Molecular medicine (Cambridge, Mass.) · 2025
Dysfunctional glycolysis-UCP2-fatty acid oxidation promotes CTLA4intFOXP3int regulatory T-cell production in rheumatoid arthritis.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Han Jiawen, Zhou Zhongyang, Wang Hongxia, Chen Yuxin, Li Wuguo, Dai Meiqin, Bian Jing, Zhao Erming, He Jiaying, Zhang Xinyao, Yi Huanfa, Shao Lan
Аннотация
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.