Role of STEROL ELEMENT BINDING PROTEIN 1C (SREBP1c) in the metabolism and suppressive function of regulatory T cells

Aim Dysfunctional immunosuppressive Treg response supports inflammation in different pathological settings, including atherosclerosis. Several studies have demonstrated that Treg intracellular lipid metabolism is critical for their function. Therefore, the aim of this study is to investigate the role of Sterol Regulatory Element Binding Protein 1c, a key protein regulating intracellular fatty acid (FA) metabolism, in Tregs immunobiology. Methods T cells isolated from WT and SREBP-1c KO mice and in vitro induced Treg (iTreg) were analyzed through flow-cytometry, western blot and RT-qPCR. iTreg metabolism was studied using the Seahorse XF technology, which provides a real time measurement of mitochondrial respiration and glycolysis in living cells. Results The percentages of in vitro induced regulatory T cells (CD25high Foxp3+ T cells), analyzed by flow-cytometry, were reduced (-6,76%, p<0,0001) in KO cells compared to WT controls. The gene expression of hexokinase 2, known to be involved in the glycolysis pathways, was significantly increased (+74,76%, p<0,001) in KO Treg cells, while ACLY and FASN, which support fatty acid synthase, are reduced (-53,47%, p<0,001). At the same time, FoxP3 gene expression, which is the master regulator of Treg function, was reduced, in line with a reduce iTreg phenptype. When cells were treated with C75 (FASN inhibitor), metabolism of WT iTregs switched to glycolysis. This was confirmed by Seahorse XF technology: glycolysis, defined as the ECAR rate, was significantly increased for KO iTreg cells compared to WT cells. Moreover, p70S6K and S6 protein activation was observed in iTreg controls (not treated), as opposed to the treatment with 2DG (glycolysis inhibitor) which decreased the activation of the pathway, suggesting that 2DG can reverse the iTreg phenotype. Conclusions Our data have identified a key role of SREBP1c in the immune-metabolic response of Tregs. Therefore, modulating Treg metabolism might enhance their suppressive function, thus representing a new pharmacological tool in cardiovascular prevention.