title: Matrix metalloproteinase-9-deficient dendritic cells have impaired migration through tracheal epithelial tight junctions.
abstract: When sampling inhaled antigens, dendritic cells (DC) must penetrate the tight junction (TJ) barrier while maintaining the TJ seal. In matrix metalloproteinase (MMP)-9-deficient mice, in vivo experiments suggest that migration of DC into air spaces is impaired. To examine the underlying mechanisms, we established a well-defined in vitro model using mouse tracheal epithelial cells and mouse bone marrow DC (BMDC). Transmigration was elicited with either macrophage inflammatory protein (MIP)-1alpha or MIP-3beta in a time-dependent manner. Control MMP-9(+/+) BMDC cultured with granulocyte macrophage-colony-stimulating factor for 7 d showed a 30-fold greater transepithelial migration toward MIP-3beta than MIP-1alpha, indicating a more mature DC phenotype. MMP-9(-/-) BMDC as well as MMP-9(+/+) BMDC in the presence of the MMP inhibitor GM6001, although showing a similar preference for MIP-3beta, were markedly impaired in their ability to traverse the epithelium. Expression levels of CCR5 and CCR7, however, were similar in both MMP-9(-/-) and MMP-9(+/+) BMDC. Expression of the integral TJ proteins, occludin and claudin-1, were examined in BMDC before and after transepithelial migration. Interestingly, occludin but not claudin-1 was degraded following transepithelial migration in both MMP-9(-/-) and control BMDC. In addition, there was a > 2-fold increase in claudin-1 expression in MMP-9(-/-) as compared with control BMDC. These observations indicate that occludin and claudin-1 are differentially regulated and suggest that the lack of MMP-9 may affect claudin-1 turnover.
authors.affiliation: Molecular Pathology Unit, Department of Pathology, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129, USA.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ichiyasu
authors.forename: Joanne M
authors.initials: JM
authors.lastname: McCormack
authors.forename: Karin M
authors.initials: KM
authors.lastname: McCarthy
authors.forename: David
authors.initials: D
authors.lastname: Dombkowski
authors.forename: Frederic I
authors.initials: FI
authors.lastname: Preffer
authors.forename: Eveline E
authors.initials: EE
authors.lastname: Schneeberger
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D054415:Chemokine CCL19; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC / Q000378:metabolism; D062445:Claudin-1; D003713:Dendritic Cells / Q000378:metabolism*; D004151:Dipeptides / Q000378:metabolism; D017097:Electric Impedance; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D008168:Lung / Q000033:anatomy & histology / Q000276:immunology / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D062793:Occludin; D011480:Protease Inhibitors / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology* / Q000378:metabolism; D019108:Tight Junctions / Q000378:metabolism*; D014132:Trachea / Q000033:anatomy & histology*
chemical_list: C515461:Ccl19 protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D062445:Claudin-1; C568113:Cldn1 protein, mouse; D004151:Dipeptides; D019402:Macrophage Inflammatory Proteins; D008565:Membrane Proteins; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D062793:Occludin; C568986:Ocln protein, mouse; D011480:Protease Inhibitors; D019713:Receptors, CCR5; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D020780:Matrix Metalloproteinase 9