Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea.
Research Institute of Aging and Metabolism, Kyungpook National University, Daegu, Republic of Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea.
Cell Mol Gastroenterol Hepatol. 2023;15(2):439-461. doi: 10.1016/j.jcmgh.2022.09.016. Epub 2022 Oct 10.
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.
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 (Pdk4CD4). 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.
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.
PDK4 deletion from CD4 T cells mitigates colitis by metabolic and calcium signaling modulation, suggesting PDK4 as a potential therapeutic target for IBD.
尽管最近有证据支持 CD4 T 细胞的代谢可塑性，但 T 细胞中的代谢检查点丙酮酸脱氢酶激酶（PDK）是否在结肠炎发病机制中发挥作用仍不确定。
为了研究 PDK4 在结肠炎中的作用，我们使用葡聚糖硫酸钠（DSS）诱导的结肠炎和基于组成型敲除（KO）或 CD4 T 细胞特异性 PDK4（Pdk4CD4）KO 小鼠的 T 细胞转移结肠炎模型。还研究了 PDK4 缺失对 T 细胞活化的影响。此外，我们检查了 PDK4 药理学抑制剂对结肠炎的影响。
在 DSS 诱导的结肠炎模型中，PDK4 的表达在结肠炎发展过程中增加。磷酸化 PDHE1α，PDK4 的底物，在炎症性肠病患者的固有层 CD4 T 细胞中积累。组成型 KO 和 CD4 T 细胞特异性 PDK4 缺失均延迟 DSS 诱导的结肠炎。缺乏 PDK4 的 CD4 T 细胞的过继转移减弱了小鼠结肠炎，并且 PDK4 缺失导致 CD4 T 细胞活化减少和有氧糖酵解减弱。从机制上讲，缺乏 PDK4 的 CD4 T 细胞中内质网-线粒体接触点较少，这些接触点负责细胞器间钙转移。与此一致，GM-10395，一种新型 PDK4 抑制剂，通过减少内质网-线粒体钙转移来抑制 T 细胞活化，从而改善小鼠结肠炎。
从 CD4 T 细胞中缺失 PDK4 通过代谢和钙信号转导调节减轻结肠炎，提示 PDK4 是 IBD 的潜在治疗靶点。
