Research ArticleNEUROINFLAMMATION

Glutathione S-transferases promote proinflammatory astrocyte-microglia communication during brain inflammation

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Sci. Signal.  19 Feb 2019:
Vol. 12, Issue 569, eaar2124
DOI: 10.1126/scisignal.aar2124

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Glutathione S-transferases enhance astrocyte-microglia communication

Astrocytes and microglia contribute to inflammatory responses in the brain. Kano et al. found that the glutathione S-transferases GSTM1 and GSTT2 contributed to astrocyte-mediated enhancement of microglia activation during brain inflammation. Knocking down either enzyme specifically in astrocytes reduced microglia activation in the brains of mice responding to systemic challenge with lipopolysaccharide (LPS). Coculture experiments with primary astrocytes and a microglial cell line showed that GSTM1 was required in astrocytes for nuclear factor κB (NF-κB)–mediated production of the proinflammatory factors GM-CSF and CCL2, which stimulate microglia activation. These findings identify a role for GSTM1 in enabling astrocytes to promote microglia activation during brain inflammation.

Abstract

Astrocytes and microglia play critical roles in brain inflammation. Here, we report that glutathione S-transferases (GSTs), particularly GSTM1, promote proinflammatory signaling in astrocytes and contribute to astrocyte-mediated microglia activation during brain inflammation. In vivo, astrocyte-specific knockdown of GSTM1 in the prefrontal cortex attenuated microglia activation in brain inflammation induced by systemic injection of lipopolysaccharides (LPS). Knocking down GSTM1 in astrocytes also attenuated LPS-induced production of the proinflammatory cytokine tumor necrosis factor–α (TNF-α) by microglia when the two cell types were cocultured. In astrocytes, GSTM1 was required for the activation of nuclear factor κB (NF-κB) and the production of proinflammatory mediators, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and C-C motif chemokine ligand 2 (CCL2), both of which enhance microglia activation. Our study suggests that GSTs play a proinflammatory role in priming astrocytes and enhancing microglia activation in a microglia-astrocyte positive feedback loop during brain inflammation.

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