Inflammatory bowel diseases (IBDs) are characterized by unrestrained innate and adaptive immune responses and compromised intestinal epithelial barrier integrity. Regulatory T (Treg) 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 Treg cell function and contributes to IBD pathogenesis remains unclear. Here, we found that the PGE2 receptor subtype 2 (EP2) is highly expressed in Treg cells. Treg cell-specific deletion of EP2 resulted in increased Treg cell numbers, and enhanced granzyme B(GzmB) expression and immunosuppressive capacity of Treg cells in mice. Adoptive transfer of EP2-deficient Treg cells attenuated naïve CD4+ T cell transfer-induced colitis in Rag1-/- mice. Mice with EP2-deficient Treg 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 Treg-dependent manner. Mechanistically, activation of EP2 suppressed Treg 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 Treg cell function, suggesting EP2 inhibition as a potential therapeutic strategy for IBD treatment.
Keywords: EP2; Inflammatory bowel disease; NF-κB; PGE(2); T(reg) cell.
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