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

Sci Signal. 2019 Feb 19;12(569):eaar2124. doi: 10.1126/scisignal.aar2124.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Astrocytes / cytology
  • Astrocytes / metabolism*
  • Cells, Cultured
  • Coculture Techniques
  • Cytokines / genetics
  • Cytokines / metabolism
  • Encephalitis / genetics
  • Encephalitis / metabolism*
  • Encephalitis / pathology
  • Female
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism*
  • HEK293 Cells
  • Humans
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Microglia / cytology
  • Microglia / metabolism*
  • RNA Interference
  • Signal Transduction / drug effects

Substances

  • Cytokines
  • Lipopolysaccharides
  • Gstt2 protein, mouse
  • Glutathione Transferase
  • glutathione S-transferase M1