Plant-Derived Polyphenols Modulate Human Dendritic Cell Metabolism and Immune Function via AMPK-Dependent Induction of Heme Oxygenase-1

Abstract

Polyphenols are important immunonutrients which have been investigated in the context of inflammatory and autoimmune disease due to their significant immunosuppressive properties. However, the mechanism of action of many polyphenols is unclear, particularly in human immune cells. The emerging field of immunometabolism has highlighted the significance of metabolic function in the regulation of immune cell activity, yet the effects of polyphenols on immune cell metabolic signaling and function has not been explored. We have investigated the effects of two plant-derived polyphenols, carnosol and curcumin, on the metabolism of primary human dendritic cells (DC). We report that human DC display an increase in glycolysis and spare respiratory capacity in response to LPS stimulation, which was attenuated by both carnosol and curcumin treatment. The regulation of DC metabolism by these polyphenols appeared to be mediated by their activation of the cellular energy sensor, AMP-activated Protein Kinase (AMPK), which resulted in the inhibition of mTOR signaling in LPS-stimulated DC. Previously we have reported that both carnosol and curcumin can regulate the maturation and function of human DC through upregulation of the immunomodulatory enzyme, Heme Oxygenase-1 (HO-1). Here we also demonstrate that the induction of HO-1 by polyphenols in human DC is dependent on their activation of AMPK. Moreover, pharmacological inhibition of AMPK was found to reverse the observed reduction of DC maturation by carnosol and curcumin. This study therefore describes a novel relationship between metabolic signaling via AMPK and HO-1 induction by carnosol and curcumin in human DC, and characterizes the effects of these polyphenols on DC immunometabolism for the first time. These results expand our understanding of the mechanism of action of carnosol and curcumin in human immune cells, and suggest that polyphenol supplementation may be useful to regulate the metabolism and function of immune cells in inflammatory and metabolic disease.

Healthy Effects of Plant Polyphenols: Molecular Mechanisms

“…AMPK is also activated by phosphorylation of two regulatory subunits by several kinases, including the energy stress-sensitive LKB [214], PKA [215], and the CAMM-GSK3β axis [216] as well as by other factors, including PPARα, associated with lipid metabolism [217] and hypoxia [218]. AMPK triggers the expression of antioxidant enzymes, notably HO-1, through Nrf2 [219,220], and improves the control of proteostasis [221] through direct activation of FOXO3 [222] and ULK1 [223] and by indirect activation of TFEB [224]; AMPK activation also improves both glucose metabolism by favoring GLUT4 translocation to the membrane [225,226] and lipid metabolism through PPARα. Finally, AMPK activation results in inhibition of mTORC following both direct phosphorylation and phosphorylation of the mTORC controller TSC [227].…”

“…Molecular chaperones, in particular Some of the mechanisms reported above are also triggered by plant polyphenols. In particular, it has been reported that OLE increases intracellular free Ca 2+ levels from the internal stores with ensuing activation of the calcium-CAMMK-GSK3β pathway [216] and reduces oxidative stress through AMPK-dependent activation of HO-1 [219], whereas in aged rats, resveratrol protects against high-fat diet-induced muscle atrophy counteracting PKA/LKB1/AMPK-mediated mitochondrial dysfunction and oxidative stress [215]. Finally, plant polyphenols including quercetin, resveratrol, and catechins activate SIRT1, a class-3 histone deacetylase involved in several aging-related pathologies, including neurodegeneration [228].…”

Activation of the C-Type Lectin MGL by Terminal GalNAc Ligands Reduces the Glycolytic Activity of Human Dendritic Cells

“…During the last decades, it became clear that changes in the immunological function of APCs are strongly associated with metabolic alterations important to adapt to new cellular requirements (21)(22)(23)(24)(25)(26). In resting DCs, fatty acid oxidation and low levels of glycolysis are the main drivers of mitochondrial respiration, and products of glycolysis pathway are fully catabolized during respiration.…”

“…In resting DCs, fatty acid oxidation and low levels of glycolysis are the main drivers of mitochondrial respiration, and products of glycolysis pathway are fully catabolized during respiration. Upon TLR activation or under hypoxic conditions, the metabolic activity of DCs changes toward increased glycolytic activity, while mitochondrial respiration is unaffected or even decreases (21)(22)(23)26). The metabolic shift upon TLR activation seems to support the increased demand of de novo fatty acid and protein synthesis required for ER and Golgi expansion, optimal antigen presentation, and protein (cytokine) secretion (23).…”

“…The metabolic shift upon TLR activation seems to support the increased demand of de novo fatty acid and protein synthesis required for ER and Golgi expansion, optimal antigen presentation, and protein (cytokine) secretion (23). Moreover, the augmentation of glycolytic activity is essential for proper DC activation, as blocking glycolysis strongly inhibits DC cytokine production, expression of co-stimulatory markers and the induction of T cell proliferation (21)(22)(23)26). However, compared to unstimulated and TLR-stimulated DCs, tolerogenic DCs display an increased mitochondrial activity, while the glycolytic rate of LPS-stimulated tolerogenic DCs was completely abolished (27).…”