Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response
Аутори
Milanović, MarijanaBekić, Marina
Đokić, Jelena
Vučević, Dragana
Čolić, Miodrag
Tomić, Sergej
Чланак у часопису (Објављена верзија)
Метаподаци
Приказ свих података о документуАпстракт
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 ca...pacity 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.
Кључне речи:
α-ketoglutarate / Dendritic cells / Th polarisation / redox metabolism / autophagy / regulatory T cellsИзвор:
International Journal of Biological Sciences, 2024, 20, 3, 1064-1087Издавач:
- Ivyspring International
Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200042 (Универзитет у Београду, Институт за молекуларну генетику и генетичко инжењерство) (RS-MESTD-inst-2020-200042)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200019 (Универзитет у Београду, Институт за примену нуклеарне енергије - ИНЕП) (RS-MESTD-inst-2020-200019)
- Nano-MDSC-Thera - Novel Immunotherapeutic Approaches for Autoimmune Diseases Based on Myeloid Derived Suppressor Cells Induced By Nanomaterials (RS-ScienceFundRS-Promis-6062673)
Институција/група
Institut za molekularnu genetiku i genetičko inženjerstvoTY - JOUR AU - Milanović, Marijana AU - Bekić, Marina AU - Đokić, Jelena AU - Vučević, Dragana AU - Čolić, Miodrag AU - Tomić, Sergej PY - 2024 UR - https://www.ijbs.com/v20p1064.htm UR - https://imagine.imgge.bg.ac.rs/handle/123456789/2313 AB - 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. PB - Ivyspring International T2 - International Journal of Biological Sciences T2 - International Journal of Biological Sciences T1 - Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response EP - 1087 IS - 3 SP - 1064 VL - 20 DO - 10.7150/ijbs.91109 ER -
@article{ author = "Milanović, Marijana and Bekić, Marina and Đokić, Jelena and Vučević, Dragana and Čolić, Miodrag and Tomić, Sergej", year = "2024", 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.", publisher = "Ivyspring International", journal = "International Journal of Biological Sciences, International Journal of Biological Sciences", title = "Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response", pages = "1087-1064", number = "3", volume = "20", doi = "10.7150/ijbs.91109" }
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. in International Journal of Biological Sciences Ivyspring International., 20(3), 1064-1087. https://doi.org/10.7150/ijbs.91109
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. in International Journal of Biological Sciences. 2024;20(3):1064-1087. doi:10.7150/ijbs.91109 .
Milanović, Marijana, Bekić, Marina, Đokić, Jelena, Vučević, Dragana, Čolić, Miodrag, Tomić, Sergej, "Exogenous α-ketoglutarate Modulates Redox Metabolism and Functions of Human Dendritic Cells, Altering Their Capacity to Polarise T Cell Response" in International Journal of Biological Sciences, 20, no. 3 (2024):1064-1087, https://doi.org/10.7150/ijbs.91109 . .