Pinosylvin Shifts Macrophage Polarization to Support Resolution of Inflammation

Pinosylvin is a natural stilbenoid found particularly in Scots pine. Stilbenoids are a group of phenolic compounds identified as protective agents against pathogens for many plants. Stilbenoids also possess health-promoting properties in humans; for instance, they are anti-inflammatory through their suppressing action on proinflammatory M1-type macrophage activation. Macrophages respond to environmental changes by polarizing towards proinflammatory M1 phenotype in infection and inflammatory diseases, or towards anti-inflammatory M2 phenotype, mediating resolution of inflammation and repair. In the present study, we investigated the effects of pinosylvin on M2-type macrophage activation, aiming to test the hypothesis that pinosylvin could polarize macrophages from M1 to M2 phenotype to support resolution of inflammation. We used lipopolysaccharide (LPS) to induce M1 phenotype and interleukin-4 (IL-4) to induce M2 phenotype in J774 murine and U937 human macrophages, and we measured expression of M1 and M2-markers. Interestingly, along with inhibiting the expression of M1-type markers, pinosylvin had an enhancing effect on the M2-type activation, shown as an increased expression of arginase-1 (Arg-1) and mannose receptor C type 1 (MRC1) in murine macrophages, and C-C motif chemokine ligands 17 and 26 (CCL17 and CCL26) in human macrophages. In IL-4-treated macrophages, pinosylvin enhanced PPAR-γ expression but had no effect on STAT6 phosphorylation. The results show, for the first time, that pinosylvin shifts macrophage polarization from the pro-inflammatory M1 phenotype towards M2 phenotype, supporting resolution of inflammation and repair.