Glutathione S-transferases: unexpected roles in astrocyte activation and astrocyte-microglia communication during brain inflammation

Abstract

Astrocytes and microglia play critical roles in brain inflammation, but their mutual regulation is not fully understood. Here we report unexpected roles for glutathione S-transferases (GSTs), particularly GSTM1, in astrocyte activation and astrocyte-mediated enhancement of microglia activation during brain inflammation. We found that astrocyte-specific silencing of GSTM1 expression in the prefrontal cortex (PFC) attenuated microglia activation in brain inflammation induced by systemic injection of lipopolysaccharides (LPS). Gstm1 silencing in astrocytes also attenuated LPS-induced TNF- production by microglia in co-culture. In astrocytes, GSTM1 was required for the activation of nuclear factor-{kappa}B (NF-{kappa}B) and c-Jun N-terminal kinases (JNK) and the production of pro-inflammatory mediators previously implicated in microglia activation, such as granulocyte-macrophage colony-stimulating factor (GM-CSF/CSF2) and chemokine (C-C motif) ligand 2 (CCL2). Similar results were also obtained with GSTT2 both in vitro and in vivo. Thus, our study identified a critical role for GSTs in priming astrocytes and enhancing microglia activation during brain inflammation.\n\nSignificant StatementAstrocytes and microglia play critical roles in brain inflammation, but it is not fully understood how astrocytes regulate microglia activation. Here we report a novel mechanism by which glutathione S-transferases (GSTs), the enzymes for phase II detoxification of xenobiotic metabolism, in astrocytes control microglia activation during brain inflammation. We found that GSTs, particularly GSTM1, regulate the induction of pro-inflammatory mediators via the activation of NF-{kappa}B and JNK in astrocytes. Our studies provide evidence that GST enzymes are active players in brain inflammation and can be targeted to regulate microglia activation.