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

Abstract

Summary 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.

Knowledge mapping of immune thrombocytopenia: a bibliometric study

“…Treg cells, which were responsible for immune tolerance, have been studied the most during a long period, and these cells were deficient in ITP and failed to suppress the excessive auto-reactive T cells ( 43 , 44 ). Furthermore, the imbalance of Th cells has been evidenced by an increasing polarization of Th1 and Th17 cells, as well as their cytokines ( 45 ). Increased Th17 cells and related cytokines have been evidenced in ITP patients and mice and correlated with the course of the disease and response to treatment ( 46 – 48 ).…”

Dapagliflozin Ameliorates Ovulation Disorders via Attenuating Activated Microglia-Mediated Hypothalamic Inflammation in HFD-Fed Mice

“…The latest research shows that HK2 regulates microglial functions by upregulating glycolytic flux and maintaining mitochondrial activity [47,48]. Furthermore, recent studies have shown that SGLT2i can modulate the polarization phenotype of peripheral immune cells by regulating glucose metabolic reprogramming by inhibiting mTOR signaling [49]. Aerobic glycolysis, phosphorylated mTOR, and HK2 expression are increased by proinflammatory microglia [44].…”

Narrative Review of Immunomodulatory and Anti-inflammatory Effects of Sodium-Glucose Cotransporter 2 Inhibitors: Unveiling Novel Therapeutic Frontiers

“…Several studies have unveiled the impact of SGLT2 inhibitors on T cell effector function and differentiation via metabolic reprograming. 12 , 60 A recent study by Jenkins et al. demonstrated that in vitro exposure to canagliflozin inhibits T cell receptor signaling, leading to compromised ERK and mTORC1 activity in T cells.…”

“…Another in vitro experiment involving T cells isolated from immune thrombocytopenia patients revealed that empagliflozin increased the regulatory T cell subset while decreasing the Th1 and Th17 T cell subsets. 60 This effect was counteracted by the use of an mTOR agonist. This study suggests that SGLT2 inhibitors may modulate the metabolic reprogramming of CD4 T cells through the mTOR signaling pathway.…”