title: Toll-like receptor 2 mediates microglia/brain macrophage MT1-MMP expression and glioma expansion.
abstract: BACKGROUND
  Glioblastomas are the most aggressive primary brain tumors in humans. Microglia/brain macrophage accumulation in and around the tumor correlates with malignancy and poor clinical prognosis of these tumors. We have previously shown that microglia promote glioma expansion through upregulation of membrane type 1 matrix metalloprotease (MT1-MMP). This upregulation depends on signaling via the Toll-like receptor (TLR) adaptor molecule myeloid differentiation primary response gene 88 (MyD88).
  
  
  METHODS
  Using in vitro, ex vivo, and in vivo techniques, we identified TLR2 as the main TLR controlling microglial MT1-MMP expression and promoting microglia-assisted glioma expansion.
  
  
  RESULTS
  The implantation of mouse GL261 glioma cells into TLR2 knockout mice resulted in significantly smaller tumors, reduced MT1-MMP expression, and enhanced survival rates compared with wild-type control mice. Tumor expansion studied in organotypic brain slices depended on both parenchymal TLR2 expression and the presence of microglia. Glioma-derived soluble factors and synthetic TLR2 specific ligands induced MT1-MMP expression in microglia from wild-type mice, but no such change in MT1-MMP gene expression was observed in microglia from TLR2 knockout mice. We also found evidence that TLR1 and TLR6 cofunction with TLR2 as heterodimers in regulating MT1-MMP expression in vitro.
  
  
  CONCLUSIONS
  Our results thus show that activation of TLR2 along with TLRs 1 and/or 6 converts microglia into a glioma supportive phenotype.
authors.affiliation: Corresponding Author: Prof Dr Helmut Kettenmann, PhD, Cellular Neurosciences, Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str. 10, 13125 Berlin, Germany. kettenmann@mdc-berlin.de.
authors.forename: Katyayni
authors.initials: K
authors.lastname: Vinnakota
authors.forename: Feng
authors.initials: F
authors.lastname: Hu
authors.forename: Min-Chi
authors.initials: MC
authors.lastname: Ku
authors.forename: Petya B
authors.initials: PB
authors.lastname: Georgieva
authors.forename: Frank
authors.initials: F
authors.lastname: Szulzewsky
authors.forename: Andreas
authors.initials: A
authors.lastname: Pohlmann
authors.forename: Sonia
authors.initials: S
authors.lastname: Waiczies
authors.forename: Helmar
authors.initials: H
authors.lastname: Waiczies
authors.forename: Thoralf
authors.initials: T
authors.lastname: Niendorf
authors.forename: Seija
authors.initials: S
authors.lastname: Lehnardt
authors.forename: Uwe-Karsten
authors.initials: UK
authors.lastname: Hanisch
authors.forename: Michael
authors.initials: M
authors.lastname: Synowitz
authors.forename: Darko
authors.initials: D
authors.lastname: Markovic
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Wolf
authors.forename: Rainer
authors.initials: R
authors.lastname: Glass
authors.forename: Helmut
authors.initials: H
authors.lastname: Kettenmann
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D008262:Macrophage Activation; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D015996:Survival Rate; D051194:Toll-Like Receptor 1 / Q000378:metabolism; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051216:Toll-Like Receptor 6 / Q000378:metabolism
chemical_list: D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D053511:Matrix Metalloproteinase 14
keywords: MT1-MMP; TLR; glioma; glioma-associated microglia/brain macrophages