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

Abstract

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.