Systemic inflammation, resulting from massive release of pro-inflammatory molecules into the circulatory system, is a major risk factor for severe illness, but the precise mechanisms underlying its control are incompletely understood. We observed that prostaglandin E2 (PGE2) through its receptor EP4 is down-regulated in human systemic inflammatory disease. Mice with reduced PGE2 synthesis develop systemic inflammation, associated with translocation of gut bacteria, which can be prevented by treating with EP4 agonists. Mechanistically, we demonstrate that PGE2–EP4 signaling directly acts on type 3 innate lymphoid cells (ILCs), promoting their homeostasis and driving them to produce interleukin-22 (IL-22). Disruption of the ILC/IL-22 axis impairs PGE2–mediated inhibition of systemic inflammation. Hence, PGE2–EP4 signaling inhibits systemic inflammation through ILC/IL-22 axis–dependent protection of gut barrier dysfunction.

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.