Modulation of astrocytic metabolic phenotype by proinflammatory cytokines

Abstract

Astrocytes play an important role in nervous system homeostasis. In particular, they contribute to the regulation of local energy metabolism and to oxidative stress defence. In previous experiments, we showed that long-term treatment with interleukin 1alpha (IL-1alpha) or tumor necrosis factor-alpha (TNFalpha) alone increases glucose utilization in primary culture of mouse astrocytes. In our study, we report that a combination of IL-1beta and TNFalpha exerts a synergistic effect on glucose utilization and markedly modifies the metabolic phenotype of astrocytes. Thus, IL-1beta+TNFalpha treated astrocytes show a marked decrease in glycogen levels, a slight but not significant decrease in lactate release as well as a massive increase in both the pentose phosphate pathway and TCA cycle activities. Glutamate-stimulated glucose utilization and lactate release, a typical feature of astrocyte energy metabolism, are altered after pretreatment with IL-1beta+TNFalpha. As far as mechanisms for oxidative stress defence are concerned, we observed that treatment with IL-1beta+TNFalpha decreases cellular glutathione content and increases glutathione release into the extracellular space while stimulating superoxide anion and nitric oxide production as well as H(2)O(2) release. Interestingly, stimulation of glucose utilization by IL-1beta+TNFalpha is not affected by the antioxidant N-acetyl-L-cysteine, suggesting that cellular stress does not account for this effect. Finally, the effects of cytokines on glucose utilization appear to involve multiple signaling cascades including the phosphoinositide 3-kinase and mitogen-activated protein kinases. Taken together these results establish that a proinflammatory environment such as observed in several neuropathological conditions including Alzheimer's disease, markedly modifies the metabolic phenotype of astrocytes.

Glucose Regulates Hypothalamic Long-chain Fatty Acid Metabolism via AMP-activated Kinase (AMPK) in Neurons and Astrocytes

“…Primary Astrocytes Culture and Immunocytochemistry-Primary cultures of hypothalamic and cortical astrocytes were prepared from 1-day-old C57Bl/6 pups using a protocol adapted from the group of Magistretti and co-workers (31). Briefly, after decapitation, the brains were removed, and the hypothalami and cortices were dissected and transferred into 6-well plates containing 2 ml of DMEM.…”

Role of the Glyoxalase System in Astrocyte-Mediated Neuroprotection

“…Primary cultures of cerebral cortical astrocytes were prepared from newborn (1-to 2-d-old) OF1 mice (Charles River Laboratories) as previously described (Gavillet et al, 2008). Cells were plated in 35 mm dishes and maintained in DMEM (D7777, Sigma-Aldrich) containing 25 mM glucose and supplemented with 44 mM NaHCO 3 , 10 ml/L antibiotic/ antimycotic solution (Invitrogen), and 10% FCS (Bioconcept), and incubated at 37°C in an atmosphere containing 5% CO 2 and 95% air.…”

“…Numerous reports have shown that astrocytes display high metabolic plasticity in terms of glucose utilization, which is not the case for neurons (Pellerin and Magistretti, 1994;Almeida et al, 2001;Prapong et al, 2002;Porras et al, 2004;Gavillet et al, 2008;Allaman et al, 2010;Bélanger et al, 2011). One striking example is the differential response of astrocytes and neurons following the inhibition of mitochondrial respiration by NO.…”

Tumour necrosis factor - alpha mediated mechanisms of cognitive dysfunction

“…TNF-α can further influence astrocytes and microglia to release nitrogen and oxygen reactive species that cause oxidative stress to neurons and glial cells [6,67,112,116]. Such oxidative damage is particularly noticeable in Figure 4.…”