title: Glioma-associated microglial MMP9 expression is upregulated by TLR2 signaling and sensitive to minocycline.
abstract: The invasiveness of malignant gliomas is one of the major obstacles in glioma therapy and the reason for the poor survival of patients. Glioma cells infiltrate into the brain parenchyma and thereby escape surgical resection. Glioma associated microglia/macrophages support glioma infiltration into the brain parenchyma by increased expression and activation of extracellular matrix degrading proteases such as matrix metalloprotease (MMP) 2, MMP9 and membrane-type 1 MMP. In this work we demonstrate that, MMP9 is predominantly expressed by glioma associated microglia/macrophages in mouse and human glioma tissue but not by the glioma cells. Supernatant from glioma cells induced the expression of MMP9 in cultured microglial cells. Using mice deficient for different Toll-like receptors we identified Toll-like receptor 2/6 as the signaling pathway for the glioma induced upregulation of microglial MMP9. Also in an experimental mouse glioma model, Toll-like receptor 2 deficiency attenuated the upregulation of microglial MMP9. Moreover, glioma supernatant triggered an upregulation of Toll-like receptor 2 expression in microglia. Both, the upregulation of MMP9 and Toll-like receptor 2 were attenuated by the antibiotic minocycline and a p38 mitogen-activated protein kinase antagonist in vitro. Minocycline also extended the survival rate of glioma bearing mice when given to the drinking water. Thus glioma cells change the phenotype of glioma associated microglia/macrophages in a complex fashion using Toll-like receptor 2 as an important signaling pathway and minocycline further proved to be a potential candidate for adjuvant glioma therapy.
authors.affiliation: Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, 13125, Berlin, Germany.
authors.forename: Feng
authors.initials: F
authors.lastname: Hu
authors.forename: Min-Chi
authors.initials: MC
authors.lastname: Ku
authors.forename: Darko
authors.initials: D
authors.lastname: Markovic
authors.forename: Omar Dildar a
authors.initials: O
authors.lastname: Dzaye
authors.forename: Seija
authors.initials: S
authors.lastname: Lehnardt
authors.forename: Michael
authors.initials: M
authors.lastname: Synowitz
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Wolf
authors.forename: Helmut
authors.initials: H
authors.lastname: Kettenmann
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008911:Minocycline / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000900:Anti-Bacterial Agents; D012333:RNA, Messenger; D051195:Toll-Like Receptor 2; D020780:Matrix Metalloproteinase 9; D008911:Minocycline
keywords: MMP9; TLR; glioma; glioma-associated microglia/brain macrophages; minocycline
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