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Glial cell line-derived neurotrophic factor increases matrix metallopeptidase 9 and 14 expression in microglia and
Yimin Huang1,2, Baole Zhang1,3, Hannah Haneke1
1Cellular Neurosciences, Max Delbrueck Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.
Abstract:
Glial cell line-derived neurotrophic factor (GDNF) is released by glioma cells and promotes tumor growth. We have previously found that GDNF released from the tumor cells is a chemoattractant for microglial cells, the immune cells of the central nervous system. Here we show that GDNF increases matrix metalloproteinase (MMP) 9 and MMP14 expression in cultured microglial cells from mixed sexes of neonatal mice. The GDNF-induced microglial MMP9 and MMP14 upregulation is mediated by GDNF family receptor alpha 1 receptors and dependent on p38 mitogen-activated protein kinase signaling. In organotypic brain slices, GDNF promotes the growth of glioma and this effect depends on the presence of microglia. We also previously found that MMP9 and MMP14 upregulation can be mediated by Toll-like receptor (TLR) 2 signaling and here we demonstrate that GDNF increases the expression of TLR1 and TLR2. In conclusion, GDNF promotes the pro-tumorigenic phenotype of microglia.
Insights
Glial cell line-derived neurotrophic factor (GDNF) fuels glioma growth by activating microglia, immune cells in the brain. GDNF upregulates matrix metalloproteinases (MMPs) in microglia, promoting tumor progression.
Area of Science:
- Neuroscience
- Immunology
- Oncology
Background:
- Glioma cells release glial cell line-derived neurotrophic factor (GDNF).
- GDNF acts as a chemoattractant for microglial cells, the immune cells of the central nervous system.
- Microglia play a role in tumor growth and progression.
Purpose of the Study:
- To investigate the role of GDNF in modulating microglial function.
- To determine the signaling pathways involved in GDNF-induced microglial activation.
- To assess the impact of GDNF on glioma growth in the presence of microglia.
Main Methods:
- Primary microglial cell cultures from neonatal mice.
- Analysis of matrix metalloproteinase (MMP) 9 and MMP14 expression.
- Investigation of signaling pathways including p38 mitogen-activated protein kinase (MAPK).
- Organotypic brain slice cultures to model glioma-microglia interactions.
Main Results:
- GDNF significantly increases MMP9 and MMP14 expression in cultured microglia.
- GDNF-induced MMP upregulation is mediated by GDNF family receptor alpha 1 (GFRα1) and p38 MAPK signaling.
- GDNF promotes glioma growth in organotypic brain slices, an effect dependent on microglia presence.
- GDNF increases the expression of Toll-like receptor 1 (TLR1) and TLR2 in microglia.
Conclusions:
- GDNF promotes a pro-tumorigenic phenotype in microglia.
- GDNF signaling pathways in microglia contribute to glioma progression.
- Targeting GDNF-microglia interactions may offer therapeutic strategies for glioma.
