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Univerziteta u Beogradu
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Exogenous alpha-ketoglutarate impair differentiation and maturation of human dendritic cells
Milanović, Marijana
Bekić, Marina
Vučević, Dragana
Čolić, Miodrag
Tomić, Sergej
ABSTRACT Alpha-ketoglutarate (AKG) is a crucial intermediate in cell metabolism. Exogenous AKG has been shown to extend the lifespan by regulating the cellular response to calorie restriction. However, how the exogenous AKG affects immune responses is unknown, particularly those mediated by critical immunoregulatory and dendritic cells (DC). Using a model of human monocyte-derived DC, we found that exogenous AKG (10 mM or 50 mM) does not induce autophagy in DC (according to LC3II expression) but impairs the differentiation of DC from monocytes (according to CD1a and CD14 co-expression). Additionally, AKG inhibited LPS/IFN-γ-induced upregulation of NLRP-3, IL-1β, HLADR, CD83, CD86, CD40, CCR7, CD209, IL-33, IL-10, and IL-12p70 expression in DC, but potentiated the capacity of these cells to express TGF-β, CD73, and IL-23 in a dose-dependent manner. Although AKG-treated DC displayed a lower ability to stimulate proliferation of alloreactive T cells than control mature DC, the normalized number of CD4+RORγt+IL17+ (Th17) and CD4+GATA3+IL-4+ (Th2) cells was higher. The number of CD4+T-bet+IFN-γ+ (Th1) and CD8+IFN-γ+GranzA+ Perf+ (CTL) was lower in co-cultures with AKG-treated DC compared to corresponding control DC. Moreover, AKG increased the capacity of DC significantly to induce CD4+ CD25hiCD127-FoxP3+ Tregs in a dose-dependent manner. These results suggested that, while exogenous AKG could have beneficial effects on lifespan, the quality of life might be compromised due to its immunomodulatory effects related to the reduction of Th1 mediated immune responses.
engleski
2021
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