Prostaglandin E2 stimulates adaptive IL-22 production and promotes allergic contact dermatitis

Abstract

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.

Human Adipose Tissue-Derived Mesenchymal Stem Cells Attenuate Atopic Dermatitis by Regulating the Expression of MIP-2, miR-122a-SOCS1 Axis, and Th1/Th2 Responses

“…Our results showed that AdMSCs prevented AD from increasing the serum PGE2 level. The prostaglandin PGE2 can induce IL-22 from T cells through its receptors such as the prostanoid receptors EP2 and EP4 ( Robb et al, 2018 ). Selective deletion of EP4 in T cells limits atopic-like skin inflammation ( Robb et al, 2018 ).…”

Prostaglandin‐cytokine crosstalk in chronic inflammation

“…Furthermore, epigenetic changes in the PTGER4 gene enhancer in Th17 cells were also found to be associated with human autoimmune diseases such as MS, CD and allergy (Farh et al ., ). Consistent with these GWAS findings, the expression of PGE 2 signalling pathway genes (including both PGE 2 synthases and receptors) was found to be positively correlated with IL‐23/Th17 signature genes as well as disease severity in biopsy samples of human inflamed tissues with various chronic inflammatory conditions such as MS, CD, psoriasis and atopic dermatitis (Lee et al ., ; Robb et al ., ; and unpublished observations). Collectively, these genetic and epigenetic studies revealed conserved associations of variants in the PGE 2 ‐EP 4 signalling pathway with various IL‐23/Th17‐dependent human chronic autoimmune diseases.…”

“…dinitro‐fluorobenzene)‐induced generation of IL‐22 + T‐cells in vivo and attenuated chronic allergic contact dermatitis induced by repeated oxazolone challenge (Robb et al ., ). Interestingly, genes related to PGE 2 and IL‐22 pathways were coordinately up‐regulated in lesional skin from human atopic dermatitis, and their expression in inflamed skin was also down‐regulated after the administration of corticosteroid or UVB treatments (Robb et al ., ). These results suggest a crucial role for PGE 2 ‐IL‐6/IL‐23 crosstalk in the generation of IL‐22 + T‐cells and the promotion of T‐cell‐mediated chronic inflammatory skin disease.…”

“…Consistently, T‐cell‐specific EP 4 receptor deficiency as well as COX inhibition reduced hapten (e.g. dinitro‐fluorobenzene)‐induced generation of IL‐22 + T‐cells in vivo and attenuated chronic allergic contact dermatitis induced by repeated oxazolone challenge (Robb et al ., ). Interestingly, genes related to PGE 2 and IL‐22 pathways were coordinately up‐regulated in lesional skin from human atopic dermatitis, and their expression in inflamed skin was also down‐regulated after the administration of corticosteroid or UVB treatments (Robb et al ., ).…”

Non‐steroidal anti‐inflammatory drugs, prostaglandins, and COVID‐19

“…PGE 2 stimulates IL-17 and aryl hydrocarbon receptor signalling pathways in human and mouse T cells through EP2/EP4 receptor -cAMP-PKA signalling, necessary for generation of pathogenic Th17 cells (Boniface et al, 2009;Lee et al, 2019;Robb et al, 2018;Yao et al, 2009). Given that SARS-CoV-2 infection specifically upregulates IL-17F signalling and aryl hydrocarbon receptor signalling (Z.…”