18 kDa Translocator Protein TSPO Is a Mediator of Astrocyte Reactivity

Abstract

An increase in astrocyte reactivity has been described in Alzheimer’s disease and seems to be related to the presence of a pro-inflammatory environment. Reactive astrocytes show an increase in the density of the 18 kDa translocator protein (TSPO), but TSPO involvement in astrocyte functions remains poorly understood. The goal of this study was to better characterize the mechanisms leading to the increase in TSPO under inflammatory conditions and the associated consequences. For this purpose, the C6 astrocytic cell line was used in the presence of lipopolysaccharide (LPS) or TSPO overexpression mediated by the transfection of a plasmid encoding TSPO. The results show that nonlethal doses of LPS induced TSPO expression at mRNA and protein levels through a STAT3-dependent mechanism and increased the number of mitochondria per cell. LPS stimulated reactive oxygen species (ROS) production and decreased glucose consumption (quantified by the [18F]FDG uptake), and these effects were diminished by FEPPA, a TSPO antagonist. The transfection-mediated overexpression of TSPO induced ROS production, and this effect was blocked by FEPPA. In addition, a synergistic effect of overexpression of TSPO and LPS on ROS production was observed. These data show that the increase of TSPO in astrocytic cells is involved in the regulation of glucose metabolism and in the pro-inflammatory response. These data suggest that the overexpression of TSPO by astrocytes in Alzheimer’s disease would have rather deleterious effects by promoting the pro-inflammatory response.

Regulation of astrocyte metabolism by mitochondrial translocator protein 18 kDa

“…Furthermore, reactive astrocytes in vivo show increased TSPO expression (Lavisse et al., 2012) in a variety of pathophysiological contexts (Nutma et al., 2021; Tournier et al., 2020; Victorio et al., 2023; Winkeler et al., 2012), and we have previously demonstrated that astrocyte reactivity correlates with altered metabolism in these cells in vitro (Robb et al., 2020). Moreover, recent in vitro work using C6 astrocytoma cells has demonstrated that overexpression of TSPO increases ROS production and mitochondrial density while reducing glucose consumption, without altering mitochondrial membrane potential (Tournier et al., 2023). This is suggestive of a shift in cellular metabolism not dissimilar to the data presented in our current study, and perhaps indicates a change to TSPO stoichiometry in conditions where it is overexpressed, potentially to alter the bioenergetic state of astrocytes or fuel metabolic responses to prolonged (24 h [present study] or overnight (Tournier et al., 2023)) proinflammatory stimulation.…”

“…Moreover, recent in vitro work using C6 astrocytoma cells has demonstrated that overexpression of TSPO increases ROS production and mitochondrial density while reducing glucose consumption, without altering mitochondrial membrane potential (Tournier et al., 2023). This is suggestive of a shift in cellular metabolism not dissimilar to the data presented in our current study, and perhaps indicates a change to TSPO stoichiometry in conditions where it is overexpressed, potentially to alter the bioenergetic state of astrocytes or fuel metabolic responses to prolonged (24 h [present study] or overnight (Tournier et al., 2023)) proinflammatory stimulation. In support of this, recent evidence from a murine model of Zika virus infection (Victorio et al., 2023) suggests that TSPO expression may correlate with the extent of glial reactivity or pathological severity (i.e., potential contribution to cellular hypermetabolism) with increased glial TSPO being observed within a relatively short timeframe.…”

“…TSPO has received attention as a potential therapeutic target for neuroinflammatory conditions given its potential role at the interface of inflammatory responses and metabolism (‘immunometabolism’) in glia (Dimitrova‐Shumkovska et al., 2020; Fairley et al., 2023; Li et al., 2017). While it was recently shown that the astrocyte response to inflammatory stimuli includes regulation of TSPO expression (Tournier et al., 2023), the role TSPO plays in regulating astrocyte basal metabolism, inflammatory responses, and the metabolic response of astrocytes to inflammatory stimulation remains unclear.…”