ISSN: EISSN: DOI: PMID: Allergic diseases. animal diseases. basic medicine. biochemical phenomena, metabolism, and nutrition. Catechin - immunology. Cell biology. chemical and pharmacologic phenomena. Curcumin - metabolism. developmental biology.

Environmental changes. Environmental regulations. Environmental stress. Epigallocatechin gallate. Epigenesis, Genetic. food and beverages. Gene expression. Hypersensitivity - immunology. Immune response. Immune system. Immunologic diseases. Inflammation - genetics. Inflammation - immunology.

medical and health sciences. Mucosal immunity. Neoplasms - immunology. Nutrition research. Nutritional Physiological Phenomena. Oxidative Stress. Polyphenols - immunology. Proinflammatory cytokine. Signal Transduction. TNF inhibitors.

Tumor necrosis factor-TNF. Egypt: Hindawi. Academic Search Alumni Edition. Academic Search Premier. Copyright © Sujuan Ding et al. COPYRIGHT Hindawi Limited. 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.

The results presented here demonstrate that human DC stimulated with LPS upregulate both glycolysis and oxidative phosphorylation within hours of activation. Furthermore, a transient increase in the glycolytic reserve and spare respiratory capacity SRC of human DC was observed within 6 h post-LPS stimulation, which was absent at 24 h post-LPS.

Therefore, it can be ascertained that while human DC also display increased glycolytic metabolism after activation, unlike BMDC, they also upregulate oxidative phosphorylation.

This disparity between murine and human DC is likely a result of their differing expression of iNOS, as human monocyte-derived DC do not readily express iNOS; however, some evidence suggests that certain human DC subsets can express iNOS in vivo , therefore the metabolic profile of these DC may differ from what is observed in vitro Interestingly, a recent study by Basit et al.

Thus, it is important to consider that differences in the metabolism of DC may exist in vivo vs. in vitro , between DC subsets, or due to the type of stimulus employed. Further study of human DC under different conditions is required to delineate the impact of these variables on DC immunometabolism.

Consistent with the results presented here, Malinarich et al. have reported that monocyte-derived human DC matured with LPS are more glycolytic than immature DC, and do not downregulate oxidative phosphorylation However, they also observed a reduced glycolytic reserve and SRC in mature compared to immature DC; a finding which, in fact, agrees with these results, as the metabolism of DC was assessed 24 h after maturation with LPS, by which time the increased glycolytic reserve and SRC observed in this study was absent.

Interestingly, Everts et al. also observed an increase in the SRC of BMDC stimulated with LPS for 1 h, which was mediated by enhanced glycolytic flux into the Kreb's cycle This increased flow of pyruvate into the Kreb's cycle was found to produce citrate necessary for de novo fatty acid synthesis in the maturing DC, providing lipids required to expand the endoplasmic reticulum and Golgi membranes in anticipation of increased protein production Therefore, the transient increase in the glycolytic reserve and SRC of LPS-stimulated DC observed in this study may represent an early adaption of maturing DC to their new immunogenic functions, which is downregulated once adequate cellular remodeling has taken place.

Meanwhile, the mature DC continues to display higher basal rates of glycolysis and oxidative phosphorylation to meet its increased energy demands. Thus, this study expands the current understanding of human DC metabolism, and also underscores the importance of accounting for temporal changes when analyzing the metabolism of immune cells.

The results of this study also further support our previous work which described the anti-inflammatory properties of the polyphenols, carnosol and curcumin, in human DC The upregulation of glycolysis by BMDC in response to LPS has been demonstrated to promote their maturation, cytokine production and activation of T cells 10 — Interestingly, DC treated with carnosol or curcumin displayed a reduced basal rate of glycolysis, and failed to upregulate their glycolytic reserve after 6 h of LPS stimulation.

This reduced glycolytic flux was also manifest in the mitochondrial activity of carnosol- and curcumin-treated DC, as both polyphenols inhibited the increased SRC seen in response to LPS. Tolerogenic human DC have been reported to possess a greater capacity for oxidative phosphorylation and fatty acid oxidation, and are less glycolytic than mature DC Therefore, it is possible that the anti-inflammatory effects of carnosol and curcumin in human DC are at least partly mediated by their inhibition of glycolysis, resulting in a diminished glycolytic reserve and SRC and failure to meet the bio-energetic requirements of maturation.

Both carnosol and curcumin have previously been reported to activate AMPK in skeletal muscle and cancer cell lines 34 — In this study, carnosol and curcumin were found to activate AMPK in human DC.

Furthermore, polyphenol-induced activation of AMPK resulted in the inhibition of mTOR activation in LPS-stimulated DC. We also demonstrate that AMPK activation by carnosol and curcumin is required to mediate their immunomodulatory effects in human DC given that pharmacological inhibition of AMPK can reverse the observed reduction of DC maturation by these polyphenols.

In line with our study, Krawczyk et al. previously reported that AMPK signaling antagonizes the maturation of BMDC and inhibits their upregulation of glycolysis in response to LPS 10 , while Carroll et al.

found that AMPK-deficient BMDC display enhanced maturation and pro-inflammatory functions Signaling via AMPK has previously been implicated in the upregulation of HO-1 by certain drugs 26 , 27 , 38 , but there have been no such reports in human immune cells.

Here, AMPK activation was found to upregulate expression of HO-1 in human DC, while inhibition of AMPK attenuated the induction of HO-1 by carnosol and curcumin.

This study is therefore the first to report an association between AMPK signaling and HO-1 expression in human DC, and that the upregulation of HO-1 by carnosol and curcumin is at least partially dependent on their ability to activate AMPK.

Indeed, a number of studies have identified cross-talk between AMPK and Nrf2, the major transcription factor in control of HO-1 expression 26 , 38 — 40 , hence it will be of interest to further explore the AMPK-Nrf2-HO-1 axis in the context of polyphenol-mediated immune modulation.

Interestingly, a number of xenobiotics, including various polyphenols, have been reported to activate AMPK via an increase in the AMP:ATP ratio; this is achieved by inhibition of the mitochondrial electron transport chain complexes Curcumin, in particular, has been shown to inhibit ATP synthase in mitochondrial preparations, thereby limiting ATP production and increasing the ratio of AMP to ATP Given that a number of polyphenols also appear to inhibit ATP synthase or complex I 24 , 43 , it is likely that carnosol acts in a similar fashion.

Therefore, elevation of AMP levels represents a probable mechanism by which carnosol and curcumin activate AMPK in human DC, however, further research is required to confirm this.

In conclusion, our data describes the metabolic changes arising from the activation of human DC, and characterizes a hitherto-unidentified role for the HO-1 system in immunometabolism.

The data presented here supports a model whereby activation of AMPK by carnosol and curcumin leads to the upregulation of HO-1, which mediates the downstream immunomodulatory activity of these polyphenols in human DC Figure 6.

These results are also suggestive that the anti-inflammatory phenotype characteristic of immune cells with higher catabolic metabolism and AMPK signaling may arise from increased expression of HO-1, however future studies in HO-1 deficient cells are required to fully validate this hypothesis.

Although our study supports the use of the polyphenols carnosol and curcumin as potential immunonutrient supplements, translation of these results to a clinical setting requires careful consideration regarding drug formulation and administration.

One of the caveats associated with these polyphenols is their poor solubility in aqueous solutions, which may limit their bioavailability by certain routes of administration. Additionally, polyphenols have been described to undergo metabolic alterations during digestion via the intestinal microbiota, which could alter their metabolic and immunological properties as described here 44 — Efforts made to improve the oral bioavailability of polyphenols such as curcumin, or to utilize alternative routes of administration, have been met with success in pre-clinical studies and clinical trials 47 — It is hoped that future research can determine whether these polyphenols display similar effects on DC immunometabolism and function in an in vivo setting.

Research into the use of polyphenols as clinically relevant immunonutrient supplements has expanded greatly over the last number of years and our data highlighting specific effects on key cells relevant to inflammatory and autoimmune disease provides further evidence attesting to their use as potential immune modulating compounds.

Figure 6. Proposed model of AMPK-dependent modulation of human DC metabolism and immune function by carnosol and curcumin. Carnosol and curcumin are polyphenols which have been shown to inhibit components of the ETC, resulting in reduced ATP production and elevated AMP levels.

AMP activates AMPK, which results in downstream activation of Nrf2. Nrf2 translocates to the nucleus and induces transcription of HO HO-1 and its products can then act as antioxidants to neutralize ROS produced by mitochondrial metabolism, and downregulate DC maturation and pro-inflammatory functions.

Additionally, AMPK or HO-1 may mediate the reduced rate of glycolysis and SRC observed in carnosol- and curcumin-treated DC red dashed arrows. NC, JF, and AD conceptualized and designed experiments.

NC and HF performed experiments. NC, HF, and AD wrote the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This work was funded by the Health Research Board, Ireland Grant No: HRA-POR O'Neill LAJ, Kishton RJ, Rathmell J.

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Biomed Res Int. Mohanty C, Sahoo SK. Curcumin and its topical formulations for wound healing applications. Drug Discov Today. Keywords: polyphenols, immunometabolism, dendritic cells, AMPK, HO-1 heme oxygenase Citation: Campbell NK, Fitzgerald HK, Fletcher JM and Dunne A Plant-Derived Polyphenols Modulate Human Dendritic Cell Metabolism and Immune Function via AMPK-Dependent Induction of Heme Oxygenase Received: 18 December ; Accepted: 11 February ; Published: 01 March Copyright © Campbell, Fitzgerald, Fletcher and Dunne.

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