Empagliflozin modulates CD4+ T-cell differentiation via metabolic reprogramming in immune thrombocytopenia

Abstract

Immune thrombocytopenia (ITP) is an acquired autoimmune disease, in which the imbalance of CD4⁺ T cell subsets play a key role in the pathogenesis. Since T cells highly depend on metabolism for their function, we hypothesized that T cell dysfunction may be due to intracellular metabolic reprogramming. We found that in ITP, T cell metabolism shifts from oxidative phosphorylation to glycolysis. Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, has shown regulatory metabolic effects on proximal tubular epithelial cells and cardiac cells beyond glucose lowering. However, the effects of empagliflozin on T cells remain unknown. To further investigate the metabolic dysfunction of CD4⁺ T cells in ITP, we explored the effect of empagliflozin on CD4⁺ T-cell differentiation in ITP. Our results are the first to show that increased glycolysis in CD4⁺ T cells resulted in an unbalanced CD4⁺ T-cell population. Furthermore, empagliflozin can affect the differentiation of CD4⁺ T-cell subsets by inhibiting Th1 and Th17 cell populations while increasing Tregs. Empagliflozin appears to regulate CD4⁺ T cells through inhibiting the mTOR signal pathway. Considering these results, we propose that empagliflozin could be used as a potential therapeutic option for ITP by modulating metabolic reprogramming in CD4⁺ T cells.

Keywords: SGLT2 inhibitor; T subsets; glycolysis; immune thrombocytopenia; oxidative phosphorylation.