TY  - 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 . .

TY  - CONF
AU  - Bekić, Marina
AU  - Đokić, Jelena
AU  - Radojević, Dušan
AU  - Vučević, Dragana
AU  - Vasilev, Saša
AU  - Tomić, Sergej
PY  - 2023
UR  - https://belbi.bg.ac.rs/
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/2042
AB  - Although genetic predisposition to Multiple Sclerosis (MS) may play an essential role in disease
development, myeloid cell overactivation and gut microbiota dysbiosis are key contributors to MS
pathogenesis. Myeloid-Derived Suppressor Cells (MDSC)s are immature myeloid cells with strong
immunosuppressive functions which can be exploited in the treatment of autoimmune diseases.
Considering the limited data on MDSCs application in MS therapy and their poorly studied effects
on the gut microbiota, we have investigated the therapeutic potential of mice MDSC differentiated
according to the standard protocol (MDSC) and modified with the addition of prostaglandin (PG)
E2 (MDSC-PGE2) to ameliorate experimental autoimmune encephalomyelitis (EAE) induced with
MOG35-55/CFA/PtX in C57BL/6 mice. Additionally, we analyzed the changes in gut microbiota
features in control and MDSC-treated animals by using a shotgun metagenomics approach. In
mice, PGE2-activated MDSC significantly inhibited the onset and clinical course of EAE. This effect
correlated with increased IL-10, TGF-β, IL-4 production, and Arginase-1 level in MDSC-PGE2,
as well as with reduced leukocyte infiltrates in the spinal cord. MDSC-PGE2 protective effect is
also reflected in the maintenance of gut microbiota composition based on Kraken2/Bracken2
and LEfSe analysis. We observed an increase of MS-associated species Romboutsia ilealis in
the control EAE group, while in both MDSC treatments the increase in relative abundances of
Muribaculum gordoncarteri and Duncaniella dubiosis, associated with immunoregulatory properties,
was observed. Microbial metabolic pathways profiling using Humann3 pipeline also reveals the
increase in pathways involved in the production of potentially immunoregulatory metabolites
in the MDSC-PGE2 group. In conclusion, we pointed to the significant association between the
efficacy of MDSC-PGE2 treatment and gut microbiota features which can be further exploited in
order to improve MDSC-based EAE therapy.
PB  - Belgrade : Institute of molecular genetics and genetic engineering
C3  - 4th Belgrade Bioinformatics Conference
T1  - Shotgun metagenomics reveals gut microbiota features associated with the efficacy of myeloid derived suppressor cells in the prevention of neuroinflammation
EP  - 97
SP  - 97
VL  - 4
UR  - https://hdl.handle.net/21.15107/rcub_imagine_2042
ER  - 

@conference{
author = "Bekić, Marina and Đokić, Jelena and Radojević, Dušan and Vučević, Dragana and Vasilev, Saša and Tomić, Sergej",
year = "2023",
abstract = "Although genetic predisposition to Multiple Sclerosis (MS) may play an essential role in disease
development, myeloid cell overactivation and gut microbiota dysbiosis are key contributors to MS
pathogenesis. Myeloid-Derived Suppressor Cells (MDSC)s are immature myeloid cells with strong
immunosuppressive functions which can be exploited in the treatment of autoimmune diseases.
Considering the limited data on MDSCs application in MS therapy and their poorly studied effects
on the gut microbiota, we have investigated the therapeutic potential of mice MDSC differentiated
according to the standard protocol (MDSC) and modified with the addition of prostaglandin (PG)
E2 (MDSC-PGE2) to ameliorate experimental autoimmune encephalomyelitis (EAE) induced with
MOG35-55/CFA/PtX in C57BL/6 mice. Additionally, we analyzed the changes in gut microbiota
features in control and MDSC-treated animals by using a shotgun metagenomics approach. In
mice, PGE2-activated MDSC significantly inhibited the onset and clinical course of EAE. This effect
correlated with increased IL-10, TGF-β, IL-4 production, and Arginase-1 level in MDSC-PGE2,
as well as with reduced leukocyte infiltrates in the spinal cord. MDSC-PGE2 protective effect is
also reflected in the maintenance of gut microbiota composition based on Kraken2/Bracken2
and LEfSe analysis. We observed an increase of MS-associated species Romboutsia ilealis in
the control EAE group, while in both MDSC treatments the increase in relative abundances of
Muribaculum gordoncarteri and Duncaniella dubiosis, associated with immunoregulatory properties,
was observed. Microbial metabolic pathways profiling using Humann3 pipeline also reveals the
increase in pathways involved in the production of potentially immunoregulatory metabolites
in the MDSC-PGE2 group. In conclusion, we pointed to the significant association between the
efficacy of MDSC-PGE2 treatment and gut microbiota features which can be further exploited in
order to improve MDSC-based EAE therapy.",
publisher = "Belgrade : Institute of molecular genetics and genetic engineering",
journal = "4th Belgrade Bioinformatics Conference",
title = "Shotgun metagenomics reveals gut microbiota features associated with the efficacy of myeloid derived suppressor cells in the prevention of neuroinflammation",
pages = "97-97",
volume = "4",
url = "https://hdl.handle.net/21.15107/rcub_imagine_2042"
}

Bekić, M., Đokić, J., Radojević, D., Vučević, D., Vasilev, S.,& Tomić, S.. (2023). Shotgun metagenomics reveals gut microbiota features associated with the efficacy of myeloid derived suppressor cells in the prevention of neuroinflammation. in 4th Belgrade Bioinformatics Conference
Belgrade : Institute of molecular genetics and genetic engineering., 4, 97-97.
https://hdl.handle.net/21.15107/rcub_imagine_2042

Bekić M, Đokić J, Radojević D, Vučević D, Vasilev S, Tomić S. Shotgun metagenomics reveals gut microbiota features associated with the efficacy of myeloid derived suppressor cells in the prevention of neuroinflammation. in 4th Belgrade Bioinformatics Conference. 2023;4:97-97.
https://hdl.handle.net/21.15107/rcub_imagine_2042 .

Bekić, Marina, Đokić, Jelena, Radojević, Dušan, Vučević, Dragana, Vasilev, Saša, Tomić, Sergej, "Shotgun metagenomics reveals gut microbiota features associated with the efficacy of myeloid derived suppressor cells in the prevention of neuroinflammation" in 4th Belgrade Bioinformatics Conference, 4 (2023):97-97,
https://hdl.handle.net/21.15107/rcub_imagine_2042 .

TY  - CONF
AU  - Radojević, Dušan
AU  - Bekić, Marina
AU  - Gruden-Movsesijan, Alisa
AU  - Ilić, Nataša
AU  - Vasilev, Saša
AU  - Dinić, Miroslav
AU  - Golić, Nataša
AU  - Vučević, Dragana
AU  - Čolić, Miodrag
AU  - Tomić, Sergej
AU  - Đokić, Jelena
PY  - 2021
UR  - https://imagine.imgge.bg.ac.rs/handle/123456789/1875
AB  - The role of gut microbiota composition in efficacy of various immune-based therapies is increasingly recognized.
Thus, the aim of our study was to investigate if the efficacy of myeloid-derived suppressor cells
(MDSC)-Prostaglandin E2 (PGE2) therapy for multiple sclerosis (MS) correlates with gut microbiota composition
and function. MDSC generated from bone marrow cells in the presence of PGE2 were applied to spinal
cord homogenate/CFA-induced experimental autoimmune encephalomyelitis (EAE) in Dark Agouti (DA)
rats, an animal model of MS. MDSC-PGE2 therapy resulted in a significant attenuation of EAE symptoms
over 30 days of disease monitoring. These results correlated with lower percentage of proinflammatory interferon-
gamma and interleukin-17 producing cells and higher percentage of anti-inflammatory IL-4 producing
cells in spinal cord and spleen. Gut microbial composition were studied using amplicon(16S rRNA)-based
metagenomic analyses of fecal samples collected prior to the induction of EAE and MDSC-PGE2 therapy application,
and at the peak of the disease. The induction of EAE resulted in a decrease of microbiota diversity,
whereas the MDSC-PGE2 therapy preserved the diversity in EAE-induced animals. The induction of EAE
in control group associated with a higher relative abundance of Peptococcaceae, but the lower levels of Veillonellaceae
and different groups of Prevotellaceae, known to produce immunosuppressive short chain fatty
acid (SCFA), and Lactobacillus reuteri, known for its anti-inflammatory function. In contrast, there were no
changes in levels of these immunoregulatory taxa in EAE-animals treated with MDSC-PGE2 therapy. Also,
SCFA producing Ruminococcaceae, and Coriobacteriaceae, known to metabolize phytoestrogens to immunosuppressive
metabolites were more abundant in EAE-animals treated with MDSC-PGE2 therapy. Predicted
metabolic profiling obtained by PICRUSt2 revealed that pathways involved in biosynthesis of polyamines,
metabolites known to contribute to homeostasis of gastrointestinal mucosa, were enriched in MDSC-PGE2
treated animals. Considering these results, the modification of gut microbiota composition and function
could further increase efficacy of MDSC-PGE-2 based therapy of autoimmune diseases.
PB  - Novi Sad : Faculty of Sciences, Department of Biology and Ecology
C3  - Biologia Serbica
T1  - Myeloid derived suppressor cells-therapy attenuates experimental autoimmune encephalomyelitis and modulates gut microbiota composition
IS  - 1 (Special Edition)
SP  - 98
VL  - 43
UR  - https://hdl.handle.net/21.15107/rcub_imagine_1875
ER  - 

@conference{
author = "Radojević, Dušan and Bekić, Marina and Gruden-Movsesijan, Alisa and Ilić, Nataša and Vasilev, Saša and Dinić, Miroslav and Golić, Nataša and Vučević, Dragana and Čolić, Miodrag and Tomić, Sergej and Đokić, Jelena",
year = "2021",
abstract = "The role of gut microbiota composition in efficacy of various immune-based therapies is increasingly recognized.
Thus, the aim of our study was to investigate if the efficacy of myeloid-derived suppressor cells
(MDSC)-Prostaglandin E2 (PGE2) therapy for multiple sclerosis (MS) correlates with gut microbiota composition
and function. MDSC generated from bone marrow cells in the presence of PGE2 were applied to spinal
cord homogenate/CFA-induced experimental autoimmune encephalomyelitis (EAE) in Dark Agouti (DA)
rats, an animal model of MS. MDSC-PGE2 therapy resulted in a significant attenuation of EAE symptoms
over 30 days of disease monitoring. These results correlated with lower percentage of proinflammatory interferon-
gamma and interleukin-17 producing cells and higher percentage of anti-inflammatory IL-4 producing
cells in spinal cord and spleen. Gut microbial composition were studied using amplicon(16S rRNA)-based
metagenomic analyses of fecal samples collected prior to the induction of EAE and MDSC-PGE2 therapy application,
and at the peak of the disease. The induction of EAE resulted in a decrease of microbiota diversity,
whereas the MDSC-PGE2 therapy preserved the diversity in EAE-induced animals. The induction of EAE
in control group associated with a higher relative abundance of Peptococcaceae, but the lower levels of Veillonellaceae
and different groups of Prevotellaceae, known to produce immunosuppressive short chain fatty
acid (SCFA), and Lactobacillus reuteri, known for its anti-inflammatory function. In contrast, there were no
changes in levels of these immunoregulatory taxa in EAE-animals treated with MDSC-PGE2 therapy. Also,
SCFA producing Ruminococcaceae, and Coriobacteriaceae, known to metabolize phytoestrogens to immunosuppressive
metabolites were more abundant in EAE-animals treated with MDSC-PGE2 therapy. Predicted
metabolic profiling obtained by PICRUSt2 revealed that pathways involved in biosynthesis of polyamines,
metabolites known to contribute to homeostasis of gastrointestinal mucosa, were enriched in MDSC-PGE2
treated animals. Considering these results, the modification of gut microbiota composition and function
could further increase efficacy of MDSC-PGE-2 based therapy of autoimmune diseases.",
publisher = "Novi Sad : Faculty of Sciences, Department of Biology and Ecology",
journal = "Biologia Serbica",
title = "Myeloid derived suppressor cells-therapy attenuates experimental autoimmune encephalomyelitis and modulates gut microbiota composition",
number = "1 (Special Edition)",
pages = "98",
volume = "43",
url = "https://hdl.handle.net/21.15107/rcub_imagine_1875"
}

Radojević, D., Bekić, M., Gruden-Movsesijan, A., Ilić, N., Vasilev, S., Dinić, M., Golić, N., Vučević, D., Čolić, M., Tomić, S.,& Đokić, J.. (2021). Myeloid derived suppressor cells-therapy attenuates experimental autoimmune encephalomyelitis and modulates gut microbiota composition. in Biologia Serbica
Novi Sad : Faculty of Sciences, Department of Biology and Ecology., 43(1 (Special Edition)), 98.
https://hdl.handle.net/21.15107/rcub_imagine_1875

Radojević D, Bekić M, Gruden-Movsesijan A, Ilić N, Vasilev S, Dinić M, Golić N, Vučević D, Čolić M, Tomić S, Đokić J. Myeloid derived suppressor cells-therapy attenuates experimental autoimmune encephalomyelitis and modulates gut microbiota composition. in Biologia Serbica. 2021;43(1 (Special Edition)):98.
https://hdl.handle.net/21.15107/rcub_imagine_1875 .

Radojević, Dušan, Bekić, Marina, Gruden-Movsesijan, Alisa, Ilić, Nataša, Vasilev, Saša, Dinić, Miroslav, Golić, Nataša, Vučević, Dragana, Čolić, Miodrag, Tomić, Sergej, Đokić, Jelena, "Myeloid derived suppressor cells-therapy attenuates experimental autoimmune encephalomyelitis and modulates gut microbiota composition" in Biologia Serbica, 43, no. 1 (Special Edition) (2021):98,
https://hdl.handle.net/21.15107/rcub_imagine_1875 .