Jin Hua, Zhong Xinjie, Zhang Chunpan, Wu Yongle, Sun Jie, Wang Xiyu, Wang Zeyu, Zhu Jingjing, Jiang Yuan, Du Xiaonan, Zhang Zihan, Zhang Dong, Sun Guangyong
Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
Medical Research Center, Beijing Institute of Respiratory Medicine and Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China; Department of Gastroenterology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.
Mol Metab. 2025 Jun;96:102131. doi: 10.1016/j.molmet.2025.102131. Epub 2025 Mar 24.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is a leading chronic liver disease characterized by chronic inflammation. Regulatory T cells (Tregs) highly express CD73 and play a critical role in modulating the immune response. However, the roles and mechanisms by which CD73 modulates Tregs in MASLD are still unknown. A choline-deficient high-fat diet (CDHFD) or methionine/choline-deficient diet (MCD) was used to establish a MASLD model. We found that CD73 expression was upregulated in Tregs via the FFA-mediated p38/GATA2 signaling pathway. Cd73 KO promoted MASLD progression, accompanied by decreased Treg viability and activity. Compared with Cd73 KO Tregs, adoptively transferred WT Tregs exhibited increased Treg activity and provided greater protection against hepatic inflammatory responses in MASLD. This immune protection is mediated by CD73 via both enzymatic and nonenzymatic pathways, degrading AMP into ADO to increase Treg function and block DR5-TRAIL-mediated cell death signaling. These findings suggest a potential immunotherapeutic approach for MASLD treatment and highlight its possible relevance for clinical application.
代谢功能障碍相关脂肪性肝病（MASLD）是一种以慢性炎症为特征的主要慢性肝病。调节性T细胞（Tregs）高表达CD73，并在调节免疫反应中起关键作用。然而，CD73在MASLD中调节Tregs的作用和机制仍不清楚。采用胆碱缺乏高脂饮食（CDHFD）或蛋氨酸/胆碱缺乏饮食（MCD）建立MASLD模型。我们发现，通过游离脂肪酸（FFA）介导的p38/ GATA2信号通路，Tregs中CD73的表达上调。Cd73基因敲除促进了MASLD的进展，同时Treg的活力和活性降低。与Cd73基因敲除的Tregs相比，过继转移的野生型Tregs表现出更高的Treg活性，并对MASLD中的肝脏炎症反应提供了更强的保护作用。这种免疫保护作用由CD73通过酶促和非酶促途径介导，将AMP降解为腺苷（ADO）以增强Treg功能，并阻断DR5-TRAIL介导的细胞死亡信号。这些发现提示了一种针对MASLD治疗的潜在免疫治疗方法，并突出了其在临床应用中的可能相关性。
