| Summary: | Macrophages are a highly versatile and heterogenic group of immune cells, known for their involvement in inflammatory reactions. However, our knowledge about distinct subpopulations of macrophages and their specific contribution to the resolution of inflammation remains incomplete. We have previously shown, in an in vivo peritonitis model, that inhibition of the synthesis of the pro-inflammatory lipid mediator prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) attenuates efficient resolution of inflammation. PGE<sub>2</sub> levels during later stages of the inflammatory process further correlate with expression of the hyaluronan (HA) receptor Lyve1 in peritoneal macrophages. In the present study, we therefore aimed to understand if PGE<sub>2</sub> might contribute to the regulation of Lyve1 and how this might impact inflammatory responses. In line with our in vivo findings, PGE<sub>2</sub> synergized with dexamethasone to enhance <i>Lyve1</i> expression in bone marrow-derived macrophages, while expression of the predominant hyaluronan receptor <i>CD44</i> remained unaltered. PGE<sub>2</sub>-mediated <i>Lyve1</i> upregulation was strictly dependent on PGE<sub>2</sub> receptor EP2 signaling. While PGE<sub>2</sub>/dexamethasone-treated macrophages, despite their enhanced <i>Lyve1</i> expression, did not show inflammatory responses upon stimulation with low (LMW) or high-molecular-weight hyaluronan (HMW)-HA, they were sensitized towards LMW-HA-dependent augmentation of lipopolysaccharide (LPS)-induced inflammatory responses. Thus, Lyve1-expressing macrophages emerged as a subpopulation of macrophages integrating inflammatory stimuli with extracellular matrix-derived signals.
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