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

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

  • Mucosal Immunol. 2024 Dec 31:S1933-0219(24)00137-5. doi: 10.1016/j.mucimm.2024.12.014.
Chenchen Wang 1,  Tingting Yu 1,  Yuexin Wang 1,  Mengtong Xu 1,  Jingjing Wang 1,  Yan Zhao 1,  Qiangyou Wan 1,  Lu Wang 1,  Jie Yang 2,  Jie Zhou 3,  Bin Li 4,  Ying Yu 5,  Yujun Shen 6
Affiliations

Affiliations

  • 1 Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 2 Department of Biochemistry and Molecular Biology, Department of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Key Laboratory of Cellular and Molecular Immunology in Tianjin, Excellent Talent Project, The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Science, Tianjin Medical University, Tianjin, China.
  • 3 Department of Immunology, Tianjin Institute of Immunology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China.
  • 4 Shanghai Institute of Immunology and Department of Immunology and Microbiology, Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 5 Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. Electronic address: yuying@tmu.edu.cn.
  • 6 Department of Pharmacology, Tianjin Key Laboratory of Inflammatory Biology, Center for Cardiovascular Diseases, Haihe Laboratory of Cell Ecosystem, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, State Key Laboratory of Experimental Hematology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China. Electronic address: yujun_shen@tmu.edu.cn.
PMID: 39746548 DOI: 10.1016/j.mucimm.2024.12.014
Abstract

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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