Ethyl pyruvate stimulates differentiation of regulatory cells in vitro and in vivo
2021
Autori:
Koprivica, IvanMićanović, Dragica
Pejnović, Nada
Saksida, Tamara
Stojanović, Ivana D.
Ostala autorstva
Saksida, TamaraStanisavljević, Suzana
Miljković, Đorđe
Tip dokumenta:
Konferencijski prilog (Objavljena verzija)
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© 2019 Institute for Biological Research "Siniša Stanković" – National Institute of Republic of Serbia, University of Belgrade
Metapodaci
Prikaz svih podataka o dokumentuApstrakt:
Ethyl pyruvate (EP) is a stable form of pyruvate that has shown potent anti-oxidant and
anti-inflammatory properties both in vitro and in vivo and was able to ameliorate
systemic inflammation and multiple organ dysfunctions in multiple animal models. Our
recent study suggests that the application of EP in the mouse model of type 1 diabetes
successfully prevents the clinical manifestation of the disease by augmenting the
number of tolerogenic dendritic cells and regulatory T cells (Treg). Our present study
indicates that during in vitro differentiation of CD4+ naïve cells into Treg, the addition
of EP stimulated Treg generation. This was in line with the observed increased
proliferation of newly differentiated Treg (Ki67+FoxP3+). Surprisingly, EP did not
scavenge reactive oxygen species (ROS), but rather stimulated ROS production by
Treg. In Treg, ROS is mainly generated during oxidative phosphorylation (OXPHOS)
during which the majority of energy for the cell is produced. EP probably acted as a
substrate in Krebs cycle because the cells produced more pyruvate dehydrogenase,
which converts pyruvate to acetyl CoA. EP treatment also resulted in less kinase of
pyruvate dehydrogenase, which acts as an inhibitor of Krebs cycle. As a result, there
was an evident stimulation of OXPHOS, confirmed by increased ATP production in
differentiated Treg. Additionally, EP exerted its stimulatory function on Treg in healthy
C57BL/6 mice. When given either intraperitoneally or per os, EP increased Treg
numbers within the peritoneal cavity or gut-associated lymphoid tissue, respectively.
Seemingly, EP promoted differentiation of Treg in vivo and did not affect their
suppressive properties (proportion of CTLA-4+, CD39+, PD-1+, IL-10+ Treg) or their
affinity towards specific effector T helper cells (RORγT+, Tbet+ or GATA-3+ Treg). In
conclusion, EP acts as specific metabolic fuel for Treg generation, likely because these
cells mainly rely on OXPHOS-derived energy
Finansiranje / projekti:
- Ministarstvo nauke, tehnološkog razvoja i inovacija Republike Srbije, institucionalno finansiranje - 200007 (Univerzitet u Beogradu, Institut za biološka istraživanja 'Siniša Stanković') (RS-MESTD-inst-2020-200007)
U:
- Saksida T, Stanisavljević S, Miljković Đ, editors. Immunology at the Confluence of Multidisciplinary Approaches : abstract book: 2019 Dec 6-8; Belgrade, Serbia. Belgrade: Institute for Biological Research "Siniša Stanković", University of Belgrade; Immunological Society of Serbia; 2019. p. 8.