Flavonoid-mediated immunomodulation of human macrophages involves key metabolites and metabolic pathways


The ability of flavonoids to attenuate macrophage pro-inflammatory activity and to promote macrophage-mediated resolution of inflammation is still poorly understood at the biochemical level. In this study, we have employed NMR metabolomics to assess how therapeutically promising flavonoids (quercetin, naringenin and naringin) affect the metabolism of human macrophages, with a view to better understand their biological targets and activity. In vitro-cultured human macrophages were polarized to the pro-inflammatory M1 phenotype, through incubation with LPS + IFN-gamma, and subsequently treated with each flavonoid. The metabolic signatures of pro-inflammatory polarization and of flavonoid incubations were then characterized and compared. The results showed that all flavonoids modulated the cells endometabolome with the strongest impact being observed for quercetin. Many of the flavonoid-induced metabolic variations were in the opposite sense to those elicited by pro-inflammatory stimulation. In particular, the metabolic processes proposed to reflect flavonoid-mediated immunomodulation of macrophages included the downregulation of glycolytic activity, observed for all flavonoids, anti-inflammatory reprogramming of the TCA cycle (mainly quercetin), increased antioxidant protection (quercetin), osmoregulation (naringin), and membrane modification (naringenin). This work revealed key metabolites and metabolic pathways involved in macrophage responses to quercetin, naringenin and naringin, providing novel insights into their immunomodulatory activity.



subject category

Science & Technology - Other Topics


Mendes, LF; Gaspar, VM; Onde, TAC; Mano, JF; Duarte, IF

our authors


This work was developed within the scope of the project CICECO - Aveiro Institute of Materials, FCT Ref. UID/CTM/50011/2019, supported by national funds through the FCT/MCTES. V.M.G. acknowledges his research contract under the project PANGEIA (PTDC/BTM-SAL/30503/2017) supported by POCI, in the component FEDER, and by national funds (OE) through FCT/MCTES. L. F. M. acknowledges FCT for the PhD grant PD/BD/147220/2019. The authors are also thankful to Bruker BioSpin (Rheinstetten, Germany), for access to software and spectral databases, and to the Portuguese Nuclear Magnetic Resonance Network (PTNMR), supported with FCT funds.

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