Pinosylvin Shifts Macrophage Polarization to Support Resolution of Inflammation

Abstract

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.

Phenolic Compounds Known to Be Present in Lingonberry (Vaccinium vitis-idaea L.) Enhance Macrophage Polarization towards the Anti-Inflammatory M2 Phenotype

“…In addition, resveratrol attenuated M1-type activation by decreasing LPS-induced production of NO, MCP-1, and IL-6 in murine J774 macrophages and TNF-α and IL-6 in human U937 macrophages. These results are consistent with previous studies reported in murine and human macrophages [ 55 , 56 , 57 ]. In a high-fat diet mouse model, resveratrol has been reported to restrict high-fat diet-induced macrophage accumulation in skeletal muscle tissue and switch macrophage polarization from the M1 to the M2 phenotype; accordingly, resveratrol decreased the expression of IL-6, TNF-α, IL-1β, and MCP-1 in skeletal muscle tissue [ 58 ].…”

“…Interestingly, resveratrol and kaempferol were found to increase the expression of PPARγ, while proanthocyanidins increased the phosphorylation of STAT6. There are few studies supporting our results on the increased expression of PPARγ by resveratrol and kaempferol [ 55 , 71 , 72 ]. To the best of our knowledge, this is the first time when data have been presented to support proanthocyanidins’ promotion of M2 polarization through STAT6 activation.…”

Effects of Lingonberry (Vaccinium vitis-idaea L.) Supplementation on Hepatic Gene Expression in High-Fat Diet Fed Mice

“…Lingonberry contains rather high amounts of the stilbenoid resveratrol (3,4,5-trihydroxystilbene), mostly as trans-resveratrol or its glycosylated form [25,98,99]. Resveratrol has been reported to have protective effects in inflammation, oxidative stress and glucose intolerance [100][101][102][103][104][105], thus likely contributing to the beneficial effects of lingonberry supplementation found in the present study.…”

Spatial transcriptomics reveals heterogeneity of macrophages in the tumor microenvironment of granulomatous slack skin

“…Rindler et al reported that ZFP36 showed significantly higher expression levels in MF [18], and Tiacci et al found that DUSP1 was upregulated in the Reed-Sternberg (RS) cells of HL [19]. CCL2, CCL13, and CCL26 are factors contributing to M2-type macrophage polarization [20][21][22] and have a significant effect on the recruitment of TAMs into the tumor niche [23][24][25]. It was also shown that KLF2 and NF-κB have similar cellular functions and that KLF2 regulates most of the NF-κB-mediated activities [26].…”