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Matrix Metalloproteinase-9–Deficient Dendritic Cells Have Impaired Migration through Tracheal Epithelial Tight Junctions

Molecular Pathology Unit, Department of Pathology, Massachusetts General Hospital, Charlestown, Massachusetts

Address correspondence to: Eveline E. Schneeberger, M.D., Molecular Pathology Unit, Room 7147, Massachusetts General Hospital, 149 13th Street, Charlestown, MA 02129. E-mail: eschneeberger{at}partners.org

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)-1 or MIP-3ß 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-3ß than MIP-1, 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-3ß, 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.

Abbreviations: bronchoalveolar lavage, BAL • bone marrow–derived dendritic cells, BMDC • bovine serum albumin, BSA • confocal laser scanning microscopy, CLSM • dendritic cells, DC • extracellular matrix, ECM • epidermal growth factor, EGF • fetal calf serum, FCS • fluorescein isothiocyanate, FITC • granulocyte macrophage–colony-stimulating factor, GM-CSF • intercellular adhesion molecule, ICAM • interleukin, IL • macrophage inflammatory protein, MIP • matrix metalloproteinase, MMP • ovalbumin, OVA • phosphate-buffered saline, PBS • polymerase chain reaction, PCR • phycoeryhtrin, PE • reverse transcriptase, RT • transepithelial electrical resistance, TER • tissue inhibitor of metalloproteinase, TIMP • tight junction, TJ

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