Hematopoietic prostaglandin D2 synthase controls the onset and resolution of acute inflammation through PGD2 and 15-deoxyΔ12-14 PGJ2

Hematopoietic prostaglandin D(2) synthase (hPGD(2)S) metabolizes cyclooxygenase (COX)-derived PGH(2) to PGD(2) and 15-deoxy Delta(12-14) PGJ(2) (15d-PGJ(2)). Unlike COX, the role of hPGD2S in host defense is ambiguous. PGD2 can be either pro- or antiinflammatory depending on disease etiology, whereas the existence of 15d-PGJ2 and its relevance to pathophysiology remain controversial. Herein, studies on hPGD2S KO mice reveal that 15d-PGJ2 is synthesized in a self-resolving peritonitis, detected by using liquid chromatography-tandem MS. Together with PGD2 working on its DP1 receptor, 15d-PGJ2 controls the balance of pro- vs. antiinflammatory cytokines that regulate leukocyte influx and monocyte-derived macrophage efflux from the inflamed peritoneal cavity to draining lymph nodes leading to resolution. Specifically, inflammation in hPGD2S KOs is more severe during the onset phase arising from a substantial cytokine imbalance resulting in enhanced polymorphonuclear leukocyte and monocyte trafficking. Moreover, resolution is impaired, characterized by macrophage and surprisingly lymphocyte accumulation. Data from this work place hPGD2S at the center of controlling the onset and the resolution of acute inflammation where it acts as a crucial checkpoint controller of cytokine/chemokine synthesis as well as leukocyte influx and efflux. Here, we provide definitive proof that 15d-PGJ2 is synthesized during mammalian inflammatory responses, and we highlight DP1 receptor activation as a potential anti inflammatory strategy.