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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.

SUBMITTER: Lee H 

PROVIDER: S-EPMC9791136 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Inhibition of Pyruvate Dehydrogenase Kinase 4 in CD4<sup>+</sup> T Cells Ameliorates Intestinal Inflammation.

Lee Hoyul H   Jeon Jae Han JH   Lee Yu-Jeong YJ   Kim Mi-Jin MJ   Kwon Woong Hee WH   Chanda Dipanjan D   Thoudam Themis T   Pagire Haushabhau S HS   Pagire Suvarna H SH   Ahn Jin Hee JH   Harris Robert A RA   Kim Eun Soo ES   Lee In-Kyu IK  

Cellular and molecular gastroenterology and hepatology 20221010 2


<h4>Background & aims</h4>Despite recent evidence supporting the metabolic plasticity of CD4<sup>+</sup> T cells, it is uncertain whether the metabolic checkpoint pyruvate dehydrogenase kinase (PDK) in T cells plays a role in the pathogenesis of colitis.<h4>Methods</h4>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<sup>+</sup> T-cell-specific KO of PDK4 (Pdk4<  ...[more]

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