Henan Key Laboratory of Immunology and Targeted Drug, Henan Collaborative Innovation Center of Molecular Diagnosis and Laboratory Medicine, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, China.
Department of Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Front Immunol. 2022 Sep 9;13:929785. doi: 10.3389/fimmu.2022.929785. eCollection 2022.
Bcl-3 is an atypical IκB family member that regulates transcription in the nucleus by binding to the p50/p52 homologous dimer subunit. Although various studies illustrate the important role of Bcl-3 in physiological function, its role in metabolism is still unclear. We found that Bcl-3 has a metabolic regulatory effect on autoimmunity. Bcl-3-depleted mice are unable to develop experimental autoimmune encephalomyelitis. The disease resistance was linked to an increase in lactate levels in Th17 cells, and lactate could alleviate EAE development in WT mice. Bcl-3 deficient mice had more differentiated Th17 cells and an increased extracellular acidification rate in these cells. Concurrently, their ultimate respiration rate and respiratory reserve capacity were significantly lower than wild-type mice. However, adding GNE-140 (LADH inhibitor) to Bcl-3-deficient Th17 cells could reverse the phenomenon, and lactate supplementation could increase the glycolysis metabolism of Th17 cells in WT mice. Mechanically, Bcl-3 could interact with Raptor through ANK and RNC domains. Therefore, Bcl-3 regulates Th17 pathogenicity by promoting Raptor mediated energy metabolism, revealing a novel regulation of adaptive immunity.
Bcl-3 是一种非典型的 IκB 家族成员，通过与 p50/p52 同源二聚体亚基结合在核内调节转录。尽管各种研究表明 Bcl-3 在生理功能中具有重要作用，但它在代谢中的作用尚不清楚。我们发现 Bcl-3 对自身免疫具有代谢调节作用。Bcl-3 耗尽的小鼠无法发展实验性自身免疫性脑脊髓炎。这种疾病抗性与 Th17 细胞中乳酸水平的增加有关，而乳酸可以减轻 WT 小鼠的 EAE 发展。Bcl-3 缺陷型小鼠的 Th17 细胞分化更多，这些细胞的细胞外酸化率增加。同时，它们的最终呼吸率和呼吸储备能力明显低于野生型小鼠。然而，向 Bcl-3 缺陷型 Th17 细胞中添加 GNE-140（LADH 抑制剂）可以逆转这种现象，并且乳酸补充可以增加 WT 小鼠 Th17 细胞的糖酵解代谢。在机制上，Bcl-3 可以通过 ANK 和 RNC 结构域与 Raptor 相互作用。因此，Bcl-3 通过促进 Raptor 介导的能量代谢来调节 Th17 致病性，揭示了适应性免疫的一种新调节。
