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

Abstract

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 inhibitor of PDK4 on colitis.

RESULTS:

Expression of PDK4 increased during colitis development in a DSS-induced colitis model. Phosphorylated PDHE1α, 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. Mechanistically, there were fewer endoplasmic reticulum-mitochondria contact sites, which are responsible for interorganelle 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 ameliorating murine colitis.

CONCLUSIONS:

PDK4 deletion from CD4+ T cells mitigates colitis by metabolic and calcium signaling modulation, suggesting PDK4 as a potential therapeutic target for IBD.

• Authors: Hoyul Lee, Jae Han Jeon, Yu-Jeong Lee, Mi-Jin Kim, Woong Hee Kwon, Dipanjan Chanda, Themis Thoudam, Haushabhau S Pagire, Suvarna H Pagire, Jin Hee Ahn, Robert A Harris, Eun Soo Kim, In-Kyu Lee
• Journal: Cellular and molecular gastroenterology and hepatology (Cell Mol Gastroenterol Hepatol) Vol. 15 Issue 2 Pg. 439-461 ( 2023) ISSN: 2352-345X [Electronic] United States
• PMID: 36229019 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Calcium
• pyruvate dehydrogenase kinase 4

Topics

• Animals
• Mice
• Calcium (metabolism)
• CD4-Positive T-Lymphocytes (metabolism)
• Colitis (chemically induced, pathology)
• Inflammation (pathology)
• Mice, Knockout
• T-Lymphocytes (metabolism)
• Gene Deletion