Monocytes and Macrophages Serve as Potent Prostaglandin D₂ Sources during Acute, Non-Allergic Pulmonary Inflammation

Acute respiratory inflammation, most commonly resulting from bacterial or viral infection, is one of the leading causes of death and disability worldwide. The inflammatory lipid mediator prostaglandin D₂ (PGD₂) and its rate-limiting enzyme, hematopoietic PGD synthase (hPGDS), are well-known drivers of allergic pulmonary inflammation. Here, we sought to investigate the source and role of hPGDS-derived PGD₂ in acute pulmonary inflammation. Murine bronchoalveolar monocytes/macrophages from LPS- but not OVA-induced lung inflammation released significant amounts of PGD₂. Accordingly, human monocyte-derived macrophages expressed high basal levels of hPGDS and released significant levels of PGD₂ after LPS/IFN-γ, but not IL-4 stimulation. Human peripheral blood monocytes secreted significantly more PGD₂ than monocyte-derived macrophages. Using human precision-cut lung slices (PCLS), we observed that LPS/IFN-γ but not IL-4/IL-13 drive PGD₂ production in the lung. HPGDS inhibition prevented LPS-induced PGD₂ release by human monocyte-derived macrophages and PCLS. As a result of hPGDS inhibition, less TNF-α, IL-6 and IL-10 could be determined in PCLS-conditioned medium. Collectively, this dataset reflects the time-dependent release of PGD₂ by human phagocytes, highlights the importance of monocytes and macrophages as PGD₂ sources and suggests that hPGDS inhibition might be a potential therapeutic option for acute, non-allergic lung inflammation.