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<p>In rheumatoid arthritis (RA), the impaired function of regulatory T cells (Tregs) induces chronic inflammatory responses in the synovium. Cytotoxic T Lymphocyte Antigen 4 (CTLA4) is crucial for Sustaining Treg function. Uncoupling Protein 2 (UCP2) plays a key role in linking the glycolysis and fatty acid oxidation (FAO) pathways. Here we observed that Tregs in RA were predominantly characterized by a CD25<sup>int</sup>CTLA4<sup>int</sup>FOXP3<sup>int</sup>CD4<sup>high</sup> Phenotype. Mechanistically, elevated expression of UCP2 in RA Tregs disrupted metabolic homeostasis by downregulating Carnitine Palmitoyltransferase 2 (CPT2), a rate-limiting enzyme in the FAO pathway. Impaired FAO trigged caveolae-mediated endocytosis, leading to reduced CTLA4 cell surface accumulation and diminished Treg suppressive capacity. Moreover, UCP2 inhibition attenuated the pro-inflammatory effects of RA T cells in a human-SCID chimeric mouse model. Our results establish a critical link between CTLA4 endocytosis and UCP2-mediated metabolic shift in Tregs and identified UCP2 as a potential therapeutic target for preventing RA autoimmunity.</p>

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Dysfunctional glycolysis-UCP2-fatty acid oxidation promotes CTLA4intFOXP3int regulatory T-cell production in rheumatoid arthritis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月9日

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  • Jiawen Han,
  • Zhongyang Zhou,
  • Hongxia Wang,
  • Yuxin Chen,
  • Wuguo Li,
  • Meiqin Dai,
  • Jing Bian,
  • Erming Zhao,
  • Jiaying He,
  • Xinyao Zhang,
  • Huanfa Yi,
  • Lan Shao

摘要

In rheumatoid arthritis (RA), the impaired function of regulatory T cells (Tregs) induces chronic inflammatory responses in the synovium. Cytotoxic T Lymphocyte Antigen 4 (CTLA4) is crucial for Sustaining Treg function. Uncoupling Protein 2 (UCP2) plays a key role in linking the glycolysis and fatty acid oxidation (FAO) pathways. Here we observed that Tregs in RA were predominantly characterized by a CD25intCTLA4intFOXP3intCD4high Phenotype. Mechanistically, elevated expression of UCP2 in RA Tregs disrupted metabolic homeostasis by downregulating Carnitine Palmitoyltransferase 2 (CPT2), a rate-limiting enzyme in the FAO pathway. Impaired FAO trigged caveolae-mediated endocytosis, leading to reduced CTLA4 cell surface accumulation and diminished Treg suppressive capacity. Moreover, UCP2 inhibition attenuated the pro-inflammatory effects of RA T cells in a human-SCID chimeric mouse model. Our results establish a critical link between CTLA4 endocytosis and UCP2-mediated metabolic shift in Tregs and identified UCP2 as a potential therapeutic target for preventing RA autoimmunity.