Free fatty acid receptor-4 regulates T-cellmediated allogeneic reaction through activating an aryl hydrocarbon receptor pathway  

作　　者：Maxwell Duah Fei Zheng Jingyi Shen Yan Xu Shuo Cao Zhiling Yan Qiu Lan Ying Wang Kailin Xu Bin Pan 

机构地区：[1]Department of Hematology,the Affiliated Hospital of Xuzhou Medical University,Xuzhou Medical University,Xuzhou 221002,China [2]Blood Diseases Institute,Xuzhou Medical University,Xuzhou 221002,China

出　　处：《Acta Pharmaceutica Sinica B》2025年第1期224-238,共15页药学学报(英文版)

基　　金：supported by National Natural Science Foundation of China(82170214,81970159 and 82370218 to Bin Pan,81930005 and 82341203 to Kailin Xu);the Jiangsu Provincial Key Research and Development Program(BE2021631 to Bin Pan,China);the Natural Science Research of Jiangsu Higher Education Institutions of China(20KJA320002 to Bin Pan);Prof.Robert Peter Gale(Imperial College of Science,Technology and Medicine)kindly revised the typescript.

摘　　要：Targeting T-cell is a strategy to control allogeneic response disorders,such as acute graftversus-host disease(GVHD)which is an important cause of therapy-failure after allogeneic hematopoietic cell transplants.Free fatty acid receptor-4(FFAR4)is a regulator of obesity but its role in T-cell and allogeneic reactions is unknown.Here,we found knockout of Ffar4 in donor T-cells in a mouse allograft model increased acute GVHD whereas the natural FFAR4 ligands and the synthetic FFAR4 agonists decreased it.FFAR4 agonist-mediated anti-acute GVHD effects depended on FFAR4-expression in donor T-cells.The FFAR4 agonist CpdA suppressed donor T-cell-mediated alloreaction by activating an aryl hydrocarbon receptor(AhR)pathway.CpdA recruited b-Arrestin2 to FFAR4 which facilitated nuclear translocation of AhR and upregulation of IL-22.The CpdA-mediated anti-acute GVHD effect was absent in mice receiving Ahr-knockout or Il22-knockout T-cells.Recipient-expressing Ffar4 was also important for the anti-acute GVHD effect of CpdA which inhibited activation of antigen presenting cells.Importantly,CpdA decreased acute GVHD in obese mice,an effect also depended on Ffar4-expression in donor T-cells and recipients.Our study shows the immunoregulatory effect of FFAR4 in T-cell,and targeting FFAR4 might be a relative option for controlling allogeneic reactions in obese patients.

关 键 词：Free fatty acid receptor-4 CpdA T-CELL Graft-versus-host disease Allogeneic reaction Aryl hydrocarbon receptor INTERLEUKIN-22 OBESITY 

分 类 号：O62[理学—有机化学]