Inhibition of PI3K/Akt/mTOR Pathway Modulates Lps-Induced Metabolic Changes in Microglia
2024
Authors:
Milošević, KatarinaMilošević, Ana
Stevanović, Ivana
Živković, Anica
Janjić, Marija
Bjelobaba, Ivana
Lavrnja, Irena
Savić, Danijela
Document Type:
Conference object (Published version)
,
© FENS 2024
Metadata
Show full item recordAbstract:
Microglia are metabolically flexible cells able to respond to environmental changes by reprogramming their intracellular metabolic pathway subsequently altering immune function. Exposure to inflammatory stimuli increases microglial reliance on aerobic glycolysis, a key metabolic adaptation required for their pro-inflammatory activation. There is evidence that the PI3K/Akt signaling pathway activates hypoxia-inducible factor-1α (HIF-1α) via its target mTOR, and HIF-1α is known for its regulatory function in metabolism and immunity. Therefore, we investigated agmatine (Agm) as a potential modulator of the PI3K/Akt/mTOR signaling pathway during microglial activation.
We analysed how pretreatment with Agm (100 µM) affects this signaling cascade and HIF-1α expression in BV-2 microglia stimulated with lipopolysaccharide (Lps, 1 µg/ml) by Western blot. To test our hypothesis that Agm's effect depends on the PI3K/Akt/mTOR signaling pathway, we used the known PI3K inhibitors wortmannin (100 nM) and LY294002 (10 µM) and analysed Akt/mTOR-HIF-1α protein levels. Lactate production and the release of TNF-α were measured as indicators of glycolysis and inflammation.
Agm inhibited Lps-induced phosphorylation of PI3K, resulting in a decrease in p-Akt and p-mTOR levels along with downregulation of HIF-1α. In response to wortmannin and LY294002, the entire PI3K/Akt/mTOR-HIF-1α signaling pathway was abolished, resulting in a significant reduction in lactate concentration and TNF-α release. Additionally, Agm pretreatment also markedly decreased both glycolytic metabolite and cytokine levels.
In conclusion, the obtained results indicate that Agm-mediated PI3K/Akt/mTOR-HIF-1α inhibition contributes to the reduced glycolytic and inflammatory capacity in Lps-stimulated BV-2 microglia.
Keywords:
Microglia; Agmatine; Aerobic glycolysis; PI3K/Akt/mTOR signaling pathway; HIF-1αFunding / projects:
- Ministry of Science, Technological Development and Innovation of the Republic of Serbia, institutional funding - 200007 (University of Belgrade, Institute for Biological Research 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
In:
- FENS Forum 2024; 2024 Jun 25-29; Vienna, Austria. Federation of European Neuroscience Societies (FENS); 2024.