Resveratrol Potentiates BCG-induced Trained Immunity in Human Monocytes

Abstract Resveratrol is a natural polyphenol derived from plants such as grapes and berries. In addition to its role in plants during injury and infection, various cardioprotective, neuroprotective, and longevity-promoting effects were reported in diverse model organisms. The primary target of resveratrol is the deacetylase Sirtuin 1, which regulates many immunological processes, including BCG-induced trained immunity response in humans. We, therefore, investigated the effect of resveratrol on trained immunity induced by BCG, β-glucan (BG), Candida albicans, or oxidized low-density lipoprotein (oxLDL). Using an in vitro model of trained immunity with monocytes obtained from healthy donors, we demonstrate that resveratrol amplifies BCG-induced trained immunity regarding IL-6 and TNFα production after a secondary challenge. Although resveratrol did not improve and even limited glycolysis, oxidative phosphorylation, and reactive oxygen species production, it enhanced the permissive epigenetic mark H3K27Ac on IL-6 and TNFα promoters. In contrast to BCG-induced trained immunity, resveratrol potently inhibited training induced by BG, C. albicans, oxLDL, and muramyl dipeptide, a peptidoglycan component of BCG. Resveratrol's unique boosting effect on BCG training depended on BCG being alive and metabolically active. These results suggest that resveratrol might amplify the effects of BCG vaccination, which should be mechanistically characterized further. In addition, resveratrol could alleviate oxLDL-induced training of innate immune cells in atherosclerosis, and in vivo studies of trained immunity combined with resveratrol are warranted to explore these therapeutic possibilities.