Targeting the EP2 receptor ameliorates inflammatory bowel disease in mice by enhancing the immunosuppressive activity of Treg cells
Chenchen Wang, Tingting Yu, Yuexin Wang, Mengtong Xu, Jingjing Wang, Yan Zhao, Qiangyou Wan, Lu Wang, Jie Yang, Jie Zhou, Bin Li, Ying Yu, Yujun Shen
Abstract
Inflammatory bowel diseases (IBDs) are characterized by unrestrained innate and adaptive immune responses and compromised intestinal epithelial barrier integrity. Regulatory T (T reg ) cells are crucial for maintaining self-tolerance and immune homeostasis in intestinal tissues. Prostaglandin E 2 (PGE 2 ), a bioactive lipid compound derived from arachidonic acid, can modulate T cell functions in a receptor subtype-specific manner. However, whether PGE 2 regulates T reg cell function and contributes to IBD pathogenesis remains unclear. Here, we found that the PGE 2 receptor subtype 2 (EP2) is highly expressed in T reg cells. T reg cell-specific deletion of EP2 resulted in increased T reg cell numbers, and enhanced granzyme B(GzmB) expression and immunosuppressive capacity of T reg cells in mice. Adoptive transfer of EP2-deficient T reg cells attenuated naïve CD4 + T cell transfer-induced colitis in Rag1 −/− mice. Mice with EP2-deficient T reg cells were protected from 2,4,6-trinitrobenzene sulfonic acid (TNBS)- and dextran sodium sulfate (DSS)-induced colitis. Pharmacological blockage of EP2 with PF-04418948 markedly alleviated DSS-induced colitis in mice in a T reg -dependent manner. Mechanistically, activation of EP2 suppressed T reg cell function, at least in part, through reduction of GzmB expression via PKA-mediated inhibition of NF-κB signaling. Thus, we identified the PGE 2 /EP2 axis as a key negative modulator of T reg cell function, suggesting EP2 inhibition as a potential therapeutic strategy for IBD treatment.