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Mini review

The interplay between central metabolism and innate immune responses Shih-Chin Cheng, Leo A.B. Joosten, Mihai G. Netea * Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands

A R T I C L E I N F O

A B S T R A C T

Article history: Available online xxx

A growing body of recent studies bring into light an important cross-talk between immune response and metabolism not only at the level of the organism as a whole, but also at the level of the individual cells. Cellular bioenergetics functions not only as a power plant to fuel up the cells, but the intermediate metabolites are shown to play an important role to modulate cellular responses. It is especially the pathways through which a cell metabolizes glucose that have been recently shown to influence both innate and adaptive immune responses, with oxidative phosphorylation used by resting or tolerant cells, while aerobic glycolysis (also termed ‘Warburg effect’) fueling activated cells. In this review we will address how the center metabolism shifts upon activation in the innate immune cells and how the intermediate metabolites modulate the function of immune cells. ß 2014 Elsevier Ltd. All rights reserved.

Keywords: Immunometabolism Cytokines Glycolysis Oxidative phosphorylation Innate immunity

1. Introduction Cellular metabolism is a complex and delicate process that is regulated by different environmental cues, acting at the level of multiple layers of biochemical regulation. The importance of the central metabolism has been mostly appreciated from its role to maintain homeostasis and bioenergetics balance of an individual. However, recent evidence argues for an important cross-talk between immune system and metabolic regulation, bringing into the spotlight an unexpected layer of metabolic regulation of immune responses. In this review we will integrate the recent literature to present a systematic picture on the mechanisms through which central metabolism regulates the innate immune responses to the intruding pathogens. Once a pathogenic microorganism breaches through the skin or mucosal barriers, it is immediately sensed by the innate immune cells such as Langerhans cell (dendritic cell) or tissue macrophages through germ-line encoded pattern recognition receptors (PRRs) including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLSs) or RigI-helicases. Subsequently, the activation of PRRs leads to either immediate phagocytosis of the pathogens or the secretion of soluble mediators such as pro-

* Corresponding author at: Department of Medicine (463), Radboud University Medical Centre, Geert Grooteplein Zuid 8, 6525 GA Nijmegen, The Netherlands. Tel.: +31 24 3618819; fax: +31 24 3541734. E-mail address: [email protected] (M.G. Netea).

inflammatory cytokines or chemokines for the further recruitment of the effector cells to the site of infection. During this activation process, the metabolic state of innate immune cells has to switch rapidly in order to meet the heightened energy need from the basal resting state to a hyper active stage. In the basal resting state, the cells use mainly the oxidative phosphorylation (OXPHOS) to generate ATP, process that takes place in the mitochondria through tricarboxylic acid cycle (TCA cycle) as the energy source, and accompanied by consumption of oxygen. However, upon immune activation the central metabolism shifts from OXPHOS to aerobic glycolysis to generate cellular ATP. Although glycolysis produces less ATP per glucose molecule compare to TCA cycle (2 versus 32 ATPs), less enzymatic steps are involved that can be easier enhanced, and therefore more ATP could be produced in a short time as compared to OXPHOS. This switch to aerobic glycolysis is called ‘Warburg effect’, after the first description of this process by Otto Warburg as a characteristic of cancer cell metabolism [1]. However, recent studies have demonstrated that the aerobic glycolysis is an important feature of the active immune metabolic signatures as well. 2. Metabolic shifts in innate immune cells after pathogen recognition 2.1. Oxidative phosphorylation Oxidative phosphorylation (OXPHOS) takes place in the mitochondria and generates ATP through the electron transport

http://dx.doi.org/10.1016/j.cytogfr.2014.06.008 1359-6101/ß 2014 Elsevier Ltd. All rights reserved.

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chain. OXPHOS is the preferred bioenergetics pathway for the immune cells in their resting state. TCA cycle intermediate succinate and the metabolite NADH play major roles in the redox reaction for the production of ATP in the OXPHOS. Hence TCA cycle serves as a central hub in the mitochondrial OXPHOS. The major substrate of TCA cycle is acetyl-CoA, which could flux into the mitochondria through different pathways such as glycolysis, fatty acid oxidation, amino acids (via ketone bodies), depending on the substrate availability. The role of OXPHOS during infections has been also shown by studies assessing the mitochondrial function in sepsis patients, that revealed that although the mitochondrial mass and proteins synthesis are not altered, the enzymatic activity of mitochondrial complex I, III and IV and oxygen consumption were significantly inhibited in sepsis. In addition, incubation of PBMCs from healthy donors with plasma from sepsis patients also reduces the oxygen consumption of healthy mitochondria [2], suggesting a plasma factor in the septic serum could modulate the mitochondrial oxygen consumption. 2.2. Aerobic glycolysis (Warburg effect) In contrast to naı¨ve or resting cells, immune activation leads to a shift of central metabolism of immune cells toward glycolysis. Aerobic glycolysis, also called ‘‘Warburg effect’’, was first described by Otto Warburg in 1923 who described that tumor cells produced lactate from glucose under normoxic condition [1]. The reason for this shift is the rapid growth of the tumor, with aerobic glycolysis serving on the one hand as a rapid source of ATP, and on the other hand as a way to generate the excess intermediate metabolites needed for the pentose phosphate pathway to synthesize nucleotides, the building blocks of tumor cell proliferation. Similarly, aerobic glycolysis is triggered in immune cells upon stimulation, resulting in a shift of the core metabolic pathways away from oxidative phosphorylation [3]. The first hints for an important role of metabolic shifts for immune cell activation were provided by the studies on the metabolic regulation in T cells [4–6]. The active T cells, as compared to quiescent naı¨ve T cells, have greater bioenergetic and biosynthetic needs to cope with the massive clonal expansion and its active functionality. To meet these needs, the metabolic rewiring shifts the core metabolism of T-cells from mainly mitochondrial oxidative phosphorylation (OXPHOS) at the resting stage, to aerobic glycolysis upon activation. The CD28/PI3K/Akt pathway has been suggested to be responsible for the increased glycolytic activity in T cell activation [7]. Upon TCR and CD28 signaling in the active T cells, stimulation of PI3K and Akt signaling pathways further activate mTOR (mammalian target of rapamycin), which plays a central role in cell proliferation and protein translation [8]. AMPK (AMP-activated protein kinase) and mTOR are two evolutionary conserved signaling molecules modulating the sensing of cellular metabolic state and directing the cell functional fate [9]. mTOR forms two distinct multi-protein complexes: mTORC1 (mTOR complex 1) and mTORC2 (mTOR complex 2). mTORC1 is regarded as a master regulator of cell growth and metabolism [10]. AMPK functions as barometer of cellular energy level. When cellular ATP level is low, AMPK is activated and phosphorylates TSC2, subsequently inhibiting the mTORC1 activity [11]. mTOR is also demonstrated to play a pivotal role in integrating the environment cues and determine the functional fate of T cell [6]. Growth factor signals upstream of mTORC1 converges on TSC1/TSC2 degradation through the PI3K/Akt pathway [12]. AMPKa-deficient CD8+ T cells have higher glycolytic activity and produce more proinflammatory cytokines in vitro, and AMPK is dispensable for T cell proliferation and the cytotoxic

function of CD8+ T cell in vivo [13]. AMPK and mTOR therefore play antagonistic roles in regulating the function of T cells. HIF-1a (hypoxia inducible transcription factor-1) is the key transcription factor responsible for the transcription of enzymes involved in glycolysis. It is a heterodimeric helix-loop-helix transcription factor composed of a and b subunits and is known to regulate the expression of genes involved in a plethora of host stress responses triggered by hypoxia. HIF-1a is implicated in most aspects of hypoxia-induced gene expression and it is essential for hypoxia-induced increases in glycolysis and angiogenesis in tumor cells, as well as normal tissues [14]. HIF-1a is hydroxylated by HIF prolyl-hydroxylases in normoxia and the hydroxylated HIF-1a is subsequently recognized and ubiquitinized by the VHL E3 ubiquitin ligase. The ubiquitinated HIF-1a is degraded then by the proteasome [15]. The prolyl-hydroxylase is inhibited by hypoxia and leads to HIF-1a stabilization and activation of the downstream pathways including glycolysis. In addition to oxygen tension, many additional endogenous or exogenous factors have been shown to stabilize HIF-1a in the myeloid innate immune cells. Endogenous factors such as growth factors can stabilize HIF-1a via PI3K/Akt pathway, which in addition to a hypoxic environment at the tissue level can also upregulate the HIF-1a regulated genes in the immune cells [16]. A number of exogenous ligands such as LPS and other TLR ligands could induce HIF-1a stabilization in the myeloid innate immune cells, including DCs [17], monocytes [18] and macrophages [19]. The stabilization of HIF-1a is an important step for the immune cells, insuring the up-regulation of the glycolysis and the energy needs of the activated leukocytes. 2.3. Dendritic cells Dendritic cells (together with tissue macrophages) are the sentinels of the immune system at the tissue level. DCs are a highly heterogeneous group of cells, consisting of different cell types depending on the specific tissue locations [20]. DCs function as a bridge between innate and adaptive immunity by sensing the intruder and instructing the adaptive immunity through antigen presentation. Resting DCs are mainly fueled by oxidative phosphorylation in the mitochondria via b-oxidation of lipids. Upon activation by TLR agonists, a profound metabolic transition to aerobic glycolysis occurs in DCs. It has been demonstrated that the shift toward aerobic glycolysis induced in DCs by TLR stimulation is driven by the PI3K/Akt pathway. In turn, this process is antagonized by AMPK [17] (Fig. 1). The upregulated aerobic glycolysis insures the energy need of DC activation, and supports the de novo synthesis of fatty acids for the expansion of the endoplasmic reticulum and Golgi for the production and secretion of the effector proteins such as cytokines [21]. The commitment to glycolysis was also demonstrated to sustain the survival of the activated DCs by down-regulating the TCA cycle in the mitochondria [22]. 2.4. Monocytes and macrophages Monocytes and macrophages are both important myeloid innate immune cells, standing at the first line of defense against pathogens. Monocytes circulate in the bloodstream where a constantly high oxygen tension is present, while macrophages locate in the tissue or at the site of inflammation where oxygen tension is generally considerably lower. It is therefore not surprisingly to find that macrophages possess higher HIF-1a activity. HIF-1a activation is associated with macrophages differentiation [23], while macrophage-colony stimulating factor (M-CSF) as well as hypoxia are demonstrated to enhance monocyte survival by increasing glycolysis pathway [24], presumably via

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Fig. 1. Central metabolism shifts upon activation. Innate immune cells, such as dendritic cells and macrophages, use mitochondrial oxidative phosphorylation (OXHPOS) as the main metabolic pathway to generate ATP. Upon activation, the glycolysis is up-regulated under the control of Akt/mTOR/HIF1a pathway and the center cellular metabolism shifts from OXPHOS to aerobic glycolysis, a process also called ‘Warburg effect’, to meet the increase energy demand.

PI3K/Akt/mTOR pathway [25]. Similar to DCs, upon stimulation with TLR agonists, both monocytes and macrophages shift the central metabolic pathways of glucose consumption from oxidative phosphorylation to aerobic glycolysis (Fig. 1). Macrophages are highly plastic and heterogeneous cells and they are functional divided into two distinct activation states: the classical activated M1 macrophages and alternative activated M2 macrophage. M1 macrophages are characterized by a proinflammatory phenotype producing more proinflammatory cytokines, ROS and iNOS upon stimulation, while M2 macrophages are regarded to be more anti-inflammatory, promoting tissue remodeling, tumor progression, and dampening inflammation [26]. Interestingly, these different functional characteristics of M1 and M2 are associated with different metabolic states [27]. M1 macrophages possess higher glycolysis activity, which enables them to respond and cope with the stimulation in a prompt manner, while M2 macrophages use oxidative glucose metabolism as main metabolic pathway to provide a sustained source of energy for tissue remodeling and repair [28]. The elevated glycolytic metabolic profile of M1 is associated with their enhanced capacity of producing proinflammatory cytokines. GLUT1 (glucose transporter 1) is the primary rate-limiting transporter of glucose and it is highly expressed in M1 macrophages. RAW264.7 macrophages that overexpress GLUT1 have a more proinflammatory phenotype and possess elevated glucose uptake and metabolism, increased pentose phosphate pathway, and reduced cellular oxygen consumption [29]. In contrast, the IL-4 activated M2 macrophages show a significant increased b-oxidation, which is in turn suppressed in M1 macrophages [28]. In line with this observation, only proinflammatory stimuli, but not IL-4, increase glycolysis capacity in macrophages [30]. This suggests that the type of stimulus not only defines the functional fate of the macrophage differentiation, but also the metabolic pathways used by the cell. In line with this hypothesis, by comparing the bioenergetics status between M1 and M2 macrophages, M2 is demonstrated to have significant higher reserved respiratory capacity due to the increased mitochondrial content [31]. In conclusion, these data demonstrate that central metabolism of myeloid cells in different activation states is different, with OXPHOS mainly used by resting cells or alternatively activated M2,

while aerobic glycolysis is the main energy source in activated myeloid cells and inflammatory M1 macrophages. An important question arises regarding the consequences of this metabolic rewiring, and the mechanisms through which changes in the metabolism influence the functional state of innate immune cells. 3. Metabolism and epigenetic changes As discussed above, the innate immune cells respond promptly to outside stimulation, and the intracellular metabolism is rewired accordingly. In turn, the differential flux of the metabolic intermediates serve as co-factors or substrates of the chromatin-modifying enzyme and influence the DNA transcription at the epigenetic level [32]. Epigenetic modifications of the DNA structure take place either directly at the cytosine residues of DNA via methylation, or indirectly through histone modification via methylation, acetylation, phosphorylation, SUMOylation, etc. Different histone modifications are associated with either gene activation or silencing. Therefore, understanding how metabolic flux leads to differential epigenetic changes will enable us to further understand how innate immune system is modulated. One of the best-characterized examples of a metabolic shift leading to long-term immunological consequences is the LPSinduced tolerance. In the acute phase upon LPS stimulation, the cellular metabolism shifts to aerobic glycolysis through the stabilization of HIF-1a and up-regulation of glycolysis-related protein expression [33]. However, after this acute phase of activation, stimulated monocytes or macrophages enter into a late adaptation state characterized by hypo-responsiveness to subsequent stimulation; this immunosuppression phenotype is known as endotoxin tolerance. During this phase, tolerant cells use fatty acid oxidation as the bioenergetics source, and histone deacetylation by the sirtuin family of enzymes has been reported to modulate it through epigenetic regulation [34,35]. Sirtuins use NAD+ as a co-factor for their deacetylase activity. It has been demonstrated that upon stimulation with LPS, the expression of nicotinamide phosphoribosyltransferase (Nampt), the rate-limiting enzyme for endogenous production of NAD+, is increased in monocytes. The function of this increase is most likely to insure the limitation of prolonged inflammatory stimulation, by

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Fig. 2. Epigenetic modification by intermediate metabolites. The fluxes of the intracellular metabolites together with chromatin modifying enzyme modulate chromatin structure and influence target gene expression. For example, upon LPS stimulation the [NAD+] increases due to the upregulation of Nampt expression. The elevated NAD+ in turn activates the Sirtuin family of proteins, which function to remove histone acetylation and results in differential gene regulation. The availability of acetyl-CoA also influences the acetylation level of the target protein and modulates corresponding gene expression.

dampening the elevated glycolysis metabolism by SIRT6, an important inhibitor of the glycolysis in tolerant THP1 monocytic cell line [36]. Glycolysis capacity is increased in SIRT6-knockdown THP1 cells, while SIRT1 knockdown does not influence glycolysis but decrease fatty acid oxidation [36]. In the late adaptation stage, the sustained release of NAD+ serves as cofactor of SIRT1, which accumulates at the promoter region of TNFa to form a repressor complex with RelB, rendering monocytes tolerant [37]. In addition to sirtuins, H3K9 (Lysine 9 residue of histone 3) methylation is also suggested to be responsible for the recruitment of heterochromatin protein HP1 for the silencing of TNF production in LPS-induced tolerance in monocyte [38]. Systemic comparison of differential histone modifications between naı¨ve and LPS tolerant cells revealed two different gene groups modulated in the LPS-tolerant macrophages, namely tolerizable genes, such as proinflammatory mediators, and nontolerizable genes, such as antimicrobial effectors [39]. Histone acetylation serves as a positive mark for transcriptional active chromatin. By assessing histone acetylation, promoter regions of genes in the no-tolerizable category are more acetylated than that in the tolerizable genes, suggesting that histone acetylation could modulate the differential gene expression in LPS tolerance at the epigenetic level [39]. These data show that the changed metabolic milieu of the cell induced by immune activation leads to long-term epigenetic modifications, resulting in reprogramming of the functional profile of the cell (Fig. 2). 4. Metabolites as signaling molecules In addition to the dramatic shift of the metabolic pathway upon activation in the immune cells, intermediate metabolites are also released outside the cell and recent studies have shown that they modulate the inflammation process, either directly or indirectly (Fig. 3). In the following section we will discuss possible signaling and modulatory role of several of these metabolites.

4.1. Citrate Citrate is an important metabolic intermediate of the TCA cycle. It is synthesized from acetyl-CoA and oxaloacetate by citrate synthase in the mitochondria. The intracellular citrate level plays a key role in regulating energy production and multiple metabolic pathways, with high level of citrate exerting a negative feedback to inhibit both glycolysis and TCA cycle, while stimulating gluconeogenesis and lipid synthesis [40]. Mitochondrial citrate is transported into cytosol via citrate carrier (CIC) [41]. Upon LPS stimulation, while macrophages rapidly shift from oxidative phosphorylation to aerobic glycolysis [3], citrate is withdrawn from the TCA cycle and exported through CIC into the cytosol. The cytosolic citrate is then cleaved by ACYL into oxaloacetate and acetyl-CoA. Oxaloacetate is coupled to the production of NADPH through the enzymatic function of malate dehydrogenase and malic enzyme. The NADPH can be used to produce reactive oxygen species (ROS) and nitric oxide (NO) by NADPH oxidase and inducible NO synthase, respectively. On the other hand, acetyl-CoA serves as the building block of lipid synthesis, and in addition it is also coupled to arachidonic acid synthesis for the production of prostaglandins. By inhibiting of CIC function with either the chemical inhibitor BTA (1,2,3-benzentricarboxylic acid) or siRNA, a clear reduction of LPS-induced ROS, NO and prostaglandins was observed in macrophages [42]. 4.2. Succinate Succinate is another important TCA intermediate that is associated with the inflammation process [43]. Upon LPS stimulation, the intracellular succinate level is accumulated through both glutamine-dependent anerplerosis and the GABAshunt pathway [33]. The elevated succinate in turn stabilizes HIF-1a, leading to glycolysis-related gene expression and also to the specific IL1B transcription [33]. In addition to its role of HIF-1a stabilization, succinate also signals directly through

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Fig. 3. Schematic illustration of how intermediates metabolites modulate the immune response. Succinate is recognized by succinate receptor (SUCNR1) and cross-talk with TLR signaling to modulate cytokine production or stabilize the HIF1a and mediate IL-1b transcription indirectly. NAD+ could modulate epigenetic status of chromatin via the function of Sirtuins. Glutamine level is increased upon LPS stimulation and could serve as precursor of succinate or through amino acid metabolism and coupled to NADPH production. Citrate could be transported from mitochondria into cytosol and coupled to the production of ROS, NO or arachidonic acid. EPA interferes the binding between LPS and TLR4 and down-regulates LPS-induced proinflammatory cytokine production.

succinate receptor (SUCNR1, originally called GPCR91) [44]. SUCNR1 triggers intracellular calcium mobilization and acts synergistically with TLR agonists for production of inflammatory cytokine in dendritic cells [45]. Succinate also functions as chemoattractant by inducing dendritic cell migration in vitro, and SUCNR-1 deficient mice show less Langerhans cells migration from skin to draining lymph nodes [45]. These data suggest a direct signaling role of succinate through SUCNR1. An indirect role of succinate has also been suggested via posttranslational modification. The elevated intracellular succinate is associated with increased protein succinylation [33]. Although the specific role of succinylation is not yet clear, one might speculate the role of succinylation would be similar to other posttranslational modifications of proteins. 4.3. Glutamine Glutamine is known to support optimal cytokine production in macrophages, and high serum glutamine concentration is beneficial to maintain an effective immune function in patients undergoing surgery, radiation treatment or bone marrow transplantation [46,47]. However, the mechanism explaining how glutamine supplementation contributes to a better protection is not well known. Recently, Tannahill et al. [48] demonstrated that LPS induces succinate, a TCA cycle intermediate, which in turn stabilizes the hypoxia-inducible factor-1a (HIF-1a) and promotes the expression of IL-1b, as discussed above. The accumulating succinate might be derived from glutamine-dependent anerplerosis. Modulation of cytokine production through enhanced intracellular succinate concentrations partly explains how supplementation of glutamine renders better immune protection. In addition, glutamine is not only used for energy production, but also for generation of substrate for the production of NADPH [49]. Glutamine also serves as the precursor to produce NO through the enzymatic activity of glutaminase and transaminase, and the

intracellular glutamine level was also elevated upon LPS stimulation of RAW macrophages [50]. 4.4. NAD+ In addition to its well-known role as a barometer of redox status of cellular metabolism, intracellular NAD+ (nicotinamide adenine dinucleotide) level regulates inflammation via NAD-dependent deacetylase Sirtuin family of proteins. The deacetylase activity of Sirtuins can modify chromatin structure and protein function by removing the acetyl group from the protein [51]. As described above in relation to endotoxin tolerance, SIRT1 and SIRT6 coordinate the switch of the activated monocyte from glycolysis toward fatty acid oxidation, process coordinated by the sustained elevated intracellular concentrations of NAD+ [34]. In addition, deacetylated HIF-1a fails to recruit p300 to HIF-1 complex and subsequently fails to regulate HIF1-dependent downstream genes, suggesting a crosstalk between the cellular redox- and oxygen-sensor pathways through the SIRT1-HIF-1a interaction [50]. In addition, autophagyrelated genes have been shown to be deacetylated by SIRT1 [52], with inhibitory effects on ROS production [53]. 4.5. Free-fatty acids Fatty acids are another important energy reservoir in the organism. Fatty acids are stored mostly in the form of triacylglycerols in adipose tissue, liver and skeletal muscle. Most of the focus on the fatty acid metabolism has been put on how they are stored and released in a regulated way among these organs. Less is known about how the lipid metabolism influences the immune responses. As discussed above that acetyl-CoA could also derived from b-oxidation and fluxes into the mitochondria TCA cycle and takes part in the OXPHOS, especially in the resting cells or the tolerant monocytes/macrophages. It is therefore logical to postulate that the free-fatty acid released from triacylglycerol might

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have direct or indirect immune modulatory functions, in addition to merely serve as alternative source for energy. Recently, several immunomodulatory roles of free-fatty acid have been suggested. Eicosapentaenoic acid (EPA) has potent anti-inflammatory effects on human primary monocytes and dose-dependently inhibits LPS binding to LPS trap. Conversely, LPS-induced TNF was significantly and positively correlated with serum triglyceride levels in 30 patients with T2D [54]. Co-incubation of glucose with palmitic acid (PAL), linolenic acid (LIN) or EPA reduced the production of IL-10 and CCL-2, while IL-18 production was up-regulated [55]. Further investigations of the differential immune status in different metabolic disorders set-up are warranted to reveal deeper insights in the immune-modulatory role of free fatty acid. 5. Metabolomics profiling in vivo The increased knowledge of the metabolic profiles of the immune system during the encountering of a pathogen may open novel avenues in the clinical setup, either for diagnostic purposes or for therapeutic intervention. Several studies have been performed to assess the metabolome changes during the course of infection or sepsis, in order to gain further insight of the immunometabolic interactions in vivo. In a Klebsiella pneumoniae infection model in rats, an acute glycolysis profile as evident by higher lactate and lower glucose in the plasma was observed in the acute phase, mimicking the known profiles of severe sepsis in humans [56]. The plasma lactate dropped after 24 h post-infection and was followed by increased concentrations of 3-hyroxybutyrate, suggesting the elevated b-oxidation [56], which is in line with the in vitro observation that acute LPS stimulation increases first glycolysis, followed by increased b-oxidation [34]. In a zymosan peritonitis model in mice, the elevated lactate production was also detected locally in the peritoneal wash fluid in the first 24 h, and the elevated plasma 3hydroxybutyric acid was evident after 24 h and peaked at 48 h [57]. Similarly, in a rat sepsis model induced by cecal ligation and puncture, elevated acetoacetate concentrations were also observed in the plasma, suggesting also the elevated b-oxidation [58]. Similar observations have been made in a number of other infection models, such as MTB [59], Plasmodium berghei [60], Streptococcus penumoniae and Staphylococcus aureus [61] infections. Interestingly, the metabolic shift seems to be a common features in the sepsis patients either with S. penumoniae, Escherichia coli or S. aureus infection [62] and therefore it is suggested to be used as a prognostic marker for the severity of the sepsis outcome and reference for therapeutic intervention. However, one must be aware that circulating concentrations of metabolites can mirror either the metabolic state of the immune system, but also a very important component of tissue circulation and oxygenation. It is thus important for future studies to disentangle the specific changes in central metabolites of the immune cells isolated from patients with infections. 6. Future perspectives Accumulated evidence suggests that the cross-talk between metabolic and immune processes takes place at different levels of regulation through either direct signaling in the acute phase of the immune response, or via epigenetic modification during prolonged, sustained effects. However, much is still unknown and this is still a field in its beginning. One relevant question that is still largely unknown asks how does sensing of the microbial stimuli lead to metabolic reprogramming. For example, most of the current knowledge is based on the signaling of TLRs, but very little is known regarding the metabolic changes induced in immune cells by other PRRs such as

C-type lectin receptors or NOD-like receptors. Is there differential regulation of the metabolic pathways in cells stimulated with these various stimuli, since their intracellular signaling pathways involved are distinct to TLRs? Or are there common metabolic regulation pathways between different microbial ligands and PRR families? Another challenge is to measure the metabolic intermediates in different cellular compartments. The current analytical protocol for metabolites measurements can only determine the total metabolites either intracellularly or extracellularly. However, determination of metabolites by compartments, such as cytosol or mitochondria, would provide a better understanding of how differential metabolite fluxes influence the function of the cell. Similarly, assessment of tissue specific and cell-type specific metabolic profiles are needed for a better understanding of the immunometabolic interaction during an infection or inflammatory reaction. While tissue-level measurements may provide an overall picture of the metabolic changes, the cell-type specific responses may be underestimated, e.g. tissue macrophage metabolic changes might be masked by the other dominant cell types within the tissue. Finally, the true challenge in the coming years will be to translate this knowledge in novel alternatives for the diagnosis and especially treatment, by the development of metabolic modulators that could either boost or dampen the immune responses, depending on the clinical situation. Acknowledgements S-C.C and M.G.N. were supported by a Vici grant of the Netherlands Organization for Scientific Research and an ERC Consolidator Grant 310372 (to MGN).

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Leo Joosten is as pathobiologist interested in host defence mechanisms triggered by pathogenic microorganisms that results in chronic inflammation. He is currently the Head of the Experimental Internal Medicine within Radboud University Medical Center Nijmegen in the Netherlands. Current projects explore the role of Toll-like receptors (TLR), Nod like receptors (NLR), and C-type lectin receptors (CLR) in recognition of pathogens, with emphasis on Borrelia burgdorferi. This latter pathogen is the causative agent of Lyme disease. In additional projects the role of the inflammasome and the autophagy machinery in the pathogenesis of Lyme disease is investigated. Apart from infectious diseases, he is working on metabolic related diseases like diabetes type 2, atherosclerosis and particularly gouty arthritis. The current research projects uses primary cells (e.g. PBMC), murine models of infections, inducible transgenic mice and several gene deficient mice. He is head of the laboratory of experimental medicine and staff member of the department of medicine. Mihai Netea is a professor of the Department of Internal Medicine in Radboud University Medical Center, Nijmegen, the Netherlands. His research focuses on pathogen recognition by pattern-recognition receptors, primarily focusing on fungal pathogens. One of his main interests is to elucidate the immune networks responsible for the host defense against Candida albicans. His research interests also encompass the understanding of the complex functional networks between PRR families responsible for the activation of the innate immune system, as well as the novel mechanisms of innate immune memory (‘‘trained immunity’’). In addition, his research has also focused on the identification of novel immunodeficiencies leading to specific susceptibility to fungal infections, leading to the first identification of a C-type lectin receptor deficiency (dectin-1 deficiency) and the discovery of the genetic defect in chronic mucocutanoeus candidiasis (STAT1-deficiency).

Please cite this article in press as: Cheng S-C, et al. The interplay between central metabolism and innate immune responses. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.06.008

The interplay between central metabolism and innate immune responses.

A growing body of recent studies bring into light an important cross-talk between immune response and metabolism not only at the level of the organism...
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