The immune system plays a pivotal role in maintaining the defense mechanism against external agents and also internal danger signals. Metabolic programming of immune cells is required for functioning of different subsets of immune cells under different physiological conditions. The field of immunometabolism has gained ground because of its immense importance in coordination and balance of immune responses. Metabolism is very much related with production of energy and certain by-products. Reactive oxygen species (ROS) are generated as one of the by-products of various metabolic pathways. The amount, localization of ROS and redox status determine transcription of genes, and also influences the metabolism of immune cells. This review discusses ROS, metabolism of immune cells at different cellular conditions and sheds some light on how ROS might regulate immunometabolism.
The concept of metabolism and its interdependent relationship with the internal and external chemical environment have shaped the evolution of living organisms on this planet. The use of various chemical elements by living organisms from the environment to meet the metabolic needs by exchange of electrons in a series of oxidation–reduction steps, mediated through different carriers, has been constantly evolving among living organisms. The ultimate aim of the living organism is to obtain energy through metabolism for cellular growth and proliferation. A wide array of cellular cross talks among different types of cells are involved in cellular growth, proliferation and maintenance of homeostasis. These cellular cross talks require fine adjustment of metabolic pathways, and their spatial and temporal regulation. The physiological system generates many metabolic by-products to meet the energy demands of the cells under various environmental stimuli. ROS are one such metabolic by-product. The basal level of ROS is required for cellular growth and proliferation (Shadel and Horvath 2015). ROS are also required for proliferation and signal transduction for the activation of T cells, a key player of adaptive immunity (Franchina et al. 2018), while excessive accumulation of ROS leads to T-cell death. The concept regarding the role of metabolism in orchestrating immune response is ushered from the fact that expression of glucose transporters (GLUTs) was upregulated in macrophages upon lipopolysaccharide (LPS) administration (Freemerman et al. 2014). Later on, questions arose such as: What is the basis of highly proliferating nature of tumor cells compared to that of normal cells? How are activated T cells, macrophages and B cells different from naive and resting counterparts? These questions lead to detailed molecular understanding of how metabolism and its by-products regulate the state of resting or activation in different immune cells of both innate and adaptive immunity. The cross talks between metabolic by-products and immune system also play a crucial role in the initiation and progress of various diseases such as cancer, diabetes and different neurodegenerative diseases. This review sheds some light on the recent advancement of the relationship of ROS and immunometabolism.
ROS and oxidative stress
Reactive oxygen species (ROS) are free radicals having one or more unpaired electrons. These free radicals are highly reactive owing to the presence of unpaired electrons. Oxygen is required by most living organisms for life. It serves as a terminal electron acceptor in the mitochondrial electron transport chain (ETC) (Jabłońska and Tawfik 2019; Raymond and Segrè 2006). Oxygen can form superoxide anion radical by accepting one electron. This superoxide anion is one of the primary sources of ROS and oxidative stress inside the cell (Valko et al. 2004). The superoxide anion is converted to hydrogen peroxide (H2O2) by superoxide dismutase (SOD) and this H2O2 serves as ROS, further augmenting the various physiological effects of ROS (Bresciani et al. 2015). Mitochondrial ETC is the major source of ROS production inside the cell (Sachdev and Davies 2008; Sinha et al. 2013). The ETC transfers electrons from TCA cycle intermediates nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucleotide (FADH2) to oxygen in a tightly controlled redox environment; however, 1–3% of the leakage of electrons directly to molecular oxygen leads to the formation of superoxide anions (Orrenius et al. 2007). Other forms of ROS include alkoxyl (RO), hydroxyl (OH−) and peroxyl radicals (ROO−). ROS are also generated from lipid peroxidation by accumulated peroxide radicals. Many other enzymes such as lipoxygenase and cyclooxygenase also produce ROS. NADH oxidase (NOX) is a membrane-bound enzyme which produces ROS during pathogen invasion directed by the innate immune system (Abo et al. 1991; Jackson et al. 2004).
A threshold level of ROS is required for normal physiological processes like signal transduction, cell growth, activation of endogenous antioxidants and anti-apoptotic signals (Cotugno et al. 2015; Janssen et al. 1999; Kamata et al. 2005; Sarsour et al. 2008; Zhang et al. 2019). Prolonged accumulation of ROS leads to perturbance of fine balance between free radical production and their scavenging by endogenous antioxidant enzymes, eventually resulting in oxidative stress. Oxidative stress causes DNA damage, thus altering the transcription of various genes, malfunctioning of proteins through formation of disulfide bonds and plasma membrane damage through lipid peroxidation (Cross et al. 1987; Schieber and Chandel 2014).
Strong nexus between oxidative stress, inflammation and metabolism
As mentioned earlier, mitochondria are the major source of ROS in cellular system because of the presence of ETC. Another source of mitochondrial ROS formation is the oxidation and inactivation of the iron–sulfur (Fe–S) protein, aconitase. Aconitase is an enzyme of the TCA cycle which converts citrate to isocitrate. This enzyme is also a sensor of the redox status of mitochondria, especially to superoxide anions. The accumulated superoxide anions oxidize the [4Fe-4S]2+ cluster, followed by the release of Fe2+. This Fe2+ in turn reacts with H2O2 generated by the catalase to produce OH. via Fenton reaction, which further amplifies oxidative burden inside mitochondria (Gardner 1997; Keyer and Imlay 1997). This mitochondrial ROS (m ROS) oxidizes mitochondrial DNA (mt DNA) and proteins (Orrenius et al. 2007). The mROS triggers release of mt DNA into the cytosol. These oxidized mt DNAs serve as danger signals for the cell and activates inflammasome through pattern recognized receptors (PRRs) (Shimada et al. 2012). Inflammasome is a multiprotein complex consisting of an adaptor, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and pro-caspase-1 (Evavold and Kagan 2019). There are several sensors/receptors of inflammasome activation such as the NOD (nucleotide-binding oligomerization)-like receptor (NLR) family members NLRP1, NLRP3, NLRC4, NLRP6, NLRP7 and NLRP12, PYHIN family members AIM2 (absent in melanoma 2) and IFI16 (interferon-inducible protein 16) (Choubey and Panchanathan 2016; Connolly and Bowie 2014; Khare et al. 2012; Moayeri et al. 2010; Rathinam et al. 2012; Schroder and Tschopp 2010; Truax et al. 2018; Wlodarska et al. 2014; Zhao et al. 2011). The sensors of inflammasome contain a domain belonging to the death domain (DD) superfamily. The various death domain (DD) superfamilies are caspase recruitment domain (CARD) and pyrin domain (PYD). The inflammasome bind to pro-caspase 1 through its caspase recruitment domain (CARD) and cleaves to form caspase 1. The activated caspase 1 in turn cleaves and activates pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18 (Rathinam and Fitzgerald 2016; Rathinam et al. 2012) (Fig. 1). The activation of these pro-inflammatory cytokines induces activation of IFN-γ and natural killer (NK) cells (Yu et al. 2018). IFN-γ reprograms the metabolic profile of macrophages to sustain the inflammation and viability of inflammatory macrophages (Su et al. 2015). IFN-γ induces macrophage production of pro-inflammatory chemokines that recruit monocytes and T cells (Corbera-Bellalta et al. 2016; Foley et al. 2005). Activation of caspase 1 leads to the release of oligomeric inflammasome complex containing NLRP3 and ASC from macrophages. These released NLRP3 and ASC act as danger signals and activate caspase 1, thereby amplifying the inflammatory response (Baroja-Mazo et al. 2014). Activation of inflammasome also releases another pro-inflammatory cytokine, IL-1α (Groß et al. 2012). These pro-inflammatory cytokines released due to oxidative stress-mediated inflammasome activation lead to metabolic reprogramming of innate immune cells for sustaining inflammation.
Metabolism of immune cells
Metabolism is a central physiological phenomenon that exerts a profound effect on a wide array of biological processes, ranging from cellular development to cell death. In the course of cellular development to cellular death, cells face challenge to fine-tune the speed and efficiency of various metabolic activities as per the demand of the cellular environment. The metabolism of immune cells is under dynamic control and regulation based on the cellular milieu. The activation of immune cells requires cell proliferation, which in turn requires the coordinated action of both catabolic and anabolic pathways. To accomplish this task, activated immune cells shift toward aerobic glycolysis (Freemerman et al. 2014; Kelly and O'neill 2015; Pavlova and Thompson 2016). Glucose enters into cells through GLUT transporters to initiate the process of glycolysis. Different GLUT family transporters are expressed in the respective cells in the presence of activation signals. Activated T cells and macrophages show upregulation of GLUT1. GLUT3 is also upregulated in RAW 264.7 cells upon induction of respiratory burst (AHMED et al. 1997; Freemerman et al. 2014). Earlier report has shown that hemopoietic growth factor, interleukin-3 (IL-3), also resulted in the upregulation of GLUT1 and GLUT3 for cellular uptake of glucose (McCoy et al. 1997). After entering into the cell, glucose is phosphorylated to glucose 6 phosphate by the action of the enzyme hexokinase. This glucose 6 phosphate serves for both anabolic and catabolic functions, as this molecule is siphoned into the pentose phosphate pathway for generation of nucleotides through formation of ribose-5-phosphate and NADPH. NADPH is required for fatty acid synthesis, nucleic acid synthesis and synthesis of glutathione. Endogenous antioxidant molecules play a crucial role during inflammatory response and activation of immune cells (Zhou et al. 2010). Activated inflammatory macrophages ‘M1’ have distinct metabolic profile compared to anti-inflammatory macrophage ‘M2’. M1 macrophages meet their metabolic demand mainly through glycolysis (Odegaard and Chawla 2011; Wynn et al. 2013) (Fig. 2). Glycolysis generates only two molecules of ATP and helps to meet the fast energy requirements of activated macrophages by supplying other metabolic products for proliferation of activated cells. OXPHOS is inhibited in inflammatory and activated macrophages. The receptors of pro-inflammatory cytokines such as TNF-α and others on macrophages are coupled to NADPH oxidase (NOX) (Blaser et al. 2016; Lambeth and Neish 2014). The activation of NOX leads to ROS production within the macrophage to counteract pathogen response or cellular stress response. This excessive ROS production results in post-translational modification of iron sulfur proteins of ETC, thereby inhibiting oxidative phosphorylation (Mailloux and Willmore 2014). Apart from glucose 6 phosphate, other glycolytic intermediates in M1 macrophages also serve for various functions. Another important enzyme of glycolysis is pyruvate kinase (PK). This enzyme controls glycolytic flux and is the last rate-limiting step of glycolysis. PK converts phosphoenolpyruvic acid (PEP) to pyruvate and generates one molecule of ATP. PK has two isozymes, PKM1 and PKM2 (Imamura and Tanaka 1982). PKM2 is highly expressed in its monomeric conformation and phosphorylated state in LPS-stimulated inflammatory macrophages. This monomeric conformation of PKM2 drives aerobic glycolysis of LPS-induced inflammatory macrophages (Vickers 2017). PKM2 in activated macrophages translocates to the nucleus and activates the transcription of IL-1β (Palsson-McDermott et al. 2015). PKM2-mediated glycolysis also activates NLRP3 and AIM2 inflammasome complex (Xie et al. 2016). This enzyme also phosphorylates molecules such as ERK, STAT3 and AKT, thereby regulating cell proliferation and inflammation (Gao et al. 2013; Keller et al. 2014; Tweedell et al. 2018). The end product of glycolysis, pyruvate, gets diverted to various metabolic pathways. Pyruvate is converted to lactate with the help of lactate dehydrogenase and generates NAD+ which helps in redox balance. Lactate plays a pivotal role in controlling T-cell effector function. Accumulation of lactate is observed in the synovial joint of rheumatoid arthritis patients. Administration of sodium lactate inhibited CD4 + and CD8 + T-cell motility. Inhibition of CD4 + T-cell motility is due to interference in glycolysis, but that of CD8 + is independent of glycolysis. Sodium lactate induced phenotypic switching in CD4 + T cell to helper T cell17 (TH17) cells, releasing a large amount of IL-17 (Haas et al. 2015). Lactate produced by gut microbiota triggered the activation of NADPH oxidase (Nox) in the intestine, which eventually generated ROS production. This ROS production caused intestinal tissue damage, dysplasia and proliferation of stem cells (Perry et al. 2018). The role of lactate in immunity and metabolism has been reviewed elsewhere (Pucino et al. 2017).
Remodeling of TCA cycle in cells is a landmark event of macrophage activation. The metabolites of TCA cycle intermediates are siphoned into other metabolic pathways for the coordinated regulation of inflammatory response. Pyruvate is converted to acetylCoA by pyruvate dehydrogenase and this acetyl CoA enters the TCA cycle. This metabolite is required for chromatin remodeling and epigenetic regulation. Histone acetylation of chromatin is required for active transcription of various genes and acetyl CoA serves for the acetyl group. GAPDH is acetylated and this inhibits IFNγ production. This acetyl CoA is converted to citrate with the help of the enzyme citrate synthase. Malonyl CoA is derived from citrate and malonylation of proteins occurs in the presence of LPS. GAPDH binds to the m RNA of pro-inflammatory cytokines in resting macrophages, but its malonylation on lysine 213 leads to its dissociation from TNF-α m-RNA and production of TNF-α (Galván-Peña et al. 2019). The TCA cycle of M1 macrophages exhibits two breaks. The first break occurs in the conversion of citrate to isocitrate by the enzyme isocitrate dehydrogenase (idh). This break allows the accumulation of citrate which is required for the synthesis of fatty acids that are mediators of inflammation. This citrate is also converted to itaconate by the enzyme immune responsive gene 1 (Irg1) and this itaconate possesses antibacterial properties (Lampropoulou et al. 2016). Lampropoulou et al. reported that itaconate inhibits succinate dehydrogenase, thereby limiting inflammatory response. Treatment of mouse bone marrow-derived macrophages (BMDMs) with dimethyl itaconate (DI) before LPS administration resulted in the suppression of iNOS protein expression and IL-12p70 and IL-6 secretion. It also reduced inflammasome-induced maturation of IL-1β (Lampropoulou et al. 2016). Acetyl CoA is also produced from citrate into the cytosol and is used for acetylation of various proteins and epigenetic regulation of chromatin in the nucleus. Mills et al. reported that itaconate alkylates cysteine residues at 151, 257, 288, 273 and 297 of keap1and abolishes its Nrf2 inhibitory properties in macrophages. Activation of Nrf2 is required for the anti-inflammatory effect mediated by itaconate (Mills et al. 2018). In vivo administration of DI has been shown to ameliorate the pathology of psoriasis by regulating the IκBζ-ATF3 inflammatory axis (Bambouskova et al. 2018). The detailed mechanism of anti-inflammatory activity of itaconate is reviewed by Bordon et al. (2018), Hooftman and O’Neill (2019). The enzyme isocitrate dehydrogenase converts isocitrate to α-ketoglutarate and this α-ketoglutarate is required for balance of ROS and oxidative stress in the mitochondria. The second break in M1 macrophages occur in the step involving the enzyme succinate dehydrogenase (SDH) (Bordon 2018). This enzyme converts succinate to fumarate and inhibition of this enzyme leads to accumulation of succinate, which is crucial to sustain and maintain inflammatory response in macrophages. Pro-inflammatory macrophages are more glycolytic, produce more ROS and accumulate more succinate compared to resting macrophages (O’Neill and Pearce 2016). Accumulation of succinate leads to succinylation of various proteins which regulate their function. Succinylation of PKM2 leads to its inhibition and activation of IL-1β. SIRT5 desuccinylates PKM2 and inhibits inflammation in macrophages. SIRT5 prevents DSS-induced colitis in mice (Wang et al. 2017a). Succinate has also been reported to limit the production of anti-inflammatory cytokine IL-10 (Mills et al. 2016). Succinate regulates pro-inflammatory cytokine gene expression through inhibition of prolyl hydroxylase (PHD), ultimately activating hypoxia-inducing factor-α (HIF-1α). This HIF-1α enhances the transcription of IL-1β (Selak et al. 2005; Tannahill et al. 2013). ROS production in macrophages during inflammatory response also stabilizes HIF-1α through oxidation of cysteine residues on PHD. Excessive ROS decarboxylate α-ketoglutarate and also oxidize iron which is required for stabilization of PHD (Corcoran and O’Neill 2016; Guzy et al. 2008; Hagen 2012). Accumulation of intracellular succinate in synovium promoted the production of vascular endothelial growth factor (VEGF) and induced angiogenesis in endothelial cell through HIF-1α. Extracellular succinate promoted angiogenesis through receptor G-protein-coupled receptor 91 (GPR91) activation, further amplifying angiogenesis and arthritis. Suppression of SDH inhibited succinate accumulation and prevented angiogenesis (Li et al. 2018).
Amino acid metabolism plays a crucial role in immune cells and their orchestration due to various stimuli. The TCA cycle intermediates are intricately linked with the production of various amino acids which serve as precursors of other biomolecules. Glutamine metabolism is required for activation of macrophages and T cells. α-Ketoglutarate is produced through glutaminolysis and favors the polarization of macrophages toward the M2 phenotype. Glutamine metabolism supports anti-inflammatory macrophages when α-ketoglutarate/succinate ratio is low through destabilization of HIF-1α. Glutamine also inhibits activation of the NF-κB pathway through αKG–PHD-dependent modulation of IKKβ activity and restricts the activation of M1 macrophages. αKG promoted the expression of M2-specific genes through Jmjd3-mediated demethylation of H3K27 (Liu et al. 2017). Glutaminase (GLS) is an enzyme that converts glutamine to glutamate. This enzyme is required for the activation and proliferation of T cells. GLS deficiency reduced T-cell activation and proliferation. It also impaired differentiation of TH17 cells (Johnson et al. 2018). Glutamine deprivation promotes the activation of Foxp3 which is the transcription factor required for regulatoryT cells (Treg) (Klysz et al. 2015). Inhibition of the enzyme, glutamic oxaloacetate transaminase 1 (GOT1, which converts glutamate to α-ketoglutarate), led to differentiation of TH17 to Treg cells through methylation of the Foxp3 locus (Xu et al. 2017). Inhibition of glutamine synthetase through genetic targeting induces M1 macrophages and inhibits metastasis of tumor (Palmieri et al. 2017).
The metabolism of tryptophan plays a crucial role in the regulation of immune response under various physiological conditions. Oxidative catabolism of tryptophan takes place through the kynurenine pathway with the help of indoleamine 2,3 dioxygenase-1 (IDO1) enzyme producing kynurenine. This kynurenine is a ligand of aryl hydrocarbon receptor (AhR) and aids in the amplification of Treg cells. IDO1 has been shown to regulate the severity of pulmonary paracoccidioidomycosis (PCM). In PCM, IDO1 induced tolerogenic phenotype of dendritic cells. Dendritic cells isolated from IDO1-deficient mice secreted more IL-6 and secretion of anti-inflammatory cytokines such as IL-12, TGF-β, IL-10, IL-27, and IL-35. These dendritic cells also expressed a higher level of co-stimulatory molecules to exacerbate inflammation. IDO1-deficient mice also showed greater influx of TH17 cells in the lung and reduced the number of TH1 and Treg cells (de Araújo et al. 2017). IFN-γ secreted by TH1 cells leads to the production of kynurenine through activation of IDO1 and kynurenine suppressed the proliferation of T cells through the catabolism of tryptophan (Munn et al. 1999). Administration of kynurenine upregulated the expression of IL10R in colon and accelerated IL-10-mediated wound healing in DSS-induced colitis (Lanis et al. 2017). Degradation of l-tryptophan with the help of IDO has been shown to preserve survival and proliferation of CD4 + T‑cell through inhibition of glycolysis and glutaminolysis by activating general control nonderepressible 2 kinase (GCN2K) and AMPK. It also stimulated the activation of AhR, leading to increased oxidation of fatty acids through carnitine palmitoyltransferase I isoenzymes. Fatty acid oxidation aids in the survival of CD4 + T cell (Eleftheriadis et al. 2018). Cystine is another amino acid required for activation of the T cells. T cells lack transporter of cystine and also the enzyme cystathionase which converts methionine to cysteine. Therefore, T cells depend on antigen-presenting cells (APCs) for cysteine. These APCs convert cystine to cysteine and T cells transport cysteine through a specific transporter (Srivastava et al. 2010). Cysteine is also required for the synthesis of glutathione and also has influence on the activity of transcription factor NF-κB, which is required for the expression of various cytokines and other inflammatory molecules (Arrigo 1999). Cysteine metabolism also generates other amino acids such as hypotaurine and taurine which have profound and diverse biological effects. Cysteine is converted to l-cysteinesulfinate by cysteine dioxygenase. Glutamate-oxaloacetate transaminase (GOT) also converts cysteine into β-sulfinylpyruvate, which ultimately decomposes to generate Sulfur dioxide and pyruvate. This cysteine sulfinic acid is also converted to taurine. Taurine has been found to alter M1 macrophage to M2 macrophage to limit inflammatory response in obesity-induced inflammatory response and also mitigates inflammation and oxidative stress induced by various drugs (Chowdhury et al. 2016; Das et al. 2010, 2012; Lin et al. 2013). Hydrogen sulfide (H2S) is a gasotransmitter produced through the metabolism of cysteine. H2S is generated with the help of cystathionine β-synthase (CBS) and cystathionine γ lyase (CSE) in mammalian tissue. Perturbed metabolism of H2S has been linked to defects in immune homeostasis. Treg cells express both CBS and CSE and also produce H2S. Treg cells require the transcription factor, Foxp3 +, for their activation. Hypomethylation of Foxp3 + is required for its binding and stable expression. This hypomethylation is directed by methylcytosine dioxygenases Tet1 and Tet2 which catalyzes the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). H2S sulfhydrates nuclear transcription factor Y subunit beta (NFYβ) to facilitate its binding to Tet1 and Tet2 for their stable function (Yang et al. 2015). This gasotransmitter also interacts with different proteins to generate persulfide which leads to structural changes of various proteins. Structural modulation of K+ and Ca2+ ion channels by H2S has been shown to mitigate oxidative stress, apoptosis and mitochondrial metabolism and function (Kar et al. 2019; Paul and Snyder 2012). Sulfur dioxide is also generated from cysteine and possesses anti-inflammatory and antioxidant properties (Huang et al. 2016; Wang et al. 2015, 2017b). l -arginine is an amino acid involved in modulating inflammation and immunological response. l-arginine is converted to l-citrulline with the help of nitric oxide synthase (NOS), thereby generating nitric oxide (Lundberg et al. 2008). This nitric oxide acts as pro-inflammatory molecules. NO reacts with Sulfur-containing molecules and amino acid residues on proteins and nitrosylates them, thereby affecting their activities (Benhar 2015). This nitrosylation of redox controlling molecules like GSH to GSNO hampers the ability of glutathione to resolve oxidative stress. Arginine also modulates the immune system indirectly through the action of arginase 1 enzyme. Arginase 1 helps in the conversion of l-arginine into urea and l-ornithine which subsequently generates proline and polyamines. Proline constitutes an essential endogenous biomaterial for collagen synthesis. Arginase 1 is expressed in non-inflammatory macrophages and limits inflammation through arginine depletion, thereby preventing NO generation (Caldwell et al. 2015; Pesce et al. 2009). Pro-inflammatory macrophages express transcription factor Fos-related antigen 1 (Fra1) during their activation. This Fra1 has been involved in rheumatoid arthritis and works by downregulation of arginase1 (Hannemann et al. 2019). A recent study suggests that serine metabolism is required for the LPS-induced production of IL-1β and GSH synthesis for redox balance (Rodriguez et al. 2019). Leucine and isoleucine also have a role in metabolism (Duan et al. 2016). Serine metabolism is required for LPS-induced production of IL-1β in macrophages. Serine is required for the generation of glycine and glutathione. Glutathione is required for the maintenance of IL-1β production. Inhibition of de novo serine synthesis protects mice from LPS-induced endotoxemia (Momeni et al. 2013).
Fatty acid metabolism has been known to play a pivotal role in inflammation since the finding of the production of cyclooxygenase through metabolism of arachidonic acid. Inflammation and polarization of macrophage have also been linked to high fat diet-induced type II diabetes. During inflammation, citrate accumulates and inhibits carnitine palmitoyl transferase (CPT) enzyme, which is required for the transport of fatty acids into mitochondria. Free citrate is used for the synthesis of free fatty acids (FFAs). Excessive accumulation of FFAs leads to the activation of NLRP3 inflammasome, ultimately resulting in the production of IL-1β. The accumulation of FFAs also causes endoplasmic reticulum stress, activation of JNK and apoptosis (Mayer and Belsham 2010). Fatty acid oxidation (FAO) is mainly preferred by anti-inflammatory macrophage M2. IL-4-induced polarization of macrophages exhibits a high level of FAO and oxidative phosphorylation. IL-4 leads to the activation of transcription factors PGC1β and CD36 through STAT6. This PGC1β upregulates various genes for mitochondrial biogenesis (Vats et al. 2006). A recent study suggested that fatty acid synthase (FAS), the enzyme responsible for synthesis of fatty acid, induces configurational change on the membrane of macrophage for promoting high fat diet-induced inflammation. Deletion of FAS in macrophages leads to impairment of cholesterol retention and disruption of Rho GTPase trafficking, which is essential for adhesion of cells, migration and activation. FAS deletion prevents high fat diet-induced insulin resistance and chronic inflammation (Wei et al. 2016). Fatty acids are integral constituent of cellular membranes. Cellular membranes and membranes of cellular organelles preserve the cellular homeostasis with the outside environment. Phosphatidylcholine is the main phospholipid present in the mitochondrial membrane and cellular membrane, and choline uptake is required for the synthesis of phosphatidyl choline in activated macrophages. Activation of macrophages during inflammation is accompanied by glycolytic switch and ROS production which requires phospholipid remodeling of mitochondria to cope with the energetic demand (Tian et al. 2008). TLR activation leads to enhanced choline uptake in macrophages through choline transporter CTL1. Inhibition of choline phosphorylation and CTL attenuates NLRP3 inflammasome activation along with IL-1β and IL-18 production. Reduced phosphatidyl choline production altered the mitochondrial membrane lipid composition, thereby reducing ATP production. Energy crisis and drop in ATP level activated the energy sensor AMP-activated protein kinase (AMPK) and mitophagy through activation of drp-1. Mitophagy activation culminates in the activation of macrophages during inflammation (Sanchez-Lopez et al. 2019).
Short chain fatty acids (SCFAs) are produced through the metabolism of dietary fibers and metabolic by-products of glycolysis and amino acids by normal gut microbiomes (den Besten et al. 2013). These microbiomes modulate gut homeostasis and also exert beneficial effects on systemic physiology. SCFAs are carboxylic acids consisting of an aliphatic tail of (1–6) carbon formed through anaerobic fermentation in the intestine from dietary fibers. Propionate, butyrate and acetate are the three SCFAs which help to maintain intestinal epithelial cells (IECs) and also modulate immune response. These SCFAs exert their beneficial effect through different G-protein-coupled receptors (GPCRs). The prominent and well-studied GPCRs for SCFAs signal transduction are GPR41 and GPR109A through which SCFAs regulate phenomenon like induction of tolerance (Venegas et al. 2019). Propionate and butyrate produced by normal gut microbiome activates AIM2 and NLRP6-mediated inflammasome activation in the IEC via GPCR signaling, ultimately producing IL-18. This cytokine, IL-18, helps in the production of antimicrobial peptides (AMPs) in the IECs to maintain intestinal homeostasis by preventing colonization by pathogenic microbes (Nowarski et al. 2015; Ratajczak et al. 2019). SCFAs induce tolerance against normal microbiome in the intestinal lumen through reprogramming of naive T cells in the lamina propria toward differentiation into Treg cells. They also induce dendritic cells to produce IL-10 (Goverseet al. 2017). IL-10 might help in metabolic reprogramming of immune cells to shift from glycolysis the toward OXPHOS pathway to meet the energy demand, thereby inducing anergy and differentiation of immune cells toward regulatory counterparts. Butyrate has been shown to suppress inflammation by inhibiting the activation of NF-κB through epigenetic modification. Butyrate inhibits HDAC, thereby reducing acetylation and activation of transcription factors involved in the gene expression of pro-inflammatory cytokines (Rooks and Garrett 2016).
SCFA, especially butyrate, exerts its beneficial role in maintaining intestinal epithelial barrier. Report shows that restoring intestinal butyrate level can mitigate Clostridium difficile-induced colitis through stabilization of HIF-1α. Long-term consumption of antibiotics leads to microbial dysbiosis and colonization of intestine with opportunistic pathogen like Clostridium difficile. Butyrate has also been found to induce the expression of tight junction proteins. Significant reduction of butyrate level along with stabilization of HIF-1α proteins has been observed in germ-free (GF) mice also (LaMonte et al. 2012).
A recent study by Sun et al. has elucidated that short chain fatty acids (SCFAs) produced by gut microbiota stimulate pancreatic cell to produce cathelicidin-related antimicrobial peptide (CRAMP). This CRAMP converts inflammatory cells into regulatory immune cells in the pancreas and has been proved to be effective against type 1 diabetes (Sun et al. 2015). CRAMP induced the conversion of pancreatic inflammatory macrophages to pancreatic regulatory macrophages with significant reduction of TNF-α and IL-12, while higher expression of IL-4, a regulatory cytokine, was observed along with increased TGF-β. CRAMP induced phenotypic switch in macrophages through activation SHP1 by modulating PI3K through inhibition of phosphorylation of Akt and NF-κB. The metabolic products of gut microbiome exert profound influence in modulating the immune landscape of pancreas. Dysbiosis of gut microbiome is also associated with chronic kidney diseases (CKD). Microbial dysbiosis leads to the production of uremic toxins through altered metabolism. The production of indoxyl sulfate, p-cresol sulfate and urea-derived ammonia leads to deleterious effect on kidney through activation of inflammatory cytokines in the kidney. SCFAs produced by normal microbiome exerts beneficial role in maintaining the proper functioning of kidney (Nallu et al. 2017).
ROS and immunometabolism
ROS production and accumulation have profound effect on the transcription factors, various protein kinases and phosphatases required for orchestration and regulation of immune response and immune metabolism. One of the transcription factors regulated by redox perturbation is NF-κB. This is a ubiquitous transcription factor required during various physiological and pathological functions. NF-κB is sequestered in the cytosol by IκB during normal physiological condition. Following cellular stress, IκB is phosphorylated by IKK kinase and NF-κB is activated. This activated NF-κB translocates to the nucleus and aids in the transcription of cytokines, chemokines and cellular adhesion molecules during inflammation (Li and Verma 2002; May and Ghosh 1997). Excess and prolonged accumulation of ROS modulates the activation of NF-κB and its inhibiting partner. ROS accumulation leads to oxidation of cysteine residue at 179 of IKKβ and activates it, which phosphorylates IκB for proteasomal degradation (Nathan and Cunningham-Bussel 2013). ROS also activates IKKβ by its dimerization through the disulfide bond formation between Cys54 and Cys347, facilitates phosphorylation of IκB and also modulates binding of NF-κB to DNA (Béraud et al. 1999; Nakajima and Kitamura 2013). NF-κB aids in the transcription of pro-inflammatory cytokines such as TNF-α and interleukins. Binding of TNF-α to its receptor leads to the production of ROS and also in turn activates NF-κB (Morgan and Liu 2011). There is a feedback loop operating between oxidative stress and inflammation. Oxidative stress leads to the formation of advanced oxidation protein products (AOPPs), which serve as a danger signal for cells. These AOPPs activate NF-κB through the receptor for advance glycation end products (RAGE) and activate pro-inflammatory cytokines (Xie et al. 2013). Activation of NF-κB is required for overexpression of pyruvate kinase M2 for sustaining glycolysis and tumorigenesis. Activation of EGFR in tumor cell induces PKCε monoubiquitination at Lys321 through phospholipaseCγ1 (PLCγ1). Monoubiquitinated (May and Ghosh 1997) PKCε activates IKKβ through phosphorylation at Ser177 and activates NF-κB. Activated Rel A subunit of NF-κB interacts with HIF-1α to promote the gene expression of PKM2 to enhance glycolysis in tumor cells (Bonello et al. 2007). Binding of LPS to toll-like receptors during pathogen invasion also mediates its effect through the joint action of transcription factors NF-κB, AP-1 and IRFs, which ultimately leads to shift in metabolism toward glycolysis to sustain inflammation. It also impairs mitochondrial respiration (Nakajima and Kitamura 2013).
Nrf2 is another redox-regulated transcription factor involved in upregulation of genes involved in amelioration of oxidative stress (Itoh et al. 1997). Under normal physiological condition, Nrf2 is inhibited by keap 1 through ubiquitination and proteasomal degradation of Nrf2. Keap1 is a sensor of redox perturbation in the cellular system. It has a domain consisting of a cysteine-rich region and a double glycine repeat-DGR binding site at the contact site with Nrf2. This domain consists of five cysteine residues (Cys151, Cys257, 273, 288, and 297) which serve for chemical modification during oxidative stress. Modification of Cys151 by ROS causes structural distortion and inhibits binding of keap-1 with Nrf2 (Zhang and Hannink 2003). Recently, Nrf2 has been shown to promote malignant phenotype by orchestrating the metabolism of cancer cells. Nrf2 upregulates the gene expression involved in the pentose phosphate pathway and NADPH production required to maintain redox balance in cancer cells. Nrf2 also promotes glutamine metabolism and purine biosynthesis required for proliferation of cancer cells. PI3K-Akt signaling is required for metabolic regulation by Nrf2 (Mitsuishi et al. 2012). There is a cross talk between Nrf2 and NF-κB in the regulation of oxidative stress and inflammation (reviewed elsewhere) which in turn regulates metabolism (Ahmed et al. 2017; Sivandzade et al. 2019). Nrf2 plays a pivotal role in the survival of hepatocellular carcinoma (HCC) against ferroptosis. Nrf2 interacted with transcriptional coactivator small v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (Maf) proteins and increased transcription of antioxidant genes like heme oxygenase (HO-1), ferritin heavy chain 1 (FTH1) and quinone oxidoreductase 1 (NQO1) to prevent HCC cell death from oxidative stress-mediated cell death upon exposure to ferroptosis-inducing agents. Nrf2 is stabilized and its nuclear translocation is enhanced by p62, a protein involved in autophagy upon induction of cellular stress with the help of ferroptosis-inducing agents. Autophagy aids in the protection of HCC cells through stabilization of Nrf2 and increasing antioxidant response (Bartolini et al. 2018; Sun et al. 2016).
The interconnection of ROS, oxidative stress and cell death is also vividly linked to calcium ion homeostasis (Ca2+). Calcium ion is stored in the sarcoplasmic reticulum and plays a pivotal role in cellular signaling involving cell growth, proliferation and various metabolic pathways. The main storehouse of calcium in the cell is endoplasmic reticulum (ER). This endoplasmic reticulum is also the site for protein folding (Braakman and Hebert 2013). There are chaperons in the ER which ensures correct folding of nascent peptides and proteins prior to their transportation to their respective organelles. The chaperons in the ER are sensitive to redox status of the cell. Prolonged ROS production and redox perturbation of cellular milieu affect protein folding in the ER (Malhotra and Kaufman 2007). Accumulation of unfolded proteins in the ER leads to the activation of unfolded protein response (UPR) (Smith and Wilkinson 2017). The physiological importance of UPR is huge. It first tries to mitigate ER stress through three different modes, i.e., through inhibition of translation, so that less protein is synthesized under ER stress, degradation of unfolded proteins through ubiquitination and increased expression of chaperons involved in protein folding. These three tasks are accomplished by three proteins, namely inositol-requiring enzyme1(IRE1), RNA-dependent protein kinase (PKR)-like ER kinase (PERK) and activating transcription factor 6 (ATF6). Accumulation of unfolded proteins leads to release of BiP or GRP78 (78 KDa glucose-regulated protein) from these sensor proteins and this release of GRP78 causes dimerization of IRE1 and PERK. The activated PERK leads to inhibition of translation initiation factor e-IF2α, thereby halting global translation (Harding et al. 2009). The activation of IRE1α causes splicing of X-box binding protein 1(Xbp1) m-RNA 3, eventually resulting in the expression of active Xbp1 transcription factor (Lee et al. 2003). This transcription factor helps in upregulation of chaperon genes needed to cope up with ER stress. Upon prolonged ER stress, IRE1α activates JNK, ultimately programming the genetic machinery toward apoptosis. IRE1α also induces apoptosis through activation of caspase 12 and apoptosis signal regulating kinase 1 (ASK1) (Ron and Hubbard 2008). JNK is also involved in phosphorylation and activation of pro-apoptotic proteins which help in mitochondrial-mediated cell death (Lei and Davis 2003) (Fig. 3). Under normal physiological condition, JNK is phosphorylated and activated for a transient period of time. It is dephosphorylated by MAPK phosphatase (MKP). Excessive production of ROS during oxidative stress leads to inactivation of MKP, thereby resulting in sustained JNK activation and apoptosis. MAPK is required for activation of T cell. ATF6 is another transmembrane protein involved in UPR. It translocates from ER to Golgi body on induction of ER stress to mitigate ER stress. Chronic UPR leads to activation of a transcription factor, CHOP, which leads to transcription of pro-apoptotic genes to shift the cellular machinery toward apoptosis (Yamaguchi and Wang 2004). Calcium ion is required for cellular signaling involved in physiological processes such as cell proliferation, growth and metabolism. Calcium ion is required by some enzymes of the TCA cycle and ETC in mitochondria (Berridge 1998). Tight regulation of calcium exchange occurs from ER to mitochondria at mitochondrial associated membrane (MAM). Under oxidative stress and cellular stress, more calcium ions flow to the mitochondria, thereby leading to activation of TCA cycle and ETC producing more ROS. Sustained oxidative stress leads to inhibition of TCA cycle and ETC due to inactivation of various enzymes. There might be a metabolic shift toward glycolysis and prepare the platform for inflammatory response and also carcinogenesis due to calcium imbalance during ER stress. Unregulated flow of calcium to mitochondria also triggers the cell death mechanism (Gutiérrez and Simmen 2018). Excess ROS can also modulate calcium channels directly through oxidative modification of cysteine residues and lead to changes in conformation and release of calcium ions adding to cellular stress (Booth et al. 2016) (Fig. 4).
Dendritic cells (DC) are one of the frontline cells constituting an innate immune defense system, which promptly acts against the invading pathogen, thus providing an early block against external attack. Nitric oxide (NO), a key mediator of metabolic switch in immune cells, exerts a dramatic change in DCs too. In response to lipopolysaccharide (LPS) and INF-γ, DCs increase their inherent inducible nitric oxide synthase (iNOS) expression for NO generation. Increased NO production in activated DCs now nitrosylates iron–sulfur proteins of Complex I as well as that of the cytochrome c oxidase of ETS (Cleeter et al. 1994; Clementi et al. 1998; Drapier and Hibbs 1988; Lu et al. 1996). This eventually leads to LPS-mediated mitochondrial collapse and increased glycolytic activity in activated DCs (Everts et al. 2012).
Similar to Warburg’s effect in tumor tissue, activation of DCs by LPS as well as TLR2 ligation in normoxic condition stimulates glycolysis and increased HIF-1α expression (Spirig et al. 2010). These in turn activate downstream genes, such as phosphoglycerate kinase (PGK) and GLUT1. Moreover, glycolysis inhibition by treatment with deoxyglucose (DG) as well as HIF-1α deficiency blocks DCs maturation and subsequently leads to reduced expression of co-stimulatory molecules CD80 and CD86 (Bhandari et al. 2013; Jantsch et al. 2008).
Murine DC activation results in mTOR signaling which might not be translated in human DCs (Ohtani et al. 2008). Surprisingly, DCs lacking tuberous sclerosis complex 1 (TSC1), an upstream negative regulator of mTOR, shows not only increased mitochondrial respiration ,but also increased expression of glycolytic enzyme hexokinase-2 (HK2) and lactate dehydrogenase (LDHA) (Amiel et al. 2012). Moreover, TSC1-deficient DCs also exhibit lower capability of TH1 response induction (Wang et al. 2013).
Other than glycolysis, modulation in the channeling of TCA cycle intermediates is another important aspect in the metabolism of activated DCs. In such activated DCs, citrate is shifted from TCA cycle to de novo fatty acid synthetic pathways, which seems to be supported by the increased glycolytic flux mediated by TANK-binding kinase 1(TBK1), Akt, etc. (Everts et al. 2014). In the absence of adequate fatty acid synthesis, reduced synthesis of proteins including an array of cytokines results in impaired DC activation. For example, liver DCs with higher lipid level are immunogenic and responsible for CD8 + T cell as well as NK cell induction, whereas those with lower level of lipid are tolerogenic and capable of regulatory T-cell induction (Ibrahim et al. 2012).
ROS, metabolism and immunity in different diseases
Diabetes is characterized by elevated blood glucose level which leads to the increase in the levels of sorbitol, protein kinase C (PKC), advanced glycation end product (AGE), hexosamine and NADPH oxidase (NOX)-1,4 and 5 (Jha et al. 2018). These in turn lead to the generation of reactive oxygen species (ROS). ROS production is characterized by lipid peroxidation, protein carbonylation and damage of DNA. All such consequences promote diabetic complications (Oguntibeju 2019). ROS generation can be analyzed by the administration Nrf2-Keap1 agonists and NOX inhibitors (NOXi) (Jha et al. 2018). Hyperglycemia also induces the activation of TNF-α which in turn activates NF-κB, iNOS, thereby inducing inflammation (Chandirasegaran et al. 2017). Inflammatory responses can be diagnosed by the administration of pentoxifylline and allopurinol (Jha et al. 2018). Serum γ-glutamyl transferase and C-reactive proteins (CRPs) are biomarkers of oxidative stress and inflammation. Levels of both the biomarkers increase in patients with poor glycemic control (Krishnamurthy et al. 2019). Recent studies have shown that various bioactive molecules function against the induction of oxidative stress and inflammation in diabetic rodents (Biswal et al. 2019; Dutta et al. 2018; Ghosh et al. 2018,2019; Mahalanobish et al. 2019). For example, Astaxanthin and Corni Fructus protect against diabetes-induced oxidative stress, inflammation and AGE in the liver of streptozotocin (STZ)-treated rats (Park et al. 2015a).
Hyperglycemia does not affect adaptive immunity, but is associated with disturbances in the innate humoral immunity [decreased complement factor 4 (C4) response, abnormal release of TNF-α, IL-1, 6, 8 and 10] and cellular innate immunological responses [phagocytosis, killing of diabetic polymorphonuclear cells and diabetic macrophages and reduced chemotaxis] (Geerlings and Hoepelman 1999).
Reduced insulin production or insulin resistance is characteristic of diabetes. It is secreted from the pancreatic β-cells, helps in reducing blood glucose levels and augments the synthesis of glycogen. The insulin signaling pathway involves the activation of PI3K, which in turn activates PKB, PKC and Akt. Akt induces the translocation of GLUT-4 from cytosol to the plasma membrane to accelerate the cellular intake of glucose for the synthesis of glycogen via the activation of GSK-3β (Chandirasegaran et al. 2017). GSK-3β regulates innate and adaptive immune responses. It regulates the balance between pro- and anti-inflammatory cytokines in the peripheral and central nervous system and also influences T-cell proliferation and differentiation (Beurel et al. 2010). According to recent reports, inhibition of GSK-3β induces the generation of ROS via the β-catenin signaling pathway in the spleen of zebrafish (Liu et al. 2018). It has also been observed that the PI3K/Akt/GSK-3β/ROS pathway promotes the growth and metastasis of breast cancer by suppressing the NK cell-mediated cytotoxicity (Jin et al. 2019).
Obesity, a metabolic disorder, induces endoplasmic reticulum (ER) stress which activates the mitogen-activated protein (MAP) kinase pathway, thereby leading to chronic inflammation. Inflammatory response, on one hand, includes plasma hyperlipidemia-mediated fatty liver disease and atherosclerosis and, on the other hand, induces insulin resistance (IR)-mediated type-II diabetes (T2DM) (Wellen and Hotamisligil 2005). Inflammatory markers like TNF-α, IL-6 and MCP-1 promote obesity and IR. Anti-inflammatory markers such as IL-10 reduce metabolic syndrome (MS) and promote obesity and insulin sensitivity. Overnutrition and hyperglycemia induce the generation of mitochondrial ROS and promote ER stress, which in turn activates the MAP kinase pathway. This pathway, on one hand, blocks the insulin signaling pathway, while on the other hand induces NF-κB and AP-1-like transcription factor-mediated inflammation. PPAR and LXR family of transcription factors function in antagonism to NF-κB and AP-1 and control lipid/cholesterol metabolism.
According to the International Diabetes Federation (IDF) 2013 consensus, MS is characterized by central obesity, IR, inflammation and oxidative stress (Nwafor et al. 2017). MS induces oxidative stress-mediated IR, dyslipidemia, β-cell dysfunction and glucose intolerance. This leads to the development of T2DM (Silva Júnior et al. 2015). It is reported that zinc, a trace element of our body, inhibits MS by promoting antioxidant defense, lipid and glucose metabolism and insulin production by blocking the onset of inflammatory responses (Olechnowicz et al. 2018). A comparative study between metabolically healthy morbidly obese (MHMO) patients and metabolically unhealthy (MUHMO) patients with MS has shown similar serum levels of CRP and TNF-α. However, the level of NO is significantly higher and that of insulin and homeostasis model assessment index of IR (HOMO-IR) is significantly lower in MUHMO patients with MS than in MHMO patients. This suggests that IR markers act as predictor of MS in MHMO patients (Tangvarasittichai 2015).
In a recent study involving 90 T2DM patients, the effect of two dipeptidyl peptidase (DPP)-IV inhibitors was investigated. Activity of DPP-IV increases in T2DM patients and acts as a link between T2DM and atherosclerosis (Silva Júnior et al. 2015). 45 patients were administered with the DPP competitive inhibitor, sitagliptin at a dose of 100 mg once daily, while the remaining 45 patients were administered with the substrate inhibitor vildagliptin at a dose of 50 mg once daily. After 12 weeks from the onset of treatment, a comparative study revealed similar changes (146–169 mg/dL approximately) in postprandial glucose levels from the baseline in both groups. The mean amplitude of glycemic excursion (MAGE) index (an index of glycemic fluctuations), nitrotyrosine, IL-6 and IL-18 levels were significantly lower in vildagliptin-treated patients than in sitagliptin-treated patients. Daily glucagon-like peptide (GLP)-1inhibition profile was also significantly better in vildagliptin-treated patients. Thus, reduction in daily acute glucose fluctuations is associated with the corresponding reduction in the level of oxidative stress and systemic inflammation in T2DM patients (Rizzo et al. 2010). Such examples point toward the interrelationship of oxidative stress, inflammation and metabolism under hyperglycemic conditions.
The kynurenine pathway involves the metabolism of tryptophan (TRP) to subsequent intermediates such as kynurenine (KYN), kynurenic acid (KYNA), 3-hydroxy kynurenine (3-HK), 3-hydroxy anthranilic acid (3-HAA), xanthurenic acid (XA) and quinolinic acid (QA) and ultimately generates NAD + . Under healthy conditions, The TRP–KYN–3-HK pathway leads to the production of 3-HAA, but oxidative stress and inflammation direct the pathway toward the production of XA, which in turn leads to the arousal of T2D symptoms, possibly via the induction of caspase 3-dependent apoptosis of pancreatic β-cells (Oxenkrug et al. 2013). Surplus TRP load has been reported to cause IR in pigs. Alloxan and STZ-treated rats exhibit excretion of urinary XA. Activity of kynureninase which converts 3-HA to 3-HAA decreases in alloxan-treated rats. All such examples point toward the diabetogenic activity of XA (Oxenkrug 2015).
The source of brain insulin is not merely pancreatic β-cells. It is also synthesized de novo from neurons and glial cells (Blanco et al. 2015; Boden 2011; Campa et al. 2015; Hurrle and Hsu 2017). In the brain, insulin modulates cognitive function, appetite, energy homeostasis, neuronal glucose metabolism, long-term potentiation (LTP) and long-term depression (LTD) (Hurrle and Hsu 2017; Kizer 2013; Salzano et al. 2014; Shehzad et al. 2012). IR is associated with reduced binding capacity and level of insulin receptor and reduced response of insulin to target tissue (Halliwell and Gutteridge 1985; Hurrle and Hsu 2017; Reczek and Chandel 2015; Schieber and Chandel 2014). Peripheral IR, i.e., high circulatory insulin level reduces the expression of endothelial insulin receptors and insulin permeability of the blood–brain barrier (BBB), thereby inducing brain IR (Hurrle and Hsu 2017; Mason et al. 2016; Niki 2014). The brain of a patient with Alzheimer’s disease (AD) is characterized by insulin deficiency and IR. Hence, it is referred to as type III diabetes (Ahmed et al. 2015; Hurrle and Hsu 2017). Brain is associated with excessive oxygen consumption and very low level of antioxidant defense. Brain IR is associated with AD, cognitive impairment, cerebral degeneration, reduced neuronal survival and low synaptic plasticity (Talbot et al. 2012). All such pathophysiological conditions are associated with oxidative stress. Reduced physical activity, genetic predisposition and overnutrition augment peripheral IR. This increased IR induces glucotoxicity via activation of PKC, AGE and polyol pathway and also lipotoxicity through increased glycolysis and ceramide levels, thereby promoting inflammation (via MAP kinase and NF-κB pathways, respectively). This, in turn, leads to generation of ROS and causes the development of brain IR (Correia et al. 2012). Increased brain ceramide levels impair insulin signaling pathway and promote ER stress-mediated inflammation. Ceramide also activates β-secretase (BACE-1), an enzyme which catalyzes the conversion of amyloid precursor protein (APP) to amyloid β. High amyloid β levels induce inflammation, which in turn promotes NOXmediated oxidative stress (Cutler et al. 2004). Brain IR is also associated with damage of mitochondrial DNA, subsequent reduction of oxidative phosphorylation and increased mitochondrial ROS. This increases mitochondrial membrane permeability and reduces membrane potential, leading to mitochondrial dysfunction (Sa-nguanmoo et al. 2017). Thus, interrelationships between oxidative stress, inflammation and metabolism are observed in type III diabetes as well (Kroner 2009; Suzanne 2009).
Injury or damage of the central nervous system (CNS) affects the astrocytes and microglia. Astrocytes generate ROS and RNS, while microglia release pro-inflammatory cytokines. Such events cumulatively lead to demyelination of neurons and neurodegenerative symptoms (Fischer and Maier 2015). Neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS) are associated with deleterious effects on hippocampal, dopaminergic and motor neurons, respectively (Molteni and Rossetti 2017). Pro-inflammatory cytokines are associated with the progression of neurodegenerative diseases. Such cytokines also induce TNF-α-mediated activation of NF-κB and release of mitochondrial ROS and RNS. Activation of NF-κB, in turn, leads to the sustained release of a wide array of pro-inflammatory mediators under neurodegenerative pathophysiological conditions. NF-κB also mediates the generation of ROS and RNS via the active role of intermediary players such as iNOS, COX-2, and NOX-2 (Fischer and Maier 2015).
Alzheimer’s disease or type III diabetes is linked with various features of the metabolic syndrome (MetS) such as hyperinsulinemia, oxidative stress and chronic inflammation. Oxidative stress leads to neuronal damage. Chronic inflammation induces dysfunction of the blood–brain barrier (BBB), thereby leading to neuroinflammatory responses. Hyperinsulinemia affects lipid metabolism, i.e., increases lipogenesis in the liver and decreases lipolysis in the adipocytes (Rojas‐Gutierrez et al. 2017). Brain lipids regulate signaling through neuronal synapses and also the proper functioning of proteins in the cell membrane. Thus, lipids may function as signal transmitters. It is already known that glycolipids, glycerophospholipids, and sphingolipids are associated with the attenuation of psychological disorders (Shamim et al. 2018). On the other hand, non-alcoholic fatty liver disease has been reported to provoke signs of AD in murine model, thereby indicating that chronic inflammation exterior to the brain is sufficient to induce neurodegeneration (Moretti et al. 2016). Insulin resistance (IR) in the brain is linked with lipid metabolism which leads to lipid accumulation in the liver and muscles (Rojas‐Gutierrez et al. 2017). IR-associated hyperinsulinemia and obesity lead to the overproduction of very low-density lipoprotein (VLDL) fraction of cholesterol (Howard 1999). Nuclear lipid sensors (e.g., LXRs, FXR), fatty acids and modified lipoproteins (e.g., LDL, HDL) augment inflammation-induced atherosclerosis. Fatty acids induce inflammatory pathways by binding to several G-protein-coupled receptors (GPR) expressed on immune cells and metabolically active tissues (Lagakos 2011; van Diepen et al. 2013). This induces neuroinflammatory responses and neurodegenerative symptoms characteristic of AD (Rojas‐Gutierrez et al. 2017). Positive feedback loops exist between amyloid-β accumulation and inflammation. AD patients exhibit the onset of inflammation at and around the sites of plaque formation. The aggregation of Aβ plaques activate microglia and astrocytes and promote the overexpression of the complement system (Doig 2018). Recent studies provide clear evidence for feedback from inflammasomes to Aβ deposition via apoptosis-associated speck-like protein (ASC) (Doig 2018; Ransohoff 2017; Venegas et al. 2017). A positive feedback loop between inflammation and Aβ is also functional via RIPK1 kinase pathway. Under pathophysiological conditions, Aβ accumulation activates RIPK1 in the microglia, thereby causing impaired lysosomal activity and impaired clearance of extracellular Aβ by phagocytosis. Activated RIPK1 causes extreme release of TNF-α and IL-6 cytokines (Doig 2018; Ofengeim et al. 2017; Rubinsztein 2017). Deposits of toxic amyloid β (Aβ) in the brain of AD patients are characterized in their early pro-inflammatory phase by the increase in complement activation and augmented release of TLR-2,4,7, CD-14, CD-163 and the anti-inflammatory IL-10 from the aged microglia. This leads to chronic inflammation and the persistence of Aβ deposits, thereby accentuating progression toward late microglial paralysis. In this phase, the aged microglia release TLR-2, CD-14, CD-163 and IL-10 excessively, while the discharge of TLR-4 decreases. This leads to further Aβ accumulation and progression of the disease (Molteni and Rossetti 2017). Deposition of Aβ in the leptomeningeal and perivascular spaces of the cerebral vessels induces the occurrence of CD4 + T cells and CD11c + dendritic cells (DCs). These CD11c + cells have been found to express elevated levels of DC maturation markers such as Class II MHC, DEC-205 and CD86. This indicates that the deposition of Aβ provides the antigenic foundation for DCs to activate Aβ-specific T cells into the brain tissue. Hence, dendritic cells (DCs) can stimulate Aβ-specific T-cell entry into the brain (Doig 2018). TLRs of DCs induce dendritic glycolytic flux via TBK1, IKKε and Akt signaling, thereby augmenting de novo fatty acid synthesis (Gao et al. 2012; Rubinsztein 2017). On the other hand, inhibition of mTOR, in turn, inhibits TLR activation-mediated metabolic switch to glycolysis in DCs (Amiel et al. 2012; Weinberg et al. 2015). This points to the multiple modes of metabolic regulation of DCs. Activation of the kynurenine pathway in microglial cells and astrocytes via LAT-1-mediated transfer of TRP across the BBB leads to the generation of KYNA, QA and NAD+ (Krawczyk et al. 2010). QA, an N-methyl-d-aspartate receptor (NMDAR) agonist, induces gliotoxicity and neurotoxicity via NMDAR-mediated Ca2+ influx which, in turn, activates protein kinases to augment dysregulation of intermediate filament assembly (Lee et al. 2010; Powers et al. 2018). On the other hand, KYNA controls the passing of ICAM-1 and VCAM-1 across the BBB (Krawczyk et al. 2010). The various steps of the kynurenine pathway are associated with both the generation (O2.−, H2O2, ONOO− etc.) and scavenging (chelation of bivalent metals etc.) of ROS (Lugo-Huitrón et al. 2013). In AD patients, TRP/KYN ratio and 3-HK levels increase in the plasma and serum, respectively (Lugo-Huitrón et al. 2013; Reyes Ocampo et al. 2014; Widner et al. 2000). However, KYNA levels increase in the putamen and decrease in the cerebrospinal fluid (CSF) and plasma (Hartai et al. 2007; Lugo-Huitrón et al. 2013; Oxenkrug 2007; Schwarz et al. 2013). Thus, a complex interaction of oxidative, inflammatory, immune and metabolic players is involved in the pathogenesis of AD.
Parkinson’s disease is associated with oxidative stress and inflammation. The lipid mediators of oxidative stress are 4-hydroxynonenal, isoprostanes, isofurans, isoketals, neuroprostanes and neurofurans. The lipid mediators of TNF-α and IL-1β-mediated inflammation are prostaglandins and platelet-activating factors (Farooqui and Farooqui 2011). In PD patients, KYNA level decreases and 3-HK level increases in the frontal cortex and putamen (LeWitt et al. 2013; Ogawa et al. 1992). PD is associated with the aggregation of α-synuclein in the neurons. Neurons may exocytose α-synuclein, which in turn can be taken up by macrophages, microglia and astrocytes. α-Synucleins act as damage-associated molecular patterns (DAMPs) which on binding with pattern recognition receptors (PRRs) accelerate the release of pro-inflammatory cytokines. α-Synuclein peptides are presented by neurons through MHC-I and by microglia through MHC-II. This initiates the adaptive immune response through either B-cell activation (via activation of Th2 or Treg through CD8 + T cell) or the release of pro-inflammatory TH1 and TH17 cells (via CD4 + TH) (Angajala et al. 2018). T-cell activation and differentiation are metabolically regulated. Stimulation and augmented functioning of T cells along with their receptors and co-receptors involve consumption of huge amounts of both glucose and glutamine (Macintyre and Rathmell 2013). Activation of T cell induces several metabolic enzymes to provoke glutamate to enter the Krebs cycle as α-ketoglutarate) (Carr et al. 2010). On the other hand, HIF-1 is also associated with activation of T cells. HIF-1, on one hand, induces TH17 gene expression, thereby activating TH17 cells, while, on the other hand, stabilizes Foxp3 to induce the generation of Tregs (Tao et al. 2015). Activated T cells exhibiting greater rate of glycolysis than mitochondrial oxidative phosphorylation (OXPHOS) undergo differentiation into TH1, TH2, TH17 (characterized by higher glycolytic rate than OXPHOS and high mTORC1 activity) and Treg cells (characterized by high rate of OXPHOS and fatty acid oxidation and variable AMPK and mTORC1 activity) (Angajala et al. 2018). On the other hand, α-synuclein also changes the expression levels of CD200 and CX3CL1 in neuro-glial interactions (Tansey and Romero‐Ramos 2019). Thus, a complex set of molecular interactions is involved in the pathogenesis of PD.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily motor neurons of the brain and spinal cord. Under such pathophysiological conditions, motor neurons are vulnerable to depletion of ATP (Vandoorne et al. 2018). Creatine and olesoxime supplementation inhibits ATP depletion in ALS patients (Tefera and Borges 2017). Blood glucose passes through the membrane of the blood vessel via GLUT1 and enters the motor neurons via GLUT3 only to be channelized toward glycolysis. This ultimately generates pyruvate which on entering the mitochondria produces various intermediate metabolites of the Kreb’s cycle and electron transport chain (ETC). ETC harvests ROS and ATP. ROS augment lipid production, the products of which are exocytosed as apolipoproteins (Apo E/D). They enter the glial cells as lipid droplets and participate in their corresponding mitochondrial Krebs cycle. Hence, decrease in glucose uptake, glycolysis, mitochondrial content and mitochondrial functions affect the motor neurons (Vandoorne et al. 2018). ALS is associated with activated CNS microglia and astroglia, pro-inflammatory peripheral lymphocytes, dysfunctional Tregs and mutations of SOD1, TARDBP and C9orf72 (Guo et al. 2019; Liu and Wang 2017). The activated microglia generate mitochondrial ROS, which in turn activates NLRP3 inflammasome (Guo et al. 2019). NOX-4-mediated upregulation of carnitine palmitoyl transferase 1A (CPT1A), rate-limiting enzyme controlling mitochondrial fatty acid oxidation and saturated fatty acid palmitate also lead to the activation of NLRP3 inflammasome in macrophages (Guo et al. 2019). It is also reported that the binding of misfolded aggregated protein TDP-43 with CD-14 on the outer surface of microglia and subsequent interaction with TLR-4 activate the NF-κB pathway, which, in turn generates NLRP3, pro IL-1β and pro IL-18 (Pollari et al. 2014). This NLRP3 inflammasome, along with apoptosis-associated speck (ASC), activates caspase 1. Caspase 1 leads to the conversion of pro IL-1β and pro IL-18 to IL-1β and IL-18 (Guo et al. 2019). The immuno-metabolic link in ALS patients is quite complex. Monocytes differentiate into M1 (induced by IFN-γ) and M2 macrophages (induced by IL-4 and IL-13 (Angajala et al. 2018). In healthy individuals, M2 macrophages release IL-4, 10 and TGF-β and along with Tregs inhibit the pro-inflammatory Th1 and Th17 cells (Guo et al. 2019; Pollari et al. 2014). Such M2 macrophages are characterized by elevated rate of β-oxidation of fatty acids (mediated by carnitine palmitoyl transferase), mitochondrial OXPHOS and AMPK and reduced rate of glycolysis due to reduced production of HIF-1α and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 1 (PFKFB1) enzyme. High α-ketoglutarate/succinate ratio promotes M2 macrophage differentiation due to glutamine metabolism (Angajala et al. 2018). On the other hand, in ALS patients, M1 macrophages and dysfunctional Treg are unable to inhibit TH1and TH17 cells (Guo et al. 2019). M1 macrophages are characterized by augmented storage of fatty acids and production of NO, reduced level of mitochondrial OXPHOS and mitochondrial uncoupling protein 2 (UCP2) and elevated glucose uptake. Increased glucose uptake in M1 macrophages inhibits isocitrate dehydrogenase (ISD) and succinate dehydrogenase (SCD). Inhibition of ISD increases the level of citrate and itaconic acid. Citrate increases fatty acid synthesis for the production of prostaglandin and NO. Itaconic acid promotes antibacterial activity. Inhibition of SCD increases the level of succinate. Succinate induces HIF-1α-mediated IL-1β production. Thus, a very complex mode of interaction involving various regulatory pathways is involved in the pathogenesis of ALS.
Cancer cell shows modification in metabolism to cope up with the high proliferation and existence in different adverse microenvironment. This alteration can be characterized by elevated consumption of glucose and glutamine. The cells get dependent on glycolytic ATP and increase lipid synthesis for membrane biosynthesis (Pavlova and Thompson 2016). Warburg effect is the most significant phenomenon of cancer cell metabolic transformation, where glycolytic activity can be seen in cancer cells under aerobic condition (Warburg 1926). The correlation between oncogenic protein dysfunction and increase glycolysis in cancer has been explored with the help of recent advancements in cancer genetics and molecular biology (Levine and Puzio-Kuter 2010). Ras, c-Myc, BCL-ABL, Akt, EGFR and ALK are some of the genes or proteins which interact to upregulate a number of glycolytic enzymes or intermediates such as GLUT1, LDHA, F1,6-BP and HK2 to promote glycolysis in cancer cells (Lim et al. 2016; Ma et al. 2016; Miller et al. 2012). Tumor cells enhance glycolysis with the help of oncoproteins that trigger HIF activation by inflicting either hypoxia-independent mechanisms or pseudohypoxic state (Cheng et al. 2013). This activated HIF then activates various glycolytic enzymes such as PFK2, HK2, PKM2, PDK and LDHA (Edwards et al. 2017). The expression of LDHA, HK2, PFKM and GLUT1 is also regulated by transcription factor c-Myc, whose amplification and overexpression are commonly noticed in several tumors (Gao et al. 2009). These above-mentioned oncogenes are also important in glutamine metabolism (Csibi et al. 2014). The expressions of glutaminase 1 (GLS1) and glutamine transporters are also elevated by oncoprotein c-Myc for glutamate and glutathione generation. This process produces α-ketoglutarate to be used in the TCA cycle (Lunt and Vander Heiden 2011). Activation of glutaminolysis is also mediated by c-Myc with the help of various oncogenic pathways (Gaglio et al. 2011). K-Ras, another pro-oncogenic factor, is also mediated by oncoprotein for activation of glutamine metabolism. Upregulation of the MYC induces the transition of immature thymocytes to αβT-cell lineage (Bianchi et al. 2006). The increased level of MYC helps to upregulate IL-15 production, which facilitates the maturation and survival of CD8αα. MYC is also an important transcription factor in TCR-mediated survival and proliferation of T cell (Sosa et al. 2013). It also regulates the differentiation of Th17 and Th2 (Rice et al. 2018).
ADP is directly phosphorylated in cancer cells for ATP production. The amount of ATP produced through direct phosphorylation is much lower than that of mitochondrial oxidative phosphorylation (OXPHOS). Cancer cells may show increased production of energy than higher ATP production (Amelio et al. 2014). Moreover, ROS generation is associated with active OXPHOS as a by-product, which runs the risk of producing oxidative stress. That is why cancer cells follow the glycolytic pathway to avoid massive ROS production and oxidative damage to DNA, protein and cell membrane. This whole procedure favors the cancer cells with long-term survival. Some recent studies have demonstrated how the growth of tumor is benefitted from the oxidative neutrophils in cancer. Rice et al. have observed that, in neutrophils, c-kit signaling is upregulated by tumor, resulting in elevated function of mitochondria accompanied by the oxidative phenotype. This enhanced mitochondrial function helps the neutrophil to uphold the level of intracellular NADPH and helps in the production of reactive oxygen species (ROS) via NADPH oxidase in restricted glucose environment (Currie et al. 2013). These oxidative neutrophils also suppress T cells in glucose-restricted environment.
Intermediates of glycolytic pathway serve as precursors for specific amino acid biosynthesis and other essential lipids that are necessary for biological membrane biosynthesis (Vander Heiden et al. 2009; Yang et al. 2009). This is the reason behind choosing glycolysis over OXPHOS in cancer cells for energy supply. But again, studies have shown that, though glycolysis might be the primary pathway to fulfill rapid ATP generation, it is not efficient enough. Depending on the energy status of cancer cells, metabolism of glutamine is initiated (Zhdanov et al. 2015). Lower energy level activates glutamine dehydrogenase (GLUD) in cancer cells (Yang et al. 2013). This GLUD converts glutamate to α-ketoglutarate with the help of transcription factor HIF-1α (Dang et al. 2009). This HIF-1α is stabilized by 2-hydroxyglutarate (2-HG), which is produced from α-KG (Laurenti and Tennant 2016). α-KG is converted to 2-HG by a catalytic action of mutated IDH1 and IDH2, a common phenomenon seen in cancer cells (Palazon et al. 2014). Succinate dehydrogenase (SDH), fumarate hydratase (FH) and isocitrate dehydrogenase (IDH) are some of enzymes of TCA cycle which get mutated in cancer cells (Neumann et al. 2005). Transcription factor HIF has an important role to play in innate as well as adaptive immunity (Read et al. 2016). Calcium signaling can be modulated by HIF-1α, which upregulates the expression of sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) and stimulates TCR in thymocytes (Kumar and Gabrilovich 2014). TH17 cell differentiation is facilitated by the accumulation of HIF-1α via elevated production of IL-6 and IL-17 (Cheng et al. 2018). On the other hand, upregulation of HIF-1α inhibits Tr1 differentiation and prevents the secretion of IL-10, an anti-inflammatory cytokine (Currie et al. 2013). Through temporal and spatial regulation of different cellular mediators, HIF-1α maintains the fine balance between TH17 and Treg.
Elevated lipid synthesis is another significant metabolic change observed in cancer cells. The lipogenic phenomenon starts at the primary stage of tumorigenesis and at advanced stage of cancer the modification in cellular lipogenesis becomes much prominent (Wang et al. 2010). Fatty acid synthase (FASN) is the key enzyme that catalyzes the final step of FA synthesis (Maier et al. 2006). FASN upregulation is considered to be the nearly universal alteration phenomenon in major human malignancies. The mechanism behind overexpression of FASN and tumor has not yet been fully understood. The expression of other important lipogenic enzymes such as ACC and ACLY are also elevated along with FASN in cancer cells (Menendez and Lupu 2017). ACC1 is a rate-limiting enzyme which gets activated by high glucose associated with Ser-79 dephosphorylation induced by insulin (Fullerton et al. 2013). Recent studies have established strong correlation between ACC dysregulation and oncoproteins or tumor suppressors in cancer cells. ACC1 gets dephosphorylated and activated when BRCA1 (a human tumor suppressor gene) loses its function (Moreau et al. 2006). Studies have shown that mitochondrial uncoupling protein-2 (UCP2)-mediated lipogenesis is able to activate NLRP3 inflammasome in macrophages (Moon et al. 2015). Cancer cells can potentially modulate fatty acid metabolism in tumor-associated macrophages (TAMs) too to enhance their tumor-promoting capability. It was also reported that Lewis lung carcinoma cells were able to facilitate cancer cell invasion by activating macrophage-intrinsic IL-10 and FASN through macrophage colony-stimulating factor (M-CSF) production (Park et al. 2015b). Moreover, in another study, functioning upstream to nuclear PPARβ/δ, FASN was also found to be a factor-promoting tumor angiogenesis (Abdollahi et al. 2007; Berod et al. 2014). The enzyme ACC1, which produces malonyl coenzyme A from acetyl coenzyme A, regulates the differentiation of Th17 (Hensley et al. 2013).
Glutamine serves as the source of nitrogen and carbon in a network of growth-promoting pathways. As cancer cells show highly proliferative state, glutaminolysis is prevalent in these cells (Wise and Thompson 2010). Glutamine is essential for the majority of non-essential amino acid production in protein synthesis. For this reason, elevated addiction and consumption can be observed in various cancer cells (Alberghina and Gaglio 2014). With the help of tracer experiments, recent in vitro studies have shown that in protein synthesis, glutamine serves as the key source of more than half of the non-essential amino acids in growing cancer cells (Welbourne 1979). Glutamine metabolism also plays a huge role in glutathione production other than proteins, amino acids and nucleotide synthesis. Glutathione is a vital antioxidant essential for mediating immune defense of cells and various cellular functions (Botman et al. 2014). Recent studies have shown that glutamine may also take part in the synthesis of reduced equivalent of NADPH to lower glutathione. Taken together, the production of NADPH and glutathione is regulated by glutamine to neutralize ROS action, so that the cancer cells can be protected from oxidative stress (Altman et al. 2016).
Endogenous antioxidant defense mechanism
Innate immune cells protect our body from external pathogens by using ROS as a weapon, since activated macrophages and neutrophils produce free radicals to kill pathogens to a significant extent (Tan et al. 2016). However, these cells though use ROS production to elicit microbicidal activities, themselves are highly sensitive to external ROS. The reason seems to be the high polyunsaturated fatty acid (PUFA) content that these cells own (Calder 2018). Thus, immune cells are atypical in comparison with other somatic cells, as they contain high level antioxidant vitamins, presumably protecting from lipid peroxidation and consequent immunosuppression: two well-known risks posed by high PUFA content. Moreover, external antioxidant administration has been found to exert immune modulation in a number of cases. For example, vitamin E administration in healthy elderly individuals was reported to produce an increased antibody titer for tetanus vaccine and hepatitis B, hence uplifting T cell-based immune response (Sharma 2018).
Autoimmunity has been considered to be the result of a breakdown in self-tolerance for years.Treg, TH2, CD25 + and NK cells, etc. are highly crucial in terms of autoimmunity (Nakagawa et al. 2018). When animals with Th2-dominated autoimmune syndrome were administered with antioxidant N-acetyl-cysteine (NAC), the result was a decrease in the mast cell-induced IgE and IL-4 production (Jeannin et al. 1995). In another study, a benzoquinone-containing product from wheat germ fermentation was shown to elicit immune-restorative properties as it affects the TH1–TH2 network through TH2 response inhibition (Ehrenfeld et al. 2001). Side by side, another novel approach to prevent transplant rejection and autoimmunity was taken by activation of antioxidant heme-oxygenase-1 (HO-1). This is one of the key proteins involved in cellular stress response and is known to be upregulated in pro-inflammatory conditions (Araujo et al. 2012). Recent works have demonstrated that Treg overexpresses HO-1 and releases carbon monoxide that simultaneously inhibits proliferation of effector cytotoxic T cells, thus reducing the chances of autoimmunity and graft rejection. Moreover, polyphenols are also known to increase HO-1 in a number of in vitro systems too.
Superoxide dismutase (SOD1) is one of the major antioxidant enzymes that helps to cut down the mitochondria-based ROS production (Fukai and Ushio-Fukai 2011). Transgenic mice harboring mutated SOD1 develop symptoms similar to that of the human ALS. Mutant SOD1 toxicity damages motor neuronal mitochondria and thus providing a trigger for functional breakdown of motor neuron and resulting the onset of ALS in mice (Nagai et al. 2007).
Antioxidant vitamins, such as vitamin A, E, C and β-carotene, are some the cofactors modulating immune responses. Vitamin A deficiency that affects nearly 140 million preschool children all over the world is highly correlated with the severity of infections including rotavirus, measles and most importantly HIV (West Jr 2002). Importantly, low serum transretinol is common in infants of HIV-1-infected mothers. Vitamin A deficiency was also found to cause panhypogammaglobulinemia, a common primary immunodeficiency disorder. Moreover, low level of Vitamin A was also reported to be linked to high occurrence of splenomegaly as well as chronic bacterial infections (McDaniel et al. 2015). Though vitamin A deficiency affects both TH1and TH2-related responses, it seems that TH2 response is affected principally (Stephensen et al. 2004). Xerophthalmia patients having avitaminosis of vitamin A show impaired functions of neutrophils, NK cells and macrophages at the mucosal barrier, making them more susceptible to diarrhea, respiratory tract infections, etc. In such cases, supplementation with vitamin A has been reported to increase serum IgA and CD40 ligand-–activated IgG levels, leading to reduced inflammatory cytokines production (Ross et al. 2011).
Another strong antioxidant Vitamin E is known to support monocyte/macrophage-mediated responses. This not only reported to influence T-cell functions to downregulate prostaglandin E2, but also has been shown to reduce serum IgE level in atopic subjects, hence, relieving the allergic reactions. Currently, it is also suggested through a number of studies that people deficient in vitamin E level might have increased susceptibility to viral infections.
Ascorbate or vitamin C is a key regulator of redox and metabolic checkpoints. It is crucially involved in activation and survival of the immune cells mostly through influencing the cytokine production by them. Ascorbate upregulates inducible nitric oxide synthetase production through macrophage activation by LPS (Saini and Singh 2019). This seems to regulate phagocytosis by decreasing free radical production and, thus, limiting the severity toward endotoxin production. Recent works also demonstrate that supplementation with vitamin E and C attenuates stress exercise-induced increase of serum IL-6 by contracting skeletal muscle.
In this review, we have discussed about production of ROS, the metabolism of immune cells under different conditions and how oxidative stress influences different transcription factors which affect metabolic pathways to polarize immune cells. ROS and redox-regulatory system exert a profound effect on immune cells and their metabolism through mitochondrial, ER and cytoplasmic network involving various second messengers. Physiological level of ROS and excess production ROS culminating in oxidative stress influence various metabolic pathways such as glycolysis, OXPHOS and lipid metabolism (lipolysis and lipogenesis) in a different way. This difference in regulation of metabolism influences a wide array of immune cells, both innate and adaptive: both inflammatory and their non-inflammatory or regulatory counterparts. For example; mtROS can lead to immune response through activation of NLRP3 inflammasome and pro-inflammatory cytokines; at the same time, mtROS can influence longevity process and modulate immune response in a different way. This might be attributed to the spatial and temporal regulation of signaling pathways that help to sense ROS differently under a given circumstance and to elicit either adaptive response or inflammatory response. mtROS has also been reported to help in the polarization of macrophages. Polarization of macrophages requires reorganization of their metabolic requirements. There are some questions which still need to be clarified.
How do subcellular compartmentalization of ROS apart from mitochondrial regulate the immune and metabolic processes?
What are the factors that determine whether mtROS will lead to detrimental effect or beneficial effect?
What is the relation between ROS, gut microbiome and immunometabolism in normal physiological condition and various diseases such as cancer, diabetes and neurodegenerative disorders?
As we gain more insights into the details of this topic, it will be easier to clearly visualize the dynamic immunometabolism processes and the role of ROS which will help to develop therapeutic approaches for treatment of different inflammatory metabolic disorders.
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Banerjee, S., Ghosh, S., Mandal, A. et al. ROS-associated immune response and metabolism: a mechanistic approach with implication of various diseases. Arch Toxicol (2020). https://doi.org/10.1007/s00204-020-02801-7
- Oxidative stress