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

Background Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are both forms of eczema and are common inflammatory skin diseases with a central role of Th22-derived IL-22 in their pathogenesis. Although prostaglandin E2 (PGE2) is known to promote inflammation, little is known about its role in processes related to AD and ACD development, including IL-22 up-regulation. Objectives To investigate whether PGE2 has a role in IL-22 induction and development of ACD, which has increased prevalence in patients with AD. Methods T-cell cultures and in vivo sensitization of mice with haptens were used to assess the role of PGE2 in production of IL-22. The involvement of PGE2 receptors and their downstream signals were also examined. The effects of PGE2 were evaluated using the oxazolone (OXA)-induced ACD mouse model. The relationship of PGE2 and IL-22 signaling pathways in skin inflammation were also investigated using genomic profiling in human lesional AD skin. Results PGE2 induces IL-22 from T cells through its receptors EP2 and EP4 and involves cyclic adenosine monophosphate (cAMP) signaling. Selective deletion of EP4 in T-cells prevents hapten-induced IL-22 production in vivo, and inhibition of PGE2 synthesis limits atopic-like skin inflammation in the OXA-induced ACD model. Moreover, both PGE2 and IL-22 pathway genes were coordinately up-regulated in human AD lesional skin, but were below significant detection levels after corticosteroid or ultraviolet band B (UVB) treatments. Conclusions Our results define a crucial role for PGE2 in promoting ACD by facilitating IL-22 production from T-cells.

BACKGROUND Atopic dermatitis (AD) and allergic contact dermatitis (ACD) are both forms of eczema and are common inflammatory skin diseases with a central role of T cell-derived IL-22 in their pathogenesis. Although prostaglandin E2 (PGE2) is known to promote inflammation, little is known about its role in processes related to AD and ACD development, including IL-22 upregulation. OBJECTIVES We set out to investigate whether PGE2 has a role in T cell-derived IL-22 induction and development of ACD, which has augmented prevalence in patients with AD. METHODS T cell cultures and in vivo sensitization of mice with powerful haptens (oxazolone and dinitrofluorobenzene) were used to assess the role of PGE2 in IL-22 production. The involvement of PGE2 receptors and their downstream signals was also examined. The specific effects of PGE2 during ACD pathogenesis were evaluated by using the oxazolone-induced ACD mouse model. Gene expression of PGE2 and IL-22 signaling pathways was also investigated by using genomic profiling in human lesional AD skin biopsies. RESULTS PGE2 promotes IL-22 production from T cells through its receptors, E prostanoid receptor 2 (EP2) and EP4. This is mediated by its downstream cAMP-PKA signaling and probably involves the transcription factor aryl hydrocarbon receptor (AHR). Selective deletion of EP4 in T cells prevents hapten-induced adaptive IL-22 production in vivo. Importantly, blockade of endogenous PGE2 production by a COX inhibitor indomethacin or deletion of EP4 in T cells limit atopic-like skin inflammation in the oxazolone-induced mouse ACD model. Moreover, both PGE2 and IL-22 pathway genes were coequally upregulated in human AD lesional skin but were down-regulated after treatment with betamethasone or ultraviolet B (UVB) radiation, both common therapies for AD. CONCLUSIONS Our results thus define a crucial role for PGE2 in promoting ACD by facilitating T cell-derived IL-22 production.

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