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

Abstract

Macrophages are pleiotropic immune cells whose phenotype can polarize towards the pro-inflammatory M1 or anti-inflammatory M2 direction as a response to environmental changes. In obesity, the number of macrophages in adipose tissue is enhanced, and they shift towards the M1 phenotype. Activated M1 macrophages secrete pro-inflammatory cytokines and adipokines involved in the development of systemic low-grade inflammation, complicating obesity. Polyphenols are widely found in the vegetable kingdom and have anti-inflammatory properties. We and others have recently found that lingonberry (Vaccinium vitis-idaea L.) supplementation is able to prevent the development of low-grade inflammation and its metabolic consequences in experimentally induced obesity. In the present study, we investigated the effects of twelve phenolic compounds known to be present in lingonberry (resveratrol, piceid, quercetin, kaempferol, proanthocyanidins, delphinidin, cyanidin, benzoic acid, cinnamic acid, coumaric acid, caffeic acid, and ferulic acid) on macrophage polarization, which is a meaningful mechanism determining the low-grade inflammation in obesity. Mouse J774 and human U937 macrophages and commercially available phenolic compounds were used in the studies. Three of the twelve compounds investigated showed an effect on macrophage polarization. Resveratrol, kaempferol, and proanthocyanidins enhanced anti-inflammatory M2-type activation, evidenced as increased expression of Arg-1 and MRC-1 in murine macrophages and CCL-17 and MRC-1 in human macrophages. Resveratrol and kaempferol also inhibited pro-inflammatory M1-type activation, shown as decreased expression of IL-6, NO, and MCP-1 in murine macrophages and TNF-α and IL-6 in human macrophages. In the further mechanistic studies, the effects of the three active compounds were investigated on two transcription factors important in M2 activation, namely on PPARγ and STAT6. Resveratrol and kaempferol were found to enhance PPARγ expression, while proanthocyanidins increased the phosphorylation of STAT6. The results suggest proanthocyanidins, resveratrol, and kaempferol as active constituents that may be responsible for the positive anti-inflammatory effects of lingonberry supplementation in obesity models. These data also extend the previous knowledge on the anti-inflammatory effects of lingonberry and encourage further studies to support the use of lingonberry and lingonberry-based products as a part of a healthy diet.

Polyphenols: immunonutrients tipping the balance of immunometabolism in chronic diseases

“…Neutrophils chemotaxis is also apparently impacted by curcumin's ability to suppress PI3K activity and Akt phosphorylation (271). On another hand, evidence suggests that PCs present in the small fruit lingonberry promote macrophage polarization to an anti-inflammatory (M2) phenotype by upregulating PPARg and STAT6 phosphorylation in experimentally induced obesity (272). Quercetin has also shown to abolish NLRP3 inflammasome activation in macrophages by upregulating Akt signaling, reducing insulin resistance in mice with particulate matter-induced metabolic disorder (273).…”

Anthocyanins as Immunomodulatory Dietary Supplements: A Nutraceutical Perspective and Micro-/Nano-Strategies for Enhanced Bioavailability

“…Proanthocyanidins found in lingonberry enhance anti-inflammatory macrophage (M2) activation and inhibit proinflammatory M1 activation in mouse and human macrophages. They also promote STAT6 phosphorylation, indicating their potential for anti-inflammatory effects and suggesting that they may provide a beneficial addition to a healthy diet [85]. D3G has been found to stimulate mesenchymal stem cell (MSC) proliferation and enhance the production of anti-inflammatory cytokines, such as IL-10 and TGF-β while reducing NF-κB expression.…”