Research Article Phenolic Compounds of Red Wine Aglianico del Vulture Modulate the Functional Activity of Macrophages via Inhibition of NF-κB and the Citrate Pathway Anna Santarsiero , 1 Paolo Convertini , 1 Antonio Vassallo , 1 Valentina Santoro, 2 Simona Todisco , 1 Dominga Iacobazzi, 3 Yvonne Fondufe-Mittendorf , 4 Giuseppe Martelli , 1 Marcos R. de Oliveira , 5 Rosangela Montanaro, 1 Vincenzo Brancaleone , 1 Johannes Stöckl , 6 and Vittoria Infantino 1 1 Department of Science, University of Basilicata, Viale dell’Ateneo Lucano 10, 85100 Potenza, Italy 2 Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Salerno, Italy 3 Bristol Heart Institute, Bristol Medical School, University of Bristol, Bristol BS2 8HW, UK 4 Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA 5 Departamento de Bioquímica Rua Ramiro Barcelos, Universidade Federal do Rio Grande do Sul (UFRGS), 2600 Anexo Santa Cecília, Porto Alegre, RS, Brazil 6 Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria Correspondence should be addressed to Vittoria Infantino; vittoria.infantino@unibas.it Received 25 February 2021; Revised 30 April 2021; Accepted 8 May 2021; Published 26 May 2021 Academic Editor: Cecile Jacovetti Copyright © 2021 Anna Santarsiero et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Phenolic compounds of red wine powder (RWP) extracted from the Italian red wine Aglianico del Vulture have been investigated for the potential immunomodulatory and anti-inflammatory capacity on human macrophages. These compounds reduce the secretion of IL-1β, IL-6, and TNF-α 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-κB protein levels, promoter activity, and nuclear translocation. As a consequence of NF-κB inhibition, reduced promoter activities of SLC25A1—encoding the mitochondrial citrate carrier (CIC)—and ATP citrate lyase (ACLY) 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 PGE 2 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 ⋅ , PGE 2 , and histone acetylation levels. Overall findings suggest that RWP potentially restores macrophage homeostasis by suppressing inflammatory pathways and activating proresolutive processes. 1. Introduction Immunomodulators are heterogeneous compounds capable to interact with the immune system to upregulate or down- regulate specific biological aspects of the host response. For example, phenolic compounds scavenge free radicals, pre- vent lipid peroxidation, modulate inflammatory pathway, and block the secretion of proinflammatory cytokines [1]. Resveratrol counteracts the production of proinflammatory cytokines, while anthocyanidins downregulate the expression of cyclooxygenase 2 (COX2) in macrophages exposed to lipo- polysaccharide (LPS) [2]. Interestingly, resveratrol is able to Hindawi Oxidative Medicine and Cellular Longevity Volume 2021, Article ID 5533793, 15 pages https://doi.org/10.1155/2021/5533793