Glial cell line‐derived neurotrophic factor increases matrix metallopeptidase 9 and 14 expression in microglia and promotes microglia‐mediated glioma progression

Yimin Huang,Baole Zhang,Pengfei Xia,Yang Yuan,Helmut Kettenmann,Hannah Haneke,Cynthia Nanvuma,Verena Haage,Omar Dzaye,Edyta Motta,Malgorzata Lubas,Feng Hu

doi:10.1002/jnr.24768

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.

Highlights

Glioblastoma is a highly malignant brain tumor which comprise approximately 80% of malignant tumors in the central nervous system (Bernstock et al, 2019; Omuro & DeAngelis, 2013)
We previously found that matrix metallopeptidase 9 (MMP9) and matrix metallopeptidase 14 (MMP14) upregulation can be mediated by Toll-like receptor (TLR) 2 signaling and here we demonstrate that Glial cell line-derived neurotrophic factor (GDNF) increases the expression of TLR1 and TLR2
By using primary microglia cell and organotypic brain slices, we demonstrate that glial cell line-derived neurotrophic factor (GDNF) increase matrix metallopeptidase 9 and 14 expression on microglia via mitogen-activated protein kinase signaling cascades, which in turn promote glioma growth on the organotypic brain slices

Summary

Introduction

Glioblastoma is a highly malignant brain tumor which comprise approximately 80% of malignant tumors in the central nervous system (Bernstock et al, 2019; Omuro & DeAngelis, 2013). It has recently been recognized that glioma cells interact with the microenvironment in particular with the intrinsic immune cells of the brain, the microglia. These cells together with peripheral monocytes infiltrate into the glioma tissue and make up 30% of the tumor mass (Hambardzumyan et al, 2015). Glial cell-derived neurotrophic factor (GDNF), a member of the transforming growth factor-β superfamily, is highly expressed in glioma (Wiesenhofer et al, 2000), and promotes the growth, invasion, and migration of glioma cells (Ku et al, 2013; Song & Moon, 2006; Xiong et al, 2017). GDNF may trigger functional changes on microglia after attracting them to the glioma microenvironment

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