Matrix metalloproteinase-9-deficient dendritic cells have impaired migration through tracheal epithelial tight junctions.
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.
Ichiyasu
Hidenori
H
Molecular Pathology Unit, Department of Pathology, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129, USA.
McCormack
Joanne M
JM
McCarthy
Karin M
KM
Dombkowski
David
D
Preffer
Frederic I
FI
Schneeberger
Eveline E
EE
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*
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