The metabolic response to inflammation in astrocytes is regulated by nuclear factor‐kappa B signaling

Abstract

Inflammation and metabolism are intrinsically linked with inflammatory stimuli inducing metabolic changes in cells and, in turn, metabolic capacity determining cellular inflammatory responses. Although well characterized in peripheral immune cells there is comparatively less known about these “immunometabolic” responses in astrocytes. In this study, we tested the hypothesis that the astrocytic inflammatory response driven by nuclear factor‐kappa B (NF‐κB) signaling is dependent on glycolytic metabolism. Using mouse primary cortical astrocyte cultures, we assessed changes in cellular metabolism after exposure to lipopolysaccharide (LPS), with cytokine ELISAs and immunoblotting being used to measure inflammatory responses. Results indicate temporally distinct metabolic adaptations to pro‐inflammatory stimulation in astrocytes: 3 hr LPS treatment increased glycolysis but did not alter mitochondrial metabolism, while following 24 hr of LPS treatment we observed increased oxidative phosphorylation, and decreased glycolytic capacity and glucose uptake, partly due to reduced glucose transporter 1 expression. Inhibition of NF‐κB signaling with the IKK‐beta inhibitor TPCA‐1 prevented the LPS induced changes to glycolysis and oxidative phosphorylation. Furthermore, TPCA‐1 treatment altered both glycolysis and oxidative phosphorylation independently from inflammatory stimulation, indicating a role for NF‐κB signaling in regulation of basal metabolism in astrocytes. Inhibition of glycolysis with 2‐deoxyglucose significantly attenuated LPS‐induced cytokine release and NF‐κB phosphorylation, indicating that intact glycolysis is required for the full inflammatory response to LPS. Together our data indicate that astrocytes display immunometabolic responses to acute LPS stimulation which may represent a potential therapeutic target for neuroinflammatory disorders.

Neuroinflammatory Response to TNFα and IL1β Cytokines Is Accompanied by an Increase in Glycolysis in Human Astrocytes In Vitro

“…In our human cells, we have observed an increase in NFκB gene expression after TNFα and IL1β exposure ( Figure 2 B) that also induced an increase in glycolysis and a reduction in oxidative phosphorylation ( Figure 6 ). These results support, for the first time in human cells, the increase in glycolysis during astrocytic activation, and suggest a possible link between NFκB signaling and glycolysis, similarly to that in mice [ 53 ].…”

“…Transcription factors of the NFκB family are considered not only as central regulators of immune and inflammatory responses, but are also directly linked with energy metabolism regulation [ 52 ]. A very recent study performed on isolated primary mouse astrocytes suggested that the astrocytic inflammatory response driven by nuclear factor kappa B (NFκB) signaling is dependent on glycolytic metabolism [ 53 ]. In our human cells, we have observed an increase in NFκB gene expression after TNFα and IL1β exposure ( Figure 2 B) that also induced an increase in glycolysis and a reduction in oxidative phosphorylation ( Figure 6 ).…”

Long-Term Glucose Starvation Induces Inflammatory Responses and Phenotype Switch in Primary Cortical Rat Astrocytes

“…In another in vitro study of diabetes, recurrent hypoglycemic phases lead to a shift from glucose metabolism to fatty acid oxidation in human primary astrocytes (Weightman Potter et al 2019 ). The same effect was shown after prolonged inflammation induced by LPS stimulation in astrocytes in vitro (Robb et al 2020 ). In addition, XBP1 regulates components of the glucose metabolism and lipogenesis.…”

Lipid metabolism in astrocytic structure and function

“…Preventing astrocyte inflammation through nuclear factor-kappa B (NF-κB) inhibition in mice astrocytes for example, has been shown to be beneficial by; reducing glial scarring in spinal cord injury; increasing glucose tolerance and promoting energy expenditure; and increasing glucose uptake and glycolytic capacity. Moreover astrocytic glycolytic inhibition by 2-deoxyglucose has recently been shown to significantly reduce LPSinduced cytokine release and NF-κB phosphorylation [32][33][34]. There is also emerging evidence of a link between astrocyte lipid signalling and the metabolic inflammatory response which will be discussed in section 2.…”