title: Matrix metalloproteinases 9 and 2 are necessary for the migration of Langerhans cells and dermal dendritic cells from human and murine skin.
abstract: Dendritic cells migrate from the skin to the draining lymph nodes. They transport immunogenic MHC-peptide complexes, present them to Ag-specific T cells in the T areas, and thus generate immunity. Migrating dendritic cells encounter physical obstacles, such as basement membranes and collagen meshwork. Prior work has revealed that matrix metalloproteinase-9 (MMP-9) contributes to mouse Langerhans cell migration. In this study, we use mouse and human skin explant culture models to further study the role of MMPs in the migration and maturation of skin dendritic cells. We found that MMP-2 and MMP-9 are expressed on the surface of dendritic cells from the skin, but not from other sources. They are also expressed in migrating Langerhans cells in situ. The migration of both Langerhans cells and dermal dendritic cells is inhibited by a broad spectrum inhibitor of MMPs (BB-3103), by Abs to MMP-9 and -2, and by the natural tissue inhibitors of metalloproteinases (TIMP), TIMP-1 and TIMP-2. Inhibition by anti-MMP-2 and TIMP-2 define a functional role for MMP-2 in addition to the previously described function of MMP-9. The importance of MMP-9 was emphasized using MMP-9-deficient mice in which Langerhans cell migration from skin explants was strikingly reduced. However, MMP-9 was only required for Langerhans cell migration and not maturation, since nonmigrating Langerhans cells isolated from the epidermis matured normally with regard to morphology, phenotype, and T cell stimulatory function. These data underscore the importance of MMPs, and they may be of relevance for therapeutically regulating dendritic cell migration in clinical vaccination approaches.
authors.affiliation: Department of Dermatology, University of Innsbruck, Innsbruck, Austria.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Ratzinger
authors.forename: Patrizia
authors.initials: P
authors.lastname: Stoitzner
authors.forename: Susanne
authors.initials: S
authors.lastname: Ebner
authors.forename: Manfred B
authors.initials: MB
authors.lastname: Lutz
authors.forename: Guy T
authors.initials: GT
authors.lastname: Layton
authors.forename: Christian
authors.initials: C
authors.lastname: Rainer
authors.forename: Robert M
authors.initials: RM
authors.lastname: Senior
authors.forename: J Michael
authors.initials: JM
authors.lastname: Shipley
authors.forename: Peter
authors.initials: P
authors.lastname: Fritsch
authors.forename: Gerold
authors.initials: G
authors.lastname: Schuler
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Romani
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000502:physiology; D002454:Cell Differentiation; D002465:Cell Movement; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D020405:Dermis / Q000166:cytology / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D000078404:Epidermal Cells; D004817:Epidermis / Q000276:immunology; D006801:Humans; D007801:Langerhans Cells / Q000276:immunology*; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000502:physiology; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D011480:Protease Inhibitors / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9