Prostaglandin E2-prostoglandin E receptor subtype 4 (EP4) signaling mediates UV irradiation-induced systemic immunosuppression

UV radiation induces systemic immunosuppression. Because nonsteroidal anti-inflammatory drugs suppress UV-induced immunosuppression, prostanoids have been suspected as a crucial mediator of this UV effect. However, the identity of the prostanoid involved and its mechanism of action remain unclear. Here, we addressed this issue by subjecting mice deficient in each prostanoid receptor individually or mice treated with a subtype-specific antagonist to UV irradiation. Mice treated with an antagonist for prostaglandin E receptor subtype 4 (EP4), but not those deficient in other prostanoid receptors, show impaired UV-induced immunosuppression, whereas administration of an EP4 agonist rescues the impairment of the UV-induced immunosuppression in indomethacin-treated mice. The EP4 antagonist treatment suppresses an increase in the number of CD4(+)/forkhead box P3-positive (Foxp3(+)) regulatory T cells (Treg cells) in the peripheral lymph nodes (LNs) and dendritic cells expressing DEC205 in the LNs and the skin after UV irradiation. Furthermore, the EP4 antagonist treatment down-regulates UV-induced expression of receptor activator of NF-kappa B ligand (RANKL) in skin keratinocytes. Finally, administration of anti-RANKL antibody abolishes the restoration of UV-induced immunosuppression by EP4 agonism in indomethacin-treated mice. Thus, prostaglandin E-2 (PGE(2))-EP4 signaling mediates UV-induced immunosuppression by elevating the number of Treg cells through regulation of RANKL expression in the epidermis.

紫外线辐射诱导全身性免疫抑制。由于非甾体抗炎药可抑制紫外线诱导的免疫抑制，前列腺素类物质被怀疑是这种紫外线效应的关键介质。然而，所涉及的前列腺素类物质的种类及其作用机制仍不清楚。在此，我们通过对单个前列腺素受体缺陷的小鼠或用亚型特异性拮抗剂处理的小鼠进行紫外线照射来解决这一问题。用前列腺素E受体亚型4（EP4）拮抗剂处理的小鼠，而非其他前列腺素受体缺陷的小鼠，表现出紫外线诱导的免疫抑制受损，而给予EP4激动剂可挽救吲哚美辛处理小鼠紫外线诱导的免疫抑制受损情况。EP4拮抗剂处理抑制了紫外线照射后外周淋巴结（LNs）中CD4(+)/叉头框P3阳性（Foxp3(+)）调节性T细胞（Treg细胞）数量的增加以及淋巴结和皮肤中表达DEC205的树突状细胞数量的增加。此外，EP4拮抗剂处理下调了紫外线诱导的皮肤角质形成细胞中核因子-κB受体激活剂配体（RANKL）的表达。最后，给予抗RANKL抗体消除了吲哚美辛处理小鼠中EP4激动作用对紫外线诱导的免疫抑制的恢复。因此，前列腺素E - 2（PGE(2)） - EP4信号通路通过调节表皮中RANKL的表达增加Treg细胞数量，从而介导紫外线诱导的免疫抑制。