Inhibition of Pyruvate Dehydrogenase Kinase 4 in CD4+ T Cells Ameliorates Intestinal Inflammation

BACKGROUND & AIMS: Despite recent evidence supporting the metabolic plasticity of CD4(+) T cells, it is uncertain whether the metabolic checkpoint pyruvate dehydrogenase kinase (PDK) in T cells plays a role in the pathogenesis of colitis.METHODS: To investigate the role of PDK4 in colitis, we used dextran sulfate sodium (DSS)-induced colitis and T-cell transfer colitis models based on mice with constitutive knockout (KO) or CD4(+) T-cell-specific KO of PDK4 (Pdk4fl/flCD4Cre). The effect of PDK4 deletion on T-cell activation was also studied in vitro. Furthermore, we examined the effects of a pharmacologic in-hibitor of PDK4 on colitis.RESULTS: Expression of PDK4 increased during colitis development in a DSS-induced colitis model. Phosphorylated PDHE1a, a substrate of PDK4, accumulated in CD4(+) T cells in the lamina propria of patients with inflammatory bowel disease. Both constitutive KO and CD4(+) T-cell-specific deletion of PDK4 delayed DSS-induced colitis. Adoptive transfer of PDK4-deficient CD4(+) T cells attenuated murine colitis, and PDK4 deficiency resulted in decreased activation of CD4(+) T cells and attenuated aerobic glycolysis. Mecha-nistically, there were fewer endoplasmic reticulum- mitochondria contact sites, which are responsible for inter -organelle calcium transfer, in PDK4-deficient CD4(+) T cells. Consistent with this, GM-10395, a novel inhibitor of PDK4, suppressed T-cell activation by reducing endoplasmic reticulum-mitochondria calcium transfer, thereby amelio-rating murine colitis.CONCLUSIONS: PDK4 deletion from CD4(+) T cells mitigates colitis by metabolic and calcium signaling modulation, sug-gesting PDK4 as a potential therapeutic target for IBD.

Automated summary

This study found that PDK4 expression increased during the development of colitis. Deletion of PDK4 from CD4(+) T cells can mitigate the development of colitis by modulating metabolism and calcium signaling. These findings suggest that PDK4 may be a potential therapeutic target for inflammatory bowel disease.