Investigation of Neuregulin-1 and Glial Cell-Derived Neurotrophic Factor in Rodent Astrocytes and Microglia.

Abstract

Growth factors play a crucial role during de- and remyelination of the central nervous system (CNS) due to their neurotrophic functions. We have previously shown that the growth factors neuregulin-1 (Nrg-1) and glial cell-derived neurotrophic factor (Gdnf) are upregulated during the first 2weeks after induction of toxic demyelination in the CNS. Nevertheless, the factors responsible for Nrg-1/Gdnf upregulation and their effects on glia cells are unknown. We investigated the effect on Nrg-1 and Gdnf expressions after stimulation of primary mouse microglia or astrocytes with various pro- and anti-inflammatory factors. Additionally, primary cells were incubated with NRG-1 and/or GDNF followed by determining the gene expression level of their receptors, chemokines, and other growth factors. We demonstrate that inflammatory stimuli have a distinct impact on the expression of Gdnf, Nrg-1, and their receptors in astrocytes and microglia. In microglia, LPS or simultaneous treatment with IFNγ plus TNFα led to downregulation of Nrg-1, whereas LPS treatment slightly increased Nrg-1 expression in astrocytes. Furthermore, Gdnf was slightly upregulated after TFG-β treatment in microglia, while Gdnf was significantly upregulated after LPS treatment in astrocytes. In contrast, treatment with GDNF or/and NRG-1 did not alter any measured gene expression in microglia or astrocytes. Taken together, our in vitro studies show that Nrg-1, Gdnf, and their receptors are differently regulated in astrocytes and microglia upon inflammatory stimuli. The lack of response of astrocytes and microglia to NRG-1 and GDNF suggests that both factors exert their effects directly on neurons.