Opposing Immunomodulatory Roles of Prostaglandin D2 during the Progression of Skin Inflammation

The effects of PGD 2 are extremely context dependent. It can have pro- or anti-inflammatory effects in clinically important pathological conditions. A greater mechanistic insight into the determinants of PGD 2 activity during inflammation is thus required. In this study, we investigated the role of PGD 2 in croton oil–induced dermatitis using transgenic (TG) mice overexpressing hematopoietic PGD synthase. Administration of croton oil caused tissue swelling and vascular leakage in the mouse ear. Compared with wild-type animals, TG mice produced more PGD 2 and showed decreased inflammation in the early phase, but more severe manifestations during the late phase. Data obtained from bone marrow transplantation between wild-type and TG mice indicated that PGD 2 produced by tissue resident cells in the TG mice attenuated early-phase inflammation, whereas PGD 2 produced from hematopoietic lineage cells exacerbated late-phase inflammation. There are two distinct PGD 2 receptors: D-prostanoid receptor (DP) and chemoattractant receptor–homologous molecule expressed on Th2 cells (CRTH2). In TG mice, treatment with a DP antagonist exacerbated inflammation in the early phase, whereas treatment with a CRTH2 antagonist attenuated inflammation during the late phase. In vitro experiments showed that DP agonism enhanced vascular endothelial barrier formation, whereas CRTH2 agonism stimulated neutrophil migration. Collectively, these results show that when hematopoietic PGD synthase is overexpressed, tissue resident cell–derived PGD 2 suppresses skin inflammation via DP in the early phase, but hematopoietic lineage cell–derived PGD 2 stimulates CRTH2 and promotes inflammation during the late phase. DP-mediated vascular barrier enhancement or CRTH2-mediated neutrophil activation may be responsible for these effects. Thus, PGD 2 represents opposite roles in inflammation, depending on the disease phase in vivo.