys Rev X"},{"key":"2026012222071985700_bib25","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1177\/000348940010900612","article-title":"Secretory differentiation of serially passaged normal human nasal epithelial cells by retinoic acid: expression of mucin and lysozyme","volume":"109","author":"Yoon","year":"2000","journal-title":"Ann Otol Rhinol Laryngol"},{"key":"2026012222071985700_bib26","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1164\/rccm.201109-1706OC","article-title":"Hypoxia-inducible factor 1 mediates nasal polypogenesis by inducing epithelial-to-mesenchymal transition","volume":"185","author":"Shin","year":"2012","journal-title":"Am J Respir Crit Care Med"},{"key":"2026012222071985700_bib27","doi-asserted-by":"crossref","first-page":"36959","DOI":"10.1038\/srep36959","article-title":"Integrins outside focal adhesions transmit tensions during stable cell adhesion","volume":"6","author":"Wang","year":"2016","journal-title":"Sci Rep"},{"key":"2026012222071985700_bib28","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1242\/jcs.064618","article-title":"Integrins and cadherins join forces to form adhesive networks","volume":"124","author":"Weber","year":"2011","journal-title":"J Cell Sci"},{"key":"2026012222071985700_bib29","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1007\/s12195-009-0057-7","article-title":"Cell-matrix de-adhesion dynamics reflect contractile mechanics","volume":"2","author":"Sen","year":"2009","journal-title":"Cell Mol Bioeng"},{"key":"2026012222071985700_bib30","doi-asserted-by":"crossref","first-page":"12526","DOI":"10.1073\/pnas.0404723101","article-title":"Rho overexpression leads to mitosis-associated detachment of cells from epithelial sheets: a link to the mechanism of cancer dissemination","volume":"101","author":"Vasiliev","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026012222071985700_bib31","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1038\/360358a0","article-title":"Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160","volume":"360","author":"Hallenberger","year":"1992","journal-title":"Nature"},{"key":"2026012222071985700_bib32","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1165\/rcmb.2007-0325OC","article-title":"Nasal epithelial cells as surrogates for bronchial epithelial cells in airway inflammation studies","volume":"39","author":"McDougall","year":"2008","journal-title":"Am J Respir Cell Mol Biol"},{"key":"2026012222071985700_bib33","doi-asserted-by":"crossref","first-page":"567","DOI":"10.2174\/138945006776818700","article-title":"Extracellular matrix, integrins, and mesenchymal cell function in the airways","volume":"7","author":"Fernandes","year":"2006","journal-title":"Curr Drug Targets"},{"key":"2026012222071985700_bib34","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1242\/dmm.006031","article-title":"Airway basal stem cells: a perspective on their roles in epithelial homeostasis and remodeling","volume":"3","author":"Rock","year":"2010","journal-title":"Dis Model Mech"},{"key":"2026012222071985700_bib35","doi-asserted-by":"crossref","first-page":"14170","DOI":"10.1073\/pnas.1009426107","article-title":"Roles of epithelial cell-derived periostin in TGF-\u03b2 activation, collagen production, and collagen gel elasticity in asthma","volume":"107","author":"Sidhu","year":"2010","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026012222071985700_bib36","doi-asserted-by":"crossref","first-page":"8545","DOI":"10.1074\/jbc.M113.539882","article-title":"Periostin induces intracellular cross-talk between kinases and hyaluronan in atrioventricular valvulogenesis","volume":"289","author":"Ghatak","year":"2014","journal-title":"J Biol Chem"},{"key":"2026012222071985700_bib37","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1083\/jcb.150.6.1445","article-title":"Expression and function of \u03b1v\u03b23 and \u03b1v\u03b25 integrins in the developing pancreas: roles in the adhesion and migration of putative endocrine progenitor cells","volume":"150","author":"Cirulli","year":"2000","journal-title":"J Cell Biol"},{"key":"2026012222071985700_bib38","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.jaci.2015.10.050","article-title":"Impaired barrier function in patients with house dust mite-induced allergic rhinitis is accompanied by decreased occludin and zonula occludens-1 expression","volume":"137","author":"Steelant","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"2026012222071985700_bib39","doi-asserted-by":"crossref","first-page":"9182","DOI":"10.1073\/pnas.0500918102","article-title":"ADAM10 mediates E-cadherin shedding and regulates epithelial cell-cell adhesion, migration, and \u03b2-catenin translocation","volume":"102","author":"Maretzky","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"2026012222071985700_bib40","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1038\/ncb2298","article-title":"Cleavage of E-cadherin by ADAM10 mediates epithelial cell sorting downstream of EphB signalling","volume":"13","author":"Solanas","year":"2011","journal-title":"Nat Cell Biol"},{"key":"2026012222071985700_bib41","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/nmat3025","article-title":"Collective cell guidance by cooperative intercellular forces","volume":"10","author":"Tambe","year":"2011","journal-title":"Nat Mater"},{"key":"2026012222071985700_bib42","doi-asserted-by":"crossref","first-page":"012712","DOI":"10.1103\/PhysRevE.91.012712","article-title":"Collective cell migration induced by mechanical stress and substrate adhesiveness","volume":"91","author":"K\u00f6pf","year":"2015","journal-title":"Phys Rev E Stat Nonlin Soft Matter Phys"},{"key":"2026012222071985700_bib43","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1042\/bj3460133","article-title":"Endoproteolytic processing of integrin pro-\u03b1 subunits involves the redundant function of furin and proprotein convertase (PC) 5A, but not paired basic amino acid converting enzyme (PACE) 4, PC5B or PC7","volume":"346","author":"Lissitzky","year":"2000","journal-title":"Biochem J"},{"key":"2026012222071985700_bib44","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1016\/j.tips.2014.09.006","article-title":"Integrins: therapeutic targets in airway hyperresponsiveness and remodelling?","volume":"35","author":"Wright","year":"2014","journal-title":"Trends Pharmacol Sci"},{"key":"2026012222071985700_bib45","doi-asserted-by":"crossref","first-page":"2590","DOI":"10.1172\/JCI58978","article-title":"Periostin promotes chronic allergic inflammation in response to Th2 cytokines","volume":"122","author":"Masuoka","year":"2012","journal-title":"J Clin Invest"},{"key":"2026012222071985700_bib46","first-page":"5358","article-title":"Periostin secreted by epithelial ovarian carcinoma is a ligand for \u03b1V\u03b23 and \u03b1V\u03b25 integrins and promotes cell motility","volume":"62","author":"Gillan","year":"2002","journal-title":"Cancer Res"},{"key":"2026012222071985700_bib47","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1242\/jcs.030478","article-title":"FAK engages multiple pathways to maintain survival of fibroblasts and epithelia: differential roles for paxillin and p130Cas","volume":"122","author":"Zouq","year":"2009","journal-title":"J Cell Sci"}],"container-title":["American Journal of Respiratory Cell and Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/60\/4\/420\/66465542\/ajrcmb_60_4_420.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article-pdf\/60\/4\/420\/66465542\/ajrcmb_60_4_420.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T03:11:50Z","timestamp":1769137910000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ajrcmb\/article\/60\/4\/420\/8430419"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,1]]},"references-count":47,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,4,1]]},"published-print":{"date-parts":[[2019,4,1]]}},"URL":"https:\/\/doi.org\/10.1165\/rcmb.2018-0081oc","relation":{},"ISSN":["1044-1549","1535-4989"],"issn-type":[{"value":"1044-1549","type":"print"},{"value":"1535-4989","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2019,4]]},"published":{"date-parts":[[2019,4,1]]}}}