T cell–intrinsic prostaglandin E2-EP2/EP4 signaling is critical in pathogenic TH17 cell–driven inflammation

Background IL-23 is the key cytokine for generation of pathogenic IL-17–producing helper T (T H 17) cells, which contribute critically to autoimmune diseases. However, how IL-23 generates pathogenic T H 17 cells remains to be elucidated. Objectives We sought to examine the involvement, molecular mechanisms, and clinical implications of prostaglandin (PG) E 2 –EP2/EP4 signaling in induction of IL-23–driven pathogenic T H 17 cells. Methods The role of PGE 2 in induction of pathogenic T H 17 cells was investigated in mouse T H 17 cells in culture in vitro and in an IL-23–induced psoriasis mouse model in vivo . Clinical relevance of the findings in mice was examined by using gene expression profiling of IL-23 and PGE 2 -EP2/EP4 signaling in psoriatic skin from patients. Results IL-23 induces Ptgs2 , encoding COX2 in T H 17 cells, and produces PGE 2 , which acts back on the PGE receptors EP2 and EP4 in these cells and enhances IL-23–induced expression of an IL-23 receptor subunit gene, Il23r , by activating signal transducer and activator of transcription (STAT) 3, cAMP-responsive element binding protein 1, and nuclear factor κ light chain enhancer of activated B cells (NF-κB) through cyclic AMP–protein kinase A signaling. This PGE 2 signaling also induces expression of various inflammation-related genes, which possibly function in T H 17 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 an IL-23–induced psoriasis mouse model. Analysis of human psoriatic skin biopsy specimens shows positive correlation between PGE 2 signaling and the IL-23/T H 17 pathway. Conclusions T cell–intrinsic EP2/EP4 signaling is critical in IL-23–driven generation of pathogenic T H 17 cells and consequent pathogenesis in the skin.