Free fatty acid receptor-4 regulates T-cell-mediated allogeneic reaction through activating an aryl hydrocarbon receptor pathway.
10.1016/j.apsb.2024.12.011
- Author:
Maxwell DUAH
1
;
Fei ZHENG
1
;
Jingyi SHEN
1
;
Yan XU
1
;
Shuo CAO
1
;
Zhiling YAN
1
;
Qiu LAN
1
;
Ying WANG
1
;
Kailin XU
1
;
Bin PAN
1
Author Information
1. Department of Hematology, the Affiliated Hospital of Xuzhou Medical University, Xuzhou Medical University, Xuzhou 221002, China.
- Publication Type:Journal Article
- Keywords:
Allogeneic reaction;
Aryl hydrocarbon receptor;
CpdA;
Free fatty acid receptor-4;
Graft-versus-host disease;
Interleukin-22;
Obesity;
T-cell
- From:
Acta Pharmaceutica Sinica B
2025;15(1):224-238
- CountryChina
- Language:English
-
Abstract:
Targeting T-cell is a strategy to control allogeneic response disorders, such as acute graft-versus-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 β-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.
