Phenolic Compounds of Red Wine <i>Aglianico del Vulture</i> Modulate the Functional Activity of Macrophages via Inhibition of <i>NF-κB</i> and the Citrate Pathway

Abstract

Phenolic compounds of red wine powder (RWP) extracted from the Italian red wine <i>Aglianico del Vulture</i> have been investigated for the potential immunomodulatory and anti-inflammatory capacity on human macrophages. These compounds reduce the secretion of IL-1<i>β</i>, IL-6, and TNF-<i>α</i> proinflammatory cytokines and increase the release of IL-10 anti-inflammatory cytokine induced by lipopolysaccharide (LPS). In addition, RWP restores Annexin A1 levels, thus involving activation of proresolutive pathways. Noteworthy, RWP lowers NF-<i>κ</i>B protein levels, promoter activity, and nuclear translocation. As a consequence of NF-<i>κ</i>B inhibition, reduced promoter activities of <i>SLC25A1</i>-encoding the mitochondrial citrate carrier (CIC)-and <i>ATP citrate lyase</i> (<i>ACLY</i>) metabolic genes have been observed. CIC, ACLY, and citrate are components of the citrate pathway: in LPS-activated macrophages, the mitochondrial citrate is exported by CIC into the cytosol where it is cleaved by ACLY in oxaloacetate and acetyl-CoA, precursors for ROS, NO^·, and PGE₂ inflammatory mediators. We identify the citrate pathway as a RWP target in carrying out its anti-inflammatory activity since RWP reduces CIC and ACLY protein levels, ACLY enzymatic activity, the cytosolic citrate concentration, and in turn ROS, NO^·, PGE₂, and histone acetylation levels. Overall findings suggest that RWP potentially restores macrophage homeostasis by suppressing inflammatory pathways and activating proresolutive processes.