Hematopoietic prostaglandin D2synthase controls the onset and resolution of acute inflammation through PGD2and 15-deoxyΔ12–14PGJ2

Abstract

Hematopoietic prostaglandin D 2 synthase (hPGD 2 S) metabolizes cyclooxygenase (COX)-derived PGH 2 to PGD 2 and 15-deoxyΔ 12–14 PGJ 2(15d-PGJ 2). Unlike COX, the role of hPGD 2 S in host defense is ambiguous. PGD 2 can be either pro- or antiinflammatory depending on disease etiology, whereas the existence of 15d-PGJ 2 and its relevance to pathophysiology remain controversial. Herein, studies on hPGD 2 S KO mice reveal that 15d-PGJ 2 is synthesized in a self-resolving peritonitis, detected by using liquid chromatography–tandem MS. Together with PGD 2 working on its DP1 receptor, 15d-PGJ 2 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 hPGD 2 S 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 hPGD 2 S 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-PGJ 2 is synthesized during mammalian inflammatory responses, and we highlight DP1 receptor activation as a potential antiinflammatory strategy.