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Article

Immunometabolic Modulatory Role of Naltrexone in BV-2 Microglia Cells

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Department of Physiology and Immunology, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia
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Department of Neurology, Clinical Hospital Center Rijeka, University of Rijeka, Krešimirova 42, 51000 Rijeka, Croatia
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Emergency Department, Clinical Hospital Center Rijeka, University of Rijeka, Krešimirova 42, 51000 Rijeka, Croatia
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Pharmacy Irena Grahovac, Trg I. Istarske brigade 5, 52100 Pula, Croatia
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Department of Pharmacology, Faculty of Medicine, University of Rijeka, Braće Branchetta 20, 51000 Rijeka, Croatia
*
Author to whom correspondence should be addressed.
Academic Editor: Laura Strauss
Int. J. Mol. Sci. 2021, 22(16), 8429; https://doi.org/10.3390/ijms22168429
Received: 18 June 2021 / Revised: 1 August 2021 / Accepted: 3 August 2021 / Published: 5 August 2021
(This article belongs to the Special Issue Immuno-Metabolism: Resisting Resistance to Immuno-Checkpoint Therapy)
Background: Naltrexone is an opioid receptor antagonist commonly used to treat opioid and alcohol dependence. The use of low dose naltrexone (LDN) was found to have anti-inflammatory properties for treatment of diseases such as fibromyalgia, Crohn’s disease, multiple sclerosis and regional pain syndromes. Related to its anti-neuroinflammatory properties, the mechanism of action is possibly mediated via Toll-like receptor 4 antagonism, which is widely expressed on microglial cells. The aim of the present study was to assess the immunometabolic effects of naltrexone on microglia cells in in vitro conditions. Methods: All experiments were performed in the BV-2 microglial cell line. The cells were treated with naltrexone at 100 μM concentrations corresponding to low dose for 24 h. Cell viability was assessed for every drug dose. To induce additional activation, the cells were pretreated with LPS and IFN-γ. Immunofluorescence was used to analyse the classical microglial activation markers iNOS and CD206, while Seahorse was used for real-time cellular metabolic assessments. mTOR activity measured over the expression of a major direct downstream target S6K was assessed using western blot. Results: LDN induced a shift from highly activated pro-inflammatory phenotype (iNOShighCD206low) to quiescent anti-inflammatory M2 phenotype (iNOSlowCD206high) in BV-2 microglia cells. Changes in the inflammatory profile were accompanied by cellular metabolic switching based on the transition from high glycolysis to mitochondrial oxidative phosphorylation (OXPHOS). LDN-treated cells were able to maintain a metabolically suppressive phenotype by supporting OXPHOS with high oxygen consumption, and also maintain a lower energetic state due to lower lactate production. The metabolic shift induced by transition from glycolysis to mitochondrial oxidative metabolism was more prominent in cells pretreated with immunometabolic modulators such as LPS and IFN-γ. In a dose-dependent manner, naltrexone also modulated mTOR/S6K expression, which underlies the cell metabolic phenotype regulating microglia immune properties and adaptation. Conclusion: By modulating the phenotypic features by metabolic switching of activated microglia, naltrexone was found to be an effective and powerful tool for immunometabolic reprogramming and could be a promising novel treatment for various neuroinflammatory conditions. View Full-Text
Keywords: naltrexone; BV-2 microglia; immunometabolism; drug repurposing naltrexone; BV-2 microglia; immunometabolism; drug repurposing
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MDPI and ACS Style

Kučić, N.; Rački, V.; Šverko, R.; Vidović, T.; Grahovac, I.; Mršić-Pelčić, J. Immunometabolic Modulatory Role of Naltrexone in BV-2 Microglia Cells. Int. J. Mol. Sci. 2021, 22, 8429. https://doi.org/10.3390/ijms22168429

AMA Style

Kučić N, Rački V, Šverko R, Vidović T, Grahovac I, Mršić-Pelčić J. Immunometabolic Modulatory Role of Naltrexone in BV-2 Microglia Cells. International Journal of Molecular Sciences. 2021; 22(16):8429. https://doi.org/10.3390/ijms22168429

Chicago/Turabian Style

Kučić, Natalia, Valentino Rački, Roberta Šverko, Toni Vidović, Irena Grahovac, and Jasenka Mršić-Pelčić. 2021. "Immunometabolic Modulatory Role of Naltrexone in BV-2 Microglia Cells" International Journal of Molecular Sciences 22, no. 16: 8429. https://doi.org/10.3390/ijms22168429

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