Targeting the EP2 receptor ameliorates inflammatory bowel disease in mice by enhancing the immunosuppressive activity of Treg cells.

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 E₂ (PGE₂), a bioactive lipid compound derived from arachidonic acid, can modulate T cell functions in a receptor subtype-specific manner. However, whether PGE₂ regulates T_reg cell function and contributes to IBD pathogenesis remains unclear. Here, we found that the PGE₂ 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 PGE₂/EP2 axis as a key negative modulator of T_reg cell function, suggesting EP2 inhibition as a potential therapeutic strategy for IBD treatment.