Hematopoietic prostaglandin D₂ synthase controls the onset and resolution of acute inflammation through PGD₂ and 15-deoxyΔ^12–14 PGJ₂

Abstract

Hematopoietic prostaglandin D₂ synthase (hPGD₂S) metabolizes cyclooxygenase (COX)-derived PGH₂ to PGD₂ and 15-deoxyΔ^12–14 PGJ₂ (15d-PGJ₂). 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 antiinflammatory strategy.

• antiinflammatory
• cyclooxygnease
• drug development
• eicosanoids
• innate immunity