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.
Highlights
The emerging field of immunometabolism has highlighted the significance of metabolic function in the regulation of immune cell activity
Unlike bone marrow derived DC (BMDC), human dendritic cells (DC) stimulated with LPS upregulate both glycolysis and oxidative phosphorylation within hours of activation, the upregulation of glycolytic metabolism and spare respiratory capacity in maturing DC is inhibited by both carnosol and curcumin
The current understanding of DC metabolism is largely based on murine studies, which have demonstrated that BMDC strongly upregulate aerobic glycolysis and downregulate oxidative phosphorylation upon TLR stimulation [10,11,12]
Summary
The emerging field of immunometabolism has highlighted the significance of metabolic function in the regulation of immune cell activity. Anabolic and catabolic metabolism have become associated with pro- and anti-inflammatory immune responses, respectively [1]. Modulation of specific metabolic pathways in immune cells may represent a novel strategy to downregulate inflammation and promote the generation of anti-inflammatory immune responses. Many polyphenols have been reported to exhibit significant anti-inflammatory activity and hold potential as immunonutrient supplements to treat inflammatory and autoimmune disease [2,3,4,5,6,7,8]. The mechanism by which polyphenols regulate the immune response is unclear, and the relationship between immunonutrients and metabolism has been under-explored
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