Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response

Milanović, Marijana; Bekić, Marina; Đokić, Jelena; Vučević, Dragana; Čolić, Miodrag; Tomić, Sergej

doi:10.7150/ijbs.91109

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Int J Biol Sci 2024; 20(3):1064-1087. doi:10.7150/ijbs.91109 This issue Cite

Research Paper

Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response

Marijana Milanović¹, Marina Bekić², Jelena Đokić³, Dragana Vučević¹, Miodrag Čolić², Sergej Tomić^2✉

1. Medical Faculty of the Military Medical Academy, University of Defense, Belgrade, Serbia.
2. Department for Immunology and Immunoparasitology, Institute for the Application of Nuclear Energy, University of Belgrade, Belgrade, Serbia.
3. Institute for Molecular Genetics and Genetical Engineering, University in Belgrade, Belgrade, Serbia.

Citation:

Milanović M, Bekić M, Đokić J, Vučević D, Čolić M, Tomić S. Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response. Int J Biol Sci 2024; 20(3):1064-1087. doi:10.7150/ijbs.91109. https://www.ijbs.com/v20p1064.htm

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Abstract

Alpha-ketoglutarate (αKG) emerged as a key regulator of energetic and redox metabolism in cells, affecting the immune response in various conditions. However, it remained unclear how the exogenous αKG modulates the functions of dendritic cells (DCs), key cells regulating T-cell response. Here we found that non-toxic doses of αKG display anti-inflammatory properties in human APC-T cell interaction models. In a model of monocyte-derived (mo)DCs, αKG impaired the differentiation, and the maturation of moDCs induced with lipopolysaccharide (LPS)/interferon (IFN)-γ, and decreased their capacity to induce Th1 cells. However, αKG also promoted IL-1β secretion by mature moDCs, despite inflammasome downregulation, potentiating their Th17 polarizing capacity. αKG induced the expression of anti-oxidative enzymes and hypoxia-induced factor (HIF)-1α in moDCs, activated Akt/FoxO1 pathway and increased autophagy flux, oxidative phosphorylation (OXPHOS) and glycolysis. This correlated with a higher capacity of immature αKG-moDCs to induce Th2 cells, and conventional regulatory T cells in an indolamine-dioxygenase (IDO)-1-dependent manner. Additionally, αKG increased moDCs' capacity to induce non-conventional T regulatory (Tr)-1 and IL-10-producing CD8+T cells via up-regulated immunoglobulin-like transcript (ILT3) expression in OXPHOS-dependent manner. These results suggested that exogenous αKG-altered redox metabolism in moDCs contributed to their tolerogenic properties, which could be relevant for designing more efficient therapeutic approaches in DCs-mediated immunotherapies.

Keywords: α-ketoglutarate, Dendritic cells, Th polarisation, redox metabolism, autophagy, regulatory T cells

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APA

Milanović, M., Bekić, M., Đokić, J., Vučević, D., Čolić, M., Tomić, S. (2024). Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response. International Journal of Biological Sciences, 20(3), 1064-1087. https://doi.org/10.7150/ijbs.91109.

ACS

Milanović, M.; Bekić, M.; Đokić, J.; Vučević, D.; Čolić, M.; Tomić, S. Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response. Int. J. Biol. Sci. 2024, 20 (3), 1064-1087. DOI: 10.7150/ijbs.91109.

NLM

CSE

Milanović M, Bekić M, Đokić J, Vučević D, Čolić M, Tomić S. 2024. Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response. Int J Biol Sci. 20(3):1064-1087.

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