Prostaglandin E(2) Boosts the Hyaluronan-Mediated Increase in Inflammatory Response to Lipopolysaccharide by Enhancing Lyve1 Expression

SIMPLE SUMMARY: Inflammatory reactions provide a crucial defense mechanism against invading pathogens by generating a highly reactive environment. To limit tissue damage due to ongoing inflammation, resolution of inflammation is a tightly regulated process, which is orchestrated amongst other cell types by macrophages. While numerous functional macrophage phenotypes have been described, there is little information on how exactly different subtypes contribute to the resolution of inflammation. In the present study, we observed that expression of hyaluronan receptor Lyve1 in macrophages correlates with efficient resolution of inflammation. We further identified prostaglandin E(2)/EP2 receptor-mediated signaling to enhance Lyve1 expression in macrophages, contributing, as a consequence, to the sensitization of macrophages to synergistic inflammatory stimulation with lipopolysaccharide and the Lyve1 ligand low-molecular-weight hyaluronan. We thus propose that Lyve1-expressing macrophages are an important macrophage subpopulation able to integrate extracellular matrix-derived signals with pathogenic, inflammatory stimuli. ABSTRACT: 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(2) (PGE(2)) attenuates efficient resolution of inflammation. PGE(2) 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(2) might contribute to the regulation of Lyve1 and how this might impact inflammatory responses. In line with our in vivo findings, PGE(2) synergized with dexamethasone to enhance Lyve1 expression in bone marrow-derived macrophages, while expression of the predominant hyaluronan receptor CD44 remained unaltered. PGE(2)-mediated Lyve1 upregulation was strictly dependent on PGE(2) receptor EP2 signaling. While PGE(2)/dexamethasone-treated macrophages, despite their enhanced Lyve1 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.