T cell-intrinsic prostaglandin E2-EP2/EP4 signaling is critical in pathogenic Th17 cell-driven inflammation

Publication date: Available online 20 June 2018
Source:Journal of Allergy and Clinical Immunology
Author(s): Jinju Lee, Tomohiro Aoki, Dean Thumkeo, Ratklao Siriwach, Chengcan Yao, Shuh Narumiya
BackgroundInterleukin-23 (IL-23) is the key cytokine for generation of pathogenic IL-17-producing helper T (Th17) cells that critically contribute to autoimmune diseases. However, how IL-23 generates pathogenic Th17 cells remains to be elucidated.ObjectivesTo examine the involvement, molecular mechanisms and clinical implications of prostaglandin (PG) E2-EP2/EP4 signaling in induction of IL-23-driven pathogenic Th17 cells.MethodsThe role of PGE2 in induction of pathogenic Th17 cells was investigated in mouse Th17 cells in culture in vitro and in IL-23-induced psoriasis mouse model in vivo. Clinical relevance of findings in mice was examined by gene expression profiling of IL-23 and PGE2-EP2/EP4 signaling in psoriatic skin from patients.ResultsIL-23 induces ptgs2 encoding cyclooxygenase 2 in Th17 cells and produces PGE2, which acts back on PGE receptors EP2 and EP4 in these cells and enhances IL-23-induced expression of an IL-23 receptor subunit gene, Il23r, by activating STAT3, CREB1 and NF-κB through cAMP-protein kinase A signaling. This PGE2 signaling also induces expression of various inflammation-related genes, which possibly function in Th17 cell-mediated pathology. Combined deletion of EP2 and EP4 selectively in T cells suppressed accumulation of IL-17A⁺ and IL-17A⁺IFN-γ⁺ pathogenic Th17 cells and abolished skin inflammation in IL-23-induced psoriasis mouse model. Analysis of human psoriatic skin biopsies shows positive correlation between PGE2 signaling and the IL-23/Th17 pathway.ConclusionsThe T cell-intrinsic EP2/EP4 signaling is critical in IL-23-driven generation of pathogenic Th17 cells and consequent pathogenesis in the skin.

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IL-23 mobilizes T cell-intrinsic PGE2-EP2/EP4 signaling, which is critical in IL-23-induced pathogenic Th17 cell generation. Combined blockade of EP2 and EP4 suppressed IL-23-induced skin inflammation, suggesting this pathway as potential therapeutic target of Th17-mediated diseases.


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