title: A novel role of MMP-13 for murine DC function: its inhibition dampens T-cell activation.
abstract: Dendritic cells (DCs) have been shown to express matrix metalloproteinase 13 (MMP-13), but little is known about its specific function in DCs and its role in inflammatory conditions. In the present study, we describe a novel role of MMP-13 in regulating the immunostimulatory function of murine DCs through moderating MHC-I surface presentation, endocytosis and cytokine/chemokine secretion. MMP-13 expression was confirmed in bone marrow-derived DCs at both the mRNA and the protein level and, furthermore, at the activity level. Remarkably, LPS treatment strongly enhanced MMP-13 mRNA expression as well as MMP-13 activity, indicating an important role of MMP-13 in inflammatory processes. Functionally, MMP-13 inhibition did not influence the DC migratory capacity, while endocytosis of ovalbumin was significantly decreased. Inhibition of MMP-13 lowered the capability of murine DCs to activate CD8+T cells, apparently through reducing MHC-I surface presentation. Decreased surface expression of CD11c on DCs, as well as changes in the DC cytokine/chemokine profile after MMP-13 inhibition, emphasizes the influence of MMP-13 on DC function. Moreover, T-cell-targeting cytokines such as IL-12, IL-23 and IL-6 were significantly reduced. Collectively, our data reveal a novel involvement of MMP-13 in regulating DC immunobiology through moderating MHC-I surface presentation, endocytosis and cytokine/chemokine secretion. Furthermore, the reduced MHC-I surface presentation by DCs resulted in a poor CD8+T-cell response in vitro This novel finding indicates that MMP-13 might be a promising target for therapeutic intervention in inflammatory diseases.
authors.affiliation: Comprehensive Pneumology Center, University Hospital of the Ludwig-Maximilians-University Munich, Asklepios Kliniken Gauting and Helmholtz Zentrum München, Member of the German Center for Lung Research, 81377 Munich, Germany.
authors.forename: Juliane
authors.initials: J
authors.lastname: Bartmann
authors.affiliation: Comprehensive Pneumology Center, University Hospital of the Ludwig-Maximilians-University Munich, Asklepios Kliniken Gauting and Helmholtz Zentrum München, Member of the German Center for Lung Research, 81377 Munich, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Frankenberger
authors.affiliation: Comprehensive Pneumology Center, University Hospital of the Ludwig-Maximilians-University Munich, Asklepios Kliniken Gauting and Helmholtz Zentrum München, Member of the German Center for Lung Research, 81377 Munich, Germany Department of Pneumology, Klinikum der Universität München-Großhadern, 81377 Munich, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Neurohr
authors.affiliation: Comprehensive Pneumology Center, University Hospital of the Ludwig-Maximilians-University Munich, Asklepios Kliniken Gauting and Helmholtz Zentrum München, Member of the German Center for Lung Research, 81377 Munich, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.affiliation: Institute of Molecular Immunology, Helmholtz Zentrum München, 81377 Munich, Germany.
authors.forename: Elfriede
authors.initials: E
authors.lastname: Noessner
authors.affiliation: Comprehensive Pneumology Center, University Hospital of the Ludwig-Maximilians-University Munich, Asklepios Kliniken Gauting and Helmholtz Zentrum München, Member of the German Center for Lung Research, 81377 Munich, Germany Department of Respiratory Diseases, Klinik Augustinum München, 81375 Munich, Germany wulffen@med.augustinum.de.
authors.forename: Werner
authors.initials: W
authors.lastname: von Wulffen
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D003713:Dendritic Cells / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D005260:Female; D007249:Inflammation / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D053509:Matrix Metalloproteinase 13
keywords: CD8+ T-cell activation; DCs; MHC-I; MMP-13; cytokine profile; endocytosis