T cell-intrinsic prostaglandin E-EP2/EP4 signaling is critical in pathogenic T17 cell-driven inflammation.

BACKGROUND

IL-23 is the key cytokine for generation of pathogenic IL-17-producing helper T (T17) cells, which contribute critically to autoimmune diseases. However, how IL-23 generates pathogenic T17 cells remains to be elucidated.

OBJECTIVES

We sought to examine the involvement, molecular mechanisms, and clinical implications of prostaglandin (PG) E-EP2/EP4 signaling in induction of IL-23-driven pathogenic T17 cells.

METHODS

The role of PGE in induction of pathogenic T17 cells was investigated in mouse T17 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-EP2/EP4 signaling in psoriatic skin from patients.

RESULTS

IL-23 induces Ptgs2, encoding COX2 in T17 cells, and produces PGE, 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 signaling also induces expression of various inflammation-related genes, which possibly function in T17 cell-mediated pathology. Combined deletion of EP2 and EP4 selectively in T cells suppressed accumulation of IL-17A and IL-17AIFN-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 signaling and the IL-23/T17 pathway.

CONCLUSIONS

T cell-intrinsic EP2/EP4 signaling is critical in IL-23-driven generation of pathogenic T17 cells and consequent pathogenesis in the skin.