GPCR-mediated regulation of glial TNF production

Abstract

Neuromodulators generally act through G-protein-coupled receptors, but their effects on glia are not well defined. Here we examine the impact of various G-protein-coupled signaling pathways on glia, using the production of the pro-inflammatory cytokine tumor necrosis factor alpha (TNF) as a measure of activation. TNF is a major component of the innate immune response but is also an important regulator of synaptic function and can be released by both astrocytes and microglia. Using pharmacological and chemogenetic approaches, we characterized the response to activation of the Gi, Gq, and Gs signaling pathways in rat astrocyte and microglia cultures and human induced pluripotent stem cells (hiPSCs) derived astrocytes. Across all tested glia, activation of the Gs pathway results in a stark decrease in TNF expression. Similarly, activation of Gq signaling also results in a reduction in TNF mRNA levels. Conversely, Gi activation in astrocytes and microglia increases TNF levels both in vitro and in vivo. The impacts of GPCRs on TNF production were not consistent for other pro-inflammatory cytokines. Overall, this work demonstrates that G protein-mediated activation and inhibition in glia should be considered separately from the effects seen in neurons.