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Glutathione - The Immune System’s Best Kept Secret 🤫Glutathikne growing body of research has demonstrated Glutathion Importance of hydration GSH is a key player Cholesterol level prevention the immune system and the pathology of infection, inflammation and Healthy habits for athlete well-being disease [ ].
The role Hydration for team sports reactive oxygen species ROS that are generated during the Importance of hydration response Glutathiond by lymphocytes and the resulting oxidative kmmune has been revealed in more detail [ desponseEesponse ].
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The major reason as desponse why maintaining a healthy cellular responwe GSH level is imnune critical for the immune Importance of hydration is related to the fact that lymphocytes perform their bacterial, viral and cancer cell killing functions by generating large amounts of ROS including superoxide and hydrogen peroxide.
These free radicals are highly toxic and an exquisite fine control of how much and where in the cell they are generated is needed. Any overproduction of these ROS can be neutralised by glutathione GSH. However, the pace of oxidant generation can often outstrip the cellular production of glutathione GSH which leads to a cascade of oxidative stress, inflammation and tissue damage.
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: Glutathione and immune response| Cookies on this website | While mTOR upregulation plays a key role in the optimal function of activated neutrophils, it should be stressed that other enzymes and transcription factors are also important regulatory elements enabling pathogen destruction. This in turn restrains extreme inflammation and prevents excessive survival. On the other hand, AMPK regulates and restrains NF-κB and the production of proinflammatory cytokines, limiting tissue inflammation and destruction while optimizing chemotaxis and phagocytosis [ , ]. Finally, PPAR-γ also regulates migration and restrains inflammation by inhibiting NF-κB while stimulating IL production [ , ]. For example, excessive ROS fabrication may compromise the initiation and outcome of phagocytosis [ ], resulting in a dysregulated or decreased oxidative burst [ ] and production of NETs [ ]. Chronically upregulated ROS and cytokine production may also result in the internalization of membrane chemokine receptors, most notably CXCR2 [ ], thereby decreasing neutrophil migration. Upregulated NO inhibits neutrophil migration, crawling, and adhesion [ , , ]. Mechanistically, this is achieved via the downregulation of adhesion factors such as E-selectin, P-selectin, ICAM-1, and VCAM As a result, neutrophil binding to the endothelium is compromised, and subsequent crawling and transmigration to inflammatory centers are damaged [ ]. Neutrophil migration may also be hampered by increased production of peroxynitrite due to the combination of NO and superoxide cations [ , , , ]. There is evidence suggesting that the tyrosine nitration mediates inhibition of P-selectins [ , , ] and upregulation of haem oxygenase HO-1 -1 [ ]. A multitude of neutrophil functions is heavily affected by the cellular antioxidant system. For example, Nrf-2 activity influences the efficiency of neutrophil phagocytosis [ ], recruitment to inflammatory sites [ ], and prolonged survival [ ]. The glutathione system regulates various functions displayed by activated neutrophils most notably the stimulation of glutathione reductase. It sustains the neutrophil respiratory burst and NET production [ , ] influencing optimal phagocytic activity [ , ]. It is noteworthy that the basal activity of the GSH system in neutrophils appears to be lower than that found in myeloid cells [ ], rendering these immune cells vulnerable to depleted GSH levels [ ]. This may result in compromised cytoskeletal reorganization, affecting chemotaxis and transmigration and leading to reduced recruitment to sites of inflammation, impaired degranulation, and early apoptosis [ , ]. In this context, it should be noted that prolonged neutrophil activity depletes levels of GSH, likely due to excessive production of myeloperoxidase MPO during chronic nitro-oxidative stress and inflammation [ , , ]. This effect appears to be a result of the desensitization of neutrophils toward MCP-1 [ , ], thereby restraining neutrophil recruitment into inflammatory tissues [ ]. The mechanisms involved are not fully understood, but they appear to rely at least in part on the oxidation state of functional cysteine residues within the TRX protein [ ]. Table 3 summarizes the redox mechanisms that affect neutrophil functions, and the metabolic reprogramming of neutrophils is presented in Fig. Мodulation of effector functions of neutrophils. PRRs pattern-recognition receptors, GPCRs G protein-coupled receptors, NET neutrophil extracellular traps, ROS reactive oxygen species, PPP pentose phosphate pathway, FA fatty acid, ATP adenosine triphosphate, NF-kB nuclear factor NF-kappa-B, HIF1α hypoxia-inducible factor 1-alpha, mTOR mechanistic target of rapamycin, PI3K phosphatidylinositol 3-kinase, AMPK AMP-activated protein kinase, PPARγ peroxisome proliferator-activated receptor. Activation of T-cells follows the ligation of the T-cell receptor TCR and the major histocompatibility complex molecules by APC. Nuclear factor of activated T cell 1 NFAT1 , activation protein-1 AP -1, and NF-κB are triggered as a result of this signaling cascade [ ]. When TCRs are ligated, ROS production increases by mitochondria and NOXs [ ], which in turn regulates the signaling pathways required to enable and modulate T-cell activation, proliferation, and differentiation [ ]. Unsurprisingly, T-cell activation and differentiation require extensive metabolic reprogramming [ , , , , ]. However, it should be stressed that the metabolic reprogramming pathways of various T-cell subsets display important differences [ , , ]. The metabolic needs of naive and memory T and Treg cells are relatively modest and are met by reliance on OXPHOS and FAO [ , , ]. However, the differentiation and various effector functions of effector CD4 and CD8 cells require ATP obtained from aerobic glycolysis and NADPH. They are supplied by increased activity of the PPP and glutaminolysis, which is largely mediated by high levels of HIF1α and mTOR [ , , , , , ]. Important differences exist between subsets when it comes to FA metabolism and T-cell activation and differentiation. For example, effector T-cell activity relies on FA uptake and FAS while T memory cells utilize stored FA [ , ]. Uniquely, the relative reliance on FA uptake versus FA synthesis exerts a major influence on the differentiation of naive T cells into Tregs or Th cells [ , ]. In particular, uptake of environmental FA is a characteristic feature of Treg development, while Th differentiation counts on ACC-mediated FA synthesis [ , ]. TCR signaling also leads to the upregulation of amino acid transporters, facilitating the uptake of branch chain amino acids such as alanine, cysteine, leucine, glycine, and glutamine [ , , ]. These amino acids, in combination with high PPP activity, promote the rapid increase of GSH needed for T-cell survival and function [ ]. Augmented glutamine catabolism following T-cell activation, mediated by mitochondria-dependent oxidation, is of particular importance as the resultant increase in α-ketoglutarate production stimulates TCA activity and fuels increased OXPHOS [ , ]. TCR-dependent uptake of glutamine, valine, and leucine is implicated in inflammatory T-cell responses, the differentiation of Th-1 and Th cells, and the development of effector and memory CD8 cells [ , , , ]. ROS levels rise rapidly after TCR engagement and are critical in driving T-cell activation, proliferation, and differentiation [ , , , ]. Unsurprisingly, given the information discussed above, ROS influences the differentiation patterns and the disparate effector functions of various T lymphocytes. For example, the Th-2 polarized phenotype is encouraged by excessive microenvironmental ROS [ ]. Conversely, Th-1 and Th polarizations occur at low microenvironmental levels of ROS [ ]. Excessive ROS resulting from either high production or damaged cellular antioxidant defenses may lead to mitochondrial membrane polarization with fatal consequences for T-cell activation and survival following TCR engagement [ ]. Similarly, prolonged or chronic ROS upregulation may result in T-cell hyperresponsiveness, exhaustion, and anergy [ , , , , ]. Several mechanisms appear to underpin this phenomenon including compromised mitochondrial ETC activity and dynamics [ , ], upregulation of PD-1 [ , ], dysregulated NF-κB signaling, chronic IKKβ signaling [ , , ], and oxidation of functional cysteine groups in proteins [ , , ]. Finally, excessive ROS production may lead to dysregulated T-cell homeostasis by differential modulation of T-cell homeostasis as effector T cells are more susceptible to ROS-mediated cell death than Tregs [ , , ]. Nrf-2 transcription is upregulated following TCR engagement on naive T cells and restrains inflammatory T-cell activity. Thus, a Th-2 pattern is activated following TCR stimulation [ , ]. Animal studies show that the upregulation of Nrf-2 increases the proliferation of Tregs [ ] and amplifies their immunosuppressive and cytotoxic functions [ ]. As previously discussed, GSH synthesis rapidly escalates following TCR activation and affects T-cell survival and function [ ]. Increased de novo GSH synthesis also suppresses Th differentiation while encouraging the production of Tregs. Conversely, GSH depletion or loss of de novo GSH synthesis in a state of chronic nitro-oxidative stress [ ] compromises mTOR, NFAT, and N-Myc function. Thus, the metabolic reprogramming is abrogated enabling the maintenance of aerobic glycolysis and leading to the termination of T-cell activation [ , , ]. Tregs also appear to exert at least some of their cytotoxic and immunosuppressive functions on effector T cells by decreasing GSH synthesis [ ]. The TRX system activity exerts a range of influences on T-cell proliferation and activation via increased TRX-1 production. This restrains their stimulation and encourages the development of Tregs from naive T cells, decreasing their differentiation down the Th-1 and Th pathways [ ]. TRX-1 upregulation is important in enabling T effector and Treg cell survival and function during chronic nitro-oxidative stress by protecting membrane protein thiols from oxidation [ , ]. Increased TRX-1 activity is needed to maintain the production of IL-2 [ ] and Th-mediated activation of B cells [ ]. The metabolic reprogramming of T cells is depicted in Fig. Metabolic reprogramming of T and B cells. B-cell receptor BCR or cytokine-associated activation of naive B cells results in PI3K phospholipase C gamma 1 expression, leading to calcium mobilization and NF-κB activation and upregulation of c-Myc, HIF1α, AKT, mTOR, and STAT-6 [ ]. Once activated, these lymphocytes migrate to germinal centers and display high rates of glycolysis and OXPHOS [ , , ]. The short-term metabolic reprogramming and increased glycolysis are controlled by PI3K, HIF1α, AKT, and STAT-6 signaling [ , , ]. The role of mTOR appears to be confined to the upregulation of GLUT-1 [ ]. It is noteworthy that GSK-3 has a key role in regulating glycolysis in activated B cells and may also adjust ROS production and changes in mitochondrial dynamics [ , ]. However, while mTOR may not be the primary player in the regulation of glycolysis, sustained germinal center B-cell BCR signaling requires activation of mTOR [ , ]. mTOR is also involved in somatic hypermutation and in the formation of memory B cells [ , , ]. The relative levels of OXPHOS and glycolysis differ in plasmablasts and memory B cells, with glycolysis being dominant in the former and OXPHOS being dominant in the latter to enable their long-term survival [ ]. B1 and B2 subsets appear to display differing metabolic profiles, with PPP, FAO, and aerobic glycolysis being more active in B1 compared to B2 cells [ ]. The production of high-affinity antibodies by plasmablasts is an energetically demanding process and requires rapid increases in glucose consumption and mitochondrial mass accompanied by significant changes in mitochondrial dynamics [ , , ], reviewed in [ ]. Unsurprisingly, functional mitochondria are an indispensable element in B-cell differentiation and effector functions [ ]. The process of antibody synthesis is also regulated by AMPK, which enables memory B-cell formation and survival in part by regulating mitochondrial dynamics and suppressing the activation of mTOR [ , , ]. High levels of hydrogen peroxide are required to initiate and maintain BCR signaling [ , ]. This is primarily provided by the activity of NOX-2 [ ], but in the longer term, the source of hydrogen peroxide is mtROS [ , ]. In addition, the cellular redox state and mtROS release play a major role in B-cell survival and differentiation and IgM synthesis [ , ]. However, excessive mitochondrial mtROS synthesis may inhibit B-cell activation and the differentiation of B cells into antibody-producing plasmablasts [ ]. Increased concentrations of mtROS may also inhibit the production of antibodies by downregulating CD19 expression [ ]. Finally, chronically upregulated ROS can upregulate the consumption of IgM antibodies [ , ]. In this context, it is noteworthy that B-cell activation is accompanied by a concomitant stimulation of the TRX and GSH system, with the latter involving triggering of the cystine transporter xCT and higher uptake of cysteine [ ]. The intensive function of both systems correlates with elevated production of IgM [ ]. Finally, there is evidence associating increased Nrf-2 expression in activated B cells with prolonged survival and resistance to ROS-mediated apoptosis [ , , ]. Table 4 summarizes the redox mechanisms that affect B-cell functions, and the metabolic reprogramming of B cells is depicted in Fig. The signaling mechanisms involved in NK-cell activation [ , ] entail the engagement of multiple activation receptors such as natural cytotoxicity receptors [ , , ] leading to the stimulation of AP-1, NFAT, and NF-κB [ , ]. Cytoskeletal reorganization and release of chemokines, inflammatory cytokines, and lytic granules containing granzyme A, B, and perforin follows [ , , ]. Unsurprisingly, the various effector and regulatory functions of activated NK-cells are enabled by metabolic programming, which is underpinned by the upregulation of glucose-driven glycolysis, OXPHOS, increased FA synthesis, and glutamine metabolism [ , , , ]. Metabolic reprogramming, glycolysis, and mitochondrial activity are controlled by mTOR that is upregulated in NK cells following stimulation by IL and IL-3 [ , , ]. The high expression of this kinase is also responsible for increased FA synthesis and glutamine metabolism by activated NK cells via the upregulation of SREBPs and N-Myc [ , ]. The importance of mTOR and HIF1α in NK-cell proliferation and function is difficult to overemphasize as reduced HIF1α and mTOR activity are associated with loss of cytotoxic effects. It is evidenced by decreased production of perforin and granzyme B, and premature apoptosis [ , , ]. Increased ROS production enables NK-cell-mediated cytolysis by promoting the release of perforin and granzyme B [ ] and NK-cell division and proliferation after pathogen invasion [ ]. Nrf-2 activation serves as an immunological checkpoint following NK-cell activation [ , ]. The upregulation of GSH synthesis may enable the proliferation and cytotoxic functions of NK-cells and, conversely, GSH downregulation results in compromised functions and recruitment to sites of inflammation [ , , ]. In an inflammatory environment, the upregulation of TRX-1 plays a role in NK-cell survival by maintaining membrane cytoprotective sulfhydryl residues in a reduced state [ , ]. This phenomenon may protect those cells from hydrogen peroxide-mediated NK-cell dysfunctions [ , ]. However, this level of protection is clearly limited as chronic nitro-oxidative stress may result in NK-cell hypofunction and loss of cytotoxic activity [ , , , ]. There is evidence suggesting that this is due to compromised hydrogen peroxide signaling following NOX-2 hyperactivity [ ]. However, there is also proof that NK-cell function may be impaired by excessive production of NO [ ]. Table 4 summarizes the redox mechanisms that affect NK-cell functions, while Fig. Metabolic reprograming in NK-cells. AP-1 activator protein-1, NFAT nuclear factor of activated T cell, NF-kB nuclear factor NF-kappa-B, OXPHOS oxidative phosphorylation, FA fatty acid. In brief, HDL attenuates the activation of TLR-4 by stimulating cholesterol efflux from membrane lipid rafts MLR , NF-κB activity, DC maturation and activation, and antigen presentation to T lymphocytes. It also affects Th-1 and Th differentiation, T-cell and BCR activation, the complement system, and monocyte and macrophage chemotaxis [ 13 , 41 , 79 , 90 , ]. HDL-mediated MLR disruption underpins anti-inflammatory and immunosuppressive effects. HDL exerts a unique immunoregulatory role by activating pentraxin 3, an immunosensory molecule. ApoA1 regulates the balance between Th and Tregs, improves mitochondrial functions, increases the activity of the ETC, and stabilizes PON1 within the HDL particle, thereby maintaining PON1 activity. The latter protects against immune cell membrane lipid peroxidation, circulating oxidized lipoproteins, and oxidative damage to mitochondria. It positively affects glucose metabolism, PPP, FAO, PPAR-γ activity, and aerobic glycolysis via upregulation of GLUT-1 [ 41 , 90 ]. Evidence suggests that the bulk of oxidized phospholipids present in the circulation exists as immune complexes with natural IgM and IgG due to their status as oxidation-specific epitopes or neoantigens [ , ]. It is also proposed that oxidized phospholipid complexes are proinflammatory [ , ] using several routes, which include recruitment of the complement cascade [ ] and production of inflammatory responses in human macrophages largely by engagement of the Fc gamma receptor 1 [ , ]. These complexes may activate mature DCs leading to a primed inflammasome thereby exaggerating IFN-γ and IL-1 production [ , , ]. Moreover, DCs activated and primed via this mechanism may trigger naive T cells and induce Th polarization [ , , ]. As a result of activating neutrophil PRR, oxidized phospholipids contribute significantly to inflammation and oxidative stress and the formation of NETs [ , ]. The process effectively endows these leucocytes with a de facto memory, resulting in an amplified inflammatory or anergic response to future antigenic challenges [ , ]. The mechanisms driving the metabolic and epigenetic changes described above appear to depend, at least in part, on mTOR-induced assembly of NADPH oxidase and subsequent increases in ROS-mediated signaling [ , ]. The final part of this review deals with the detrimental effects of chronic oxidative and nitrosative stress on the immune response as a whole. In physiological conditions, NOX-derived cytosolic hydrogen peroxide regulates redox-sensitive intracellular signaling pathways [ , , , , ]. However, in conditions of excessive ROS production, hyperoxidation of thiolate anions to sulfonic acid essentially incapacitates reversible cysteine oxidation. It is an effective signaling mechanism, locking functional cysteines in the oxidized mode [ 90 , ]. The other signaling system involved in regulating the activity of redox-sensitive proteins and enzymes is reversible S-nitrosylation [ 17 , ]. However, pathological levels of ROS disable the mechanisms responsible for maintaining the reversibility of S-nitrosylation inducing a cellular state described as protein hypernitrosylation [ ]. Hyperoxidation and S-nitrosylation can result in impaired function of the redox-sensitive transcription factors and enzymes regulating metabolic reprogramming in immune cells. Compromised mitochondrial functions and seriously suppressed immune cell activation and function may follow. Chronic nitro-oxidative stress also affects the activity of HDL, apoA1, and PON1 whilst increasing the density of oxidized phospholipids further dysregulates the immune response [ 41 ]. Finally, chronic nitro-oxidative stress and inflammation also stimulate IDO that may result in a state of profound immune suppression [ ]. The section below deals with these processes, beginning with the effects of hypernitrosylation and hyperoxidation on transcription factors and enzymes. S-nitrosylation exerts a significant inhibition of NF-κB function by reducing the binding of its subunits to DNA thereby decreasing the activity of the complex as a transcription factor [ , , ], as well as the expression of target effector genes [ , ]. The outcomes involve decreased levels of IL [ ], IL-1β [ ], IL-6, IL-8, and iNOS [ , ]. Moreover, S-nitrosylation may inhibit TLR-4 [ , ] and TLR-2 signaling [ ]. S-nitrosylation is additionally involved in Nrf-2 triggering, which appears to be affected via the conformational modification of crucial thiol groups [ , , ]. Moreover, mTOR may be directly activated following S -nitrosylation of the tuberous sclerosis complex 2 [ ] and the nitrosylation of small GTPases [ ]. Prolonged nitrosylation may also compromise immune cells via the chronic upregulation of GSK-3 [ ]. In addition, in an environment of chronic nitro-oxidative stress, mTOR may be inactivated by oxidation of Cys [ ] and AMPK activation [ , ]. In an environment of increased ROS, several enzymes involved in regulating metabolic reprogramming in immune cells are triggered most notably via PPAR-γ [ , ]. The most prominent results are damage to the enzymes of the ETC [ , , , ] and a range of structural and functional phospholipids, basically cardiolipin [ , , ]. This ultimately leads to altered ATP production and accelerated ROS, provoking further impairement of macromolecules, forming the basis of self-amplifying pathology [ , , , ]. Increased NO production by mitochondria in an environment of nitrosative stress may also be a source of dysfunction and damage [ , , ]. In essence, two pathways are implicated. The first involves reversible inhibition of ETC enzymes by NO-mediated S-nitrosylation [ 17 , , ]. The second comprises irreversible nitration of functional enzymes and structural proteins by ONOO - [ , ]. This pattern of pathology leads to a vicious circle of bioenergetic failure and elevated mtROS production [ , , , ]. Clearly compromised mitochondrial function has many direct adverse effects on the activity of immune cells, as discussed above. However, mitochondrial dysfunction may also lead to numerous indirect negative consequences related to depleted levels of NADPH, which results from the distorted activity of this organelle [ , , ]. Lowered levels of malic enzyme 2 and IDH may affect the TCA cycle [ , ]. Chronic nitro-oxidative stress may cause nitrosylation and hyperoxidation of the key cysteine residues within TRX and thioredoxin reductase thereby compromising or abrogating TRX activity [ , , , ]. Mechanistically, this is achieved via the oxidation and nitrosylation or tyrosine nitration or via inhibiting the activity of GSH, glutathione peroxidase, and glutathione reductase [ 13 , , ]. Increased production of radical species also raises the activity of multidrug resistance-associated proteins, resulting in extrusion of GSH and GSSH into the intercellular environment. The decreased importation of cysteine, which follows, leads to reduced synthesis of replacement GSH [ , , , ]. A state of persistent nitro-oxidative stress may also cause Nrf-2 inhibition via several mechanisms, including activation of MAPK kinase, decreased DJ-1 [ , ], and reduced TRX system activity [ , ]. Such inactivated enzymes are α-ketoglutarate dehydrogenase [ , , ] and conitase, which catalyze the conversion of citrate to isocitrate [ , ], IDH [ , , ], ME2 [ , ], and pyruvate dehydrogenase kinase [ ]. The negative consequences of lowered α-ketoglutarate dehydrogenase and aconitase are of particular importance, and may lead to reduced TCA cycle activity and NADPH synthesis [ , ] and accumulation of citrate [ ]. The inactivation of pyruvate dehydrogenase kinase also results in adverse metabolic consequences by attenuating the conversion of pyruvate to acetyl-CoA [ ]. Chronic oxidative stress induces HDL [ , , ] and ApoA1 [ , , ] dysfunctions. PON1 is rendered dysfunctional in such an environment, which appears to be mediated by the high activity of MPO [ , , ]. The mechanisms underpinning the development of a dysfunctional HDL particle and reduced activity of ApoA1 are complex and readers are referred to the work of Morris et al. Chronic nitro-oxidative stress can induce the development of endotoxin tolerance by provoking IDO activation [ , ]. Increased IDO activity upregulates the tryptophan catabolite TRYCAT pathway, as well as TGF-β1 and IL [ , ], which exert multiple inhibitory effects on TLR signaling [ , ]. Neutrophils with endotoxin tolerance are characterized by decreased oxidative burst, downregulated TLR-4 receptors, and impaired cell adhesion, rolling, and migration [ , , ]. Macrophages with endotoxin tolerance display significant dysregulation of their function as APCs [ ]. Impaired antigen presentation is also seen in DCs following IDO activation [ ]. In this state, DC activation of naive T cells leads to Th-2 polarization [ , ]. DCs may inhibit T memory and T effector cells and induce CD4 and CD8 T-cell anergy and activation of Tregs [ , ]. This explains that prolonged endotoxin tolerance is typified by impaired proliferation and anergy of CD4 T and CD8 T cells and increased Treg cell numbers [ , , ]. Finally, endotoxin tolerance is characterized by a reduced number and cytolytic function of NK cells [ , , ]. Hypernitrosylation and chronic nitro-oxidative stress may inhibit these antioxidant systems, thereby decreasing the activity levels of the TCA cycle, mitochondrial functions, and immune cell metabolism. As such, redox mechanisms regulate and modulate many different immune functions, including but not limited to macrophage and Th cell polarization, phagocytosis, production of pro- and anti-inflammatory cytokines, metabolic reprogramming of immune cells, immune training and tolerance, chemotaxis, pathogen sensing, antiviral and antibacterial effects, TLR activity, and endotoxin tolerance. Griffith JW, Sokol CL, Luster AD. Chemokines and chemokine receptors: positioning cells for host defense and immunity. 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NF-κB signaling in macrophages: dynamics, crosstalk, and signal integration. Liu T, Zhang L, Joo D, Sun S-C. NF-κB signaling in inflammation. Signal Transduct Target Ther. Ernst O, Vayttaden SJ, Fraser IDC. Measurement of NF-κB activation in TLR-activated macrophages. Methods Mol Biol Clifton, NJ. Sharif O, Brunner JS, Vogel A, Schabbauer G. Macrophage rewiring by nutrient associated PI3K dependent pathways. Vergadi E, Ieronymaki E, Lyroni K, Vaporidi K, Tsatsanis C. J Immunol. Joshi S, Singh AR, Zulcic M, Durden DL. A macrophage-dominant PI3K isoform controls hypoxia-induced HIF1α and HIF2α stability and tumor growth, angiogenesis, and metastasis. Mol Cancer Res. Arranz A, Doxaki C, Vergadi E, Martinez de la Torre Y, Vaporidi K, Lagoudaki ED, et al. Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization. Cheng SC, Quintin J, Cramer RA, Shepardson KM, Saeed S, Kumar V, et al. mTOR- and HIF-1 -mediated aerobic glycolysis as metabolic basis for trained immunity. ha AK, Huang SC-C, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Feingold KR, Shigenaga JK, Kazemi MR, McDonald CM, Patzek SM, Cross AS, et al. Mechanisms of triglyceride accumulation in activated macrophages. van Uden P, Kenneth Niall S, Rocha S. Regulation of hypoxia-inducible factor-1α by NF-κB. Biochemical J. Freemerman AJ, Johnson AR, Sacks GN, Milner JJ, Kirk EL, Troester MA, et al. Metabolic reprogramming of macrophages. Wang T, Liu H, Lian G, Zhang S-Y, Wang X, Jiang C. HIF1α-induced glycolysis metabolism is essential to the activation of inflammatory macrophages. Mediators Inflamm. Pavlou S, Wang L, Xu H, Chen M. Higher phagocytic activity of thioglycollate-elicited peritoneal macrophages is related to metabolic status of the cells. J Inflamm Lond. Blouin CC, Pagé EL, Soucy GM, Richard DE. Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1α. Cimmino F, Avitabile M, Lasorsa VA, Montella A, Pezone L, Cantalupo S, et al. HIF-1 transcription activity: HIF1A driven response in normoxia and in hypoxia. BMC Med Genet. Semenza GL. Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning. Biochim Biophys Acta. Okamoto A, Sumi C, Tanaka H, Kusunoki M, Iwai T, Nishi K, et al. HIFmediated suppression of mitochondria electron transport chain function confers resistance to lidocaine-induced cell death. Kierans SJ, Taylor CT. Regulation of glycolysis by the hypoxia-inducible factor HIF : implications for cellular physiology. J Physiol. Percival, Immunomodulatory Effects of Glutathione, Garlic Derivatives, and Hydrogen Sulfide. Nutrients, Checconi, P. Ballatori, N. Previous article Glutathione and Gastrointestinal Disease. Next article Glutathione and Lung Disease. You may also like. Glutathione Depletion in Mitochondrial Diseases. Glutathione and Eye Disease. Glutathione and other diseases. LEAVE A REPLY Cancel reply. Comment: Please enter your comment! Recent posts. Glutathione Depletion in Mitochondrial Diseases January 27, Glutathione Depletion and Osteoporosis November 26, Glutathione and Cystic Fibrosis December 18, All Rights Reserved. To support our immune system, we can consume immunity supporting supplements. Glutathione is an important ingredient that we want to mention in this list of immune support ingredients. Glutathione is a combination of three simple building blocks of protein or amino acids-cysteine, glycine, and glutamine-and is produced naturally in the body. Free radicals are often the byproduct of normal cellular metabolic oxidation and toxic overload. They can lead to autoimmune diseases, several types of cancer, and even heart attacks. Keeping yourself healthy, boosting your performance, preventing disease, and aging well all depend on keeping glutathione levels high. It is crucial for immune function and controlling inflammation. Researchers have indicated that a healthy immune system depends on well-functioning and healthy lymph cells infused with a balanced level of glutathione. Eating, exercising, and even breathing result in the creation of free radicals. These imbalanced molecules attack your body at the cellular level, robbing other molecules of electrons and setting off a chain reaction. This constant barrage impacts overall health and wellness, as well as how quickly you age. Like most antioxidants, glutathione works by supplying an extra electron to unpaired free radical molecules, returning them to a benign state. |
| Glutathione and the Immune system | Biochemistry Mosc. Submit Desponse. Yang Polyphenols and fertility, Gu J, Lv H, Li H, Cheng Glutathione and immune response, Liu Y, Adn al. As a result, neutrophil amd to the endothelium is compromised, and subsequent crawling and transmigration to inflammatory centers are damaged [ ]. TNF receptor I sensitizes neurons to erythropoietin- and VEGF-mediated neuroprotection after ischemic and excitotoxic injury. Mol Cancer Res. Reviewed by: Cecilia GarlandaIstituto Clinico Humanitas, Italy Shi YueUniversity of Southern California, United States. |
| Glutathione helps fortify immune system against the coronavirus - Ingredients Insight | Sekhar RV, et al. Deficient synthesis of glutathione underlies oxidative stress in aging and can be corrected by dietary cysteine and glycine supplementation. Minich DM, Brown BI. A Review of Dietary Phyto Nutrients for Glutathione Support. Kwon DH, et al. Protective Effect of Glutathione against Oxidative Stress-induced Cytotoxicity in RAW Gould RL, Pazdro R. Impact of Supplementary Amino Acids, Micronutrients, and Overall Diet on Glutathione Homeostasis. Kumar P, et al. Glycine and N-acetylcysteine GlyNAC supplementation in older adults improves glutathione deficiency, oxidative stress, mitochondrial dysfunction, inflammation, insulin resistance, endothelial dysfunction, genotoxicity, muscle strength, and cognition: Results of a pilot clinical trial. Diotallevi M, et al. Glutathione Fine-Tunes the Innate Immune Response toward Antiviral Pathways in a Macrophage Cell Line Independently of Its Antioxidant Properties. Sinha R, et al. Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. Aoyama K. Glutathione in the Brain. Sechi G, et al. Salim S. Oxidative Stress and the Central Nervous System. Stine D. The effects of 3 weeks of oral glutathione supplementation on whole body insulin sensitivity in obese males with and without type 2 diabetes: a randomized trial. Beever A, et al. L-GSH Supplementation in Conjunction With Rifampicin Augments the Treatment Response to Mycobacterium tuberculosis in a Diabetic Mouse Model. Correcting glutathione deficiency improves impaired mitochondrial fat burning, insulin resistance in aging Honda Y, et al. Efficacy of glutathione for the treatment of nonalcoholic fatty liver disease: an open-label, single-arm, multicenter, pilot study. Ballatori N, et al. Glutathione dysregulation and the etiology and progression of human diseases. Shah D, et al. Interaction between glutathione and apoptosis in systemic lupus erythematosus. Carlo Perricone, et al. Glutathione: A key player in autoimmunity. Severe Glutathione Deficiency, Oxidative Stress and Oxidant Damage in Adults Hospitalized with COVID Implications for GlyNAC Glycine and N-Acetylcysteine Supplementation. Sido B, et al Impairment of intestinal glutathione synthesis in patients with inflammatory bowel disease Aoi W, et al. Glutathione supplementation suppresses muscle fatigue induced by prolonged exercise via improved aerobic metabolism. Goutzourelas N, et al. GSH levels affect weight loss in individuals with metabolic syndrome and obesity following dietary therapy. Seymour EM, et al. Diet-relevant phytochemical intake affects the cardiac AhR and nrf2 transcriptome and reduces heart failure in hypertensive rats. Lenzi A, et al. Glutathione therapy for male infertility. Coppola L, et al. Glutathione GSH improved haemostatic and haemorheological parameters in atherosclerotic subjects. Sedlak, T. et al Sulforaphane Augments Glutathione and Influences Brain Metabolites in Human Subjects: A Clinical Pilot. Park, S. Vitamin C in Cancer: A Metabolomics Perspective. Flaim, C. Effects of Whey Protein Supplementation on Oxidative Stress, Body Composition and Glucose Metabolism Among Overweight People Affected by Diabetes Mellitus or Impaired Fasting Glucose: A Pilot Study Gulec, A. Berry, S Changes in Glutathione System in Response to Exercise Training are Sex-Dependent in Humans. Ramgir, S et al Impact of Smoking and Alcohol Consumption on Oxidative Status in Male Infertility and Sperm Quality. Allen J, Bradley RD. Effects of oral glutathione supplementation on systemic oxidative stress biomarkers in human volunteers. Richie JP Jr, et al. Randomized controlled trial of oral glutathione supplementation on body stores of glutathione. Below are the best ways. to increase glutathione in your body:. That said, the publication does indeed point to the important mechanisms involved with glutathione and a deficiency thereof. We definitely recommend glutathione for immune support. Call: to order today. BOOK IV THERAPY TODAY! LEARN MORE ULTIMATE IMMUNE BUNDLE: Emulsi-D3 Synergy 2fl oz Liposomal Vitmain C 4fl oz Liposomal Glutathione 1. Your email address will not be published. com Facebook Instagram. Facebook Instagram. July 9, GlutathionE and YOUR IMMUNE SYSTEM. BY MATTEO ROSSELLI, D. Glutathione plays some major roles in immune function. However, most of that evidence is based on in vitro or in vivo experiments using exogenously administered thiol antioxidants or pro-oxidants. What our data do not support is the extrapolation of evidence from those experiments to the conclusion that GSH is an endogenous anti-inflammatory molecule through its ROS-scavenging activity. In fact, previous reports noted that exogenous GSH or its precursor NAC inhibits the production and expression of TNF, IL-6, and IL-8 by LPS-stimulated macrophages in the absence of any significant change in intracellular GSH The results reported here are also in agreement with our previous studies where we observed that there are more H 2 O 2 -induced genes that require GSH for their upregulation than genes whose induction by H 2 O2 is exacerbated by GSH depletion Interestingly, in that study using human monocytic cells, many of the H 2 O 2 -induced genes for which GSH had a facilitatory role were related to immunity In addition, the only LPS-induced transcripts mapping to innate immunity in their functional annotation were inhibited, rather than upregulated, by GSH depletion Group 2 genes. Not only innate immunity genes in Group 2 require GSH for their induction but also they were not induced by ROS alone using menadione as a ROS-generating chemical and their LPS induction was not inhibited by NAC, ruling out the possibility that ROS act as signaling molecules in their induction by LPS. The only exception was il1b whose LPS induction was inhibited by NAC but was also inhibited by GSH depletion, suggesting that GSH is important for IL-1b induction by LPS but possibly not through an antioxidant mechanism because i exogenous NAC and endogenous GSH appear to have an opposite role, and ii an oxidant alone does not induce IL-1b expression. In line with these findings, it has been shown that molecules altering intracellular thiol content with different mechanisms i. The innate immune response is also important for antiviral defense and activation of TLR4 leads to induction of antiviral proteins including IFNs and IFN-related genes 27 , 28 such as MxA and Oas 29 , Our data, although obtained in a model where infectivity was low, suggest that GSH is important for the activation of an antiviral response. This happens without affecting inflammatory genes, except for IL-1b whose induction was also facilitated by the presence of GSH. There is evidence for a fine-tuning of TLR signaling 31 , and these data indicate that GSH may be important in directing it toward specific small patterns of genes implicated in host defense rather than toward those responsible for the inflammatory response, as outlined in Figure Figure GSH fine-tuning of TLR4 signaling. GSH orients the TLR4-mediated changes in gene expression profile toward activation of host defense. GSH, glutathione; LPS, lipopolysaccharide; TLR4, toll-like receptor 4. The behavior of genes in Group 1 is what one would expect. They include enzymes for GSH synthesis and antioxidant enzymes such as Prdx1, Srxn1, and Hmox. All these genes map to nrf2, a master regulator of redox homeostasis Their regulation by BSO is in accordance with the hypothesis that endogenous GSH acts as an ROS scavenger because menadione induces their expression. However, NAC did not inhibit their induction by LPS, suggesting that LPS induces nrf2 target gene expression independently of the increase in ROS production. This agrees with a recent study by Cuadrado et al. showing that LPS can activate nrf2 via the small GTPase RAC1, independently of ROS In this picture, endogenous GSH might be important through other mechanisms than just scavenging ROS. In fact, nrf2 activation is dependent on oxidation of its redox sensor, keap1. Several studies have indicated that activation of nrf2 by administration of electrophilic compounds has an anti-inflammatory effect and decreases LPS-induced transcription of other NF-kB target genes, including TNF, IL-1b, and IL-6, in RAW cells 35 , However, as mentioned earlier, in our experimental conditions in which nrf2 was likely activated by GSH depletion, as suggested by the increased expression of nrf2 target genes, we have not observed an effect on any inflammatory cytokine other than IL-1b. Once again, the difference might be that we did not use exogenous electrophiles to induce nrf2. This highlights one point that is often overlooked. GSH is not just an antioxidant that participates in ROS elimination either via its direct ROS scavenging activity or as a substrate for GSH peroxidases but, like any other thiol including NAC, is also a reducing agent, as well as GSSG is a thiol oxidizing agent. Therefore, these two molecular species, GSH and GSSG, can regulate biological pathways in a redox-dependent manner, independently of ROS scavenging. In fact, protein glutathionylation is a major mechanism of redox regulation of immunity 10 , 37 , affecting the function of key proteins including NF-kB 38 , STAT3 39 , PKA 40 , TRAF3, and TRAF6 41 , as well as participating in the release of danger signals 42 , However, in this experimental model, the induction of host defense genes in Group 2 at least those shown in Figure 7 , il1b, Mx2, and Irf9 is inhibited by BSO, evidencing the need for GSH, but is not amplified by NAC, suggesting that scavenging LPS-induced ROS is not the main mechanism of action of endogenous GSH. The finding that several genes that are important for the antiviral response, mostly part of IFN signaling pathways, including the antiviral proteins Oas and Mx2, require GSH for optimal induction by LPS adds knowledge to previous findings, indicating that GSH can inhibit viral infection 44 , 45 and that viral infection causes release of glutathionylated thioredoxin and Prdx There is a large body of evidence showing the importance of GSH in immunity, including antiviral immunity 47 , but so far this was ascribed to its action as ROS scavenger to inhibit oxidative stress. The present study indicates that GSH has other important signaling roles independently of protection from oxidative stress, and its action may not be vicariated by another thiol antioxidant. However, to understand the validity of our conclusions to other models, one needs to bear in mind the limitations of this study that is investigating mRNAs in a cell line. Future studies will need to measure the proteins of interest for instance, IL-1b to see whether the changes observed at the level of transcripts are reflected in changes in protein levels. To generalize the relevance of this mechanism, the observation will need to be confirmed in primary cells, including human cells, and possibly in vivo. MD, PC, MM, IC, LC, FP, and KA performed experiments. AH, PG, KA, LC, MM, FP, and AP designed and supervised experiments. MD, PG, MM, FP, and PC wrote the paper. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. This work was supported by a fellowship program from Istituto Pasteur Italia——Fondazione Cenci Bolognetti to PC , PRIN CUP grant number B to AP , and RM Phillips Trust to PG. File S1. Transcripts in bold are those also significantly affected by BSO alone BSO vs control, with a cutoff of FC 1. The log 2 -transformed gProcessed signals of the three biological replicates are shown. The FC between the two groups indicated is expressed as log 2 ratio. File S2. NF-kB target genes upregulated by LPS. Transcripts in bold are those in Group 2 significantly affected by BSO with a cutoff of 1. BSO, buthionine sulfoximine; LPS, lipopolysaccharide. Ghezzi P, Jaquet V, Marcucci F, Schmidt HH. The oxidative stress theory of disease: levels of evidence and epistemological aspects. Br J Pharmacol 12 — CrossRef Full Text Google Scholar. Haddad JJ, Harb HL. L-gamma-glutamyl-L-cysteinyl-glycine glutathione; GSH and GSH-related enzymes in the regulation of pro- and anti-inflammatory cytokines: a signaling transcriptional scenario for redox y immunologic sensor s? Mol Immunol — PubMed Abstract CrossRef Full Text Google Scholar. Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal — Bernard GR, Lucht WD, Niedermeyer ME, Snapper JR, Ogletree ML, Brigham KL. Effect of N-acetylcysteine on the pulmonary response to endotoxin in the awake sheep and upon in vitro granulocyte function. J Clin Invest — Villa P, Saccani A, Sica A, Ghezzi P. Glutathione protects mice from lethal sepsis by limiting inflammation and potentiating host defense. J Infect Dis — Szakmany T, Hauser B, Radermacher P. N-acetylcysteine for sepsis and systemic inflammatory response in adults. Cochrane Database Syst Rev 9:CD Fraternale A, Crinelli R, Casabianca A, Paoletti MF, Orlandi C, Carloni E, et al. PLoS One 8:e Nathan C, Cunningham-Bussel A. Nat Rev Immunol — Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Curr Biol R— Ghezzi P. Protein glutathionylation in health and disease. Biochim Biophys Acta — Rosenblat M, Aviram M. Macrophage glutathione content and glutathione peroxidase activity are inversely related to cell-mediated oxidation of LDL: in vitro and in vivo studies. Free Radic Biol Med — Yang X, Yao H, Chen Y, Sun L, Li Y, Ma X, et al. Inhibition of glutathione production induces macrophage CD36 expression and enhances cellular-oxidized low density lipoprotein oxLDL uptake. J Biol Chem — Kobayashi M, Li L, Iwamoto N, Nakajima-Takagi Y, Kaneko H, Nakayama Y, et al. The antioxidant defense system Keap1-Nrf2 comprises a multiple sensing mechanism for responding to a wide range of chemical compounds. Mol Cell Biol — Rahman I, Kode A, Biswas SK. Assay for quantitative determination of glutathione and glutathione disulfide levels using enzymatic recycling method. Nat Protoc — Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem — Zhao H, Joseph J, Zhang H, Karoui H, Kalyanaraman B. Synthesis and biochemical applications of a solid cyclic nitrone spin trap: a relatively superior trap for detecting superoxide anions and glutathiyl radicals. Abbas K, Hardy M, Poulhes F, Karoui H, Tordo P, Ouari O, et al. Detection of superoxide production in stimulated and unstimulated living cells using new cyclic nitrone spin traps. Abbas K, Babic N, Peyrot F. Use of spin traps to detect superoxide production in living cells by electron paramagnetic resonance EPR spectroscopy. Methods — Sturn A, Quackenbush J, Trajanoski Z. Genesis: cluster analysis of microarray data. Bioinformatics —8. Taoufik E, Petit E, Divoux D, Tseveleki V, Mengozzi M, Roberts ML, et al. TNF receptor I sensitizes neurons to erythropoietin- and VEGF-mediated neuroprotection after ischemic and excitotoxic injury. Proc Natl Acad Sci U S A — Nencioni L, Iuvara A, Aquilano K, Ciriolo MR, Cozzolino F, Rotilio G, et al. Influenza A virus replication is dependent on an antioxidant pathway that involves GSH and Bcl FASEB J — Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Kwon AT, Arenillas DJ, Worsley Hunt R, Wasserman WW. oPOSSUM advanced analysis of regulatory motif over-representation across genes or ChIP-Seq datasets. |
Glutathione and immune response -
It found that cells in the hippocampus which is key to memory and learning and amygdala a hotbed of emotional regulation may be most susceptible to oxidative stress.
Promising research suggests that even healthy brains could get a cognitive boost from supplementation that improves glutathione levels 6.
Beyond the link to oxidative stress, higher GSH levels have been linked to improved insulin sensitivity—how sensitive your body is to the effects of insulin—which has been associated with a lower risk for diabetes People with type 2 diabetes have lower levels of glutathione, says Venketaraman.
Other research on aging mice 14 also found that eating foods that were high in cysteine and glycine which, remember, are amino acids used to make glutathione boosted their ability to burn fat and improved insulin resistance.
A lack of antioxidants, including glutathione, may lead to fatty liver disease. And GSH supplementation may improve liver function.
One study found that people with non-alcoholic fatty liver disease who took high doses of GSH intravenously for four months saw positive improvements in liver health Large-scale research published in 16 connected disturbances in glutathione homeostasis with everything from cancer to metabolic, immune, and inflammatory diseases.
All of these conditions have been linked to oxidative stress, and if you can stave them off, you have a better chance of living longer, says Venketaraman. More recent research from Baylor College of Medicine in Houston found that glutathione increases lifespan in mice by 24 percent 6.
Oxidative stress has been linked to age-related illnesses and conditions. Stop it in its track with glutathione. One study noted a strong link between oxidative stress and apoptosis—a normal process of programmed cell death—in patients living with lupus, an autoimmune disease.
A recent study published in the journal Antioxidants 19 found that people who contracted the COVID virus and were hospitalized had significantly increased levels of oxidative stress, and significantly lower levels of glutathione, when compared to blood samples from healthy adults of the same age.
The study authors suggest that giving glutathione precursors to people who test positive for COVID might help treat the disease, though they note that more research is needed.
Venketaraman notes that glutathione may also help people suffering from long Covid. People with inflammatory bowel disease IBD in particular may find glutathione helpful. People with IBD have decreased activity of the enzymes involved in glutathione synthesis, and lower levels of its main ingredient, cysteine IBD is also an autoimmune disease, Venketaraman points out.
It may also restore cytokine balance to diminish the extent of the disease. If taken before a workout, glutathione may enhance your gains. In one small study, men who received glutathione before a workout performed better and felt less fatigued after their exercise session Another study in healthy older adults showed supplementing with glyNAC, which increases glutathione levels, led to improvements in strength, gait speed, and body composition 6.
Metabolic syndrome is a cluster of health conditions—including high blood pressure, elevated blood sugar, high cholesterol, high triglycerides, and a high waist circumference—which can raise the risk for diabetes, heart disease, and stroke.
One study in the journal Experimental and Therapeutic Medicine 22 found that adults who were diagnosed with metabolic syndrome and who initially tested with higher glutathione levels lost more weight and showed greater reductions in body fat after following a healthy eating plan for six months.
Glutathione appears to protect against heart disease—at least in animals. Scientists at the University of Michigan Health System put rats with high blood pressure on an antioxidant-rich diet of grapes.
After 18 weeks, they found that rats were less likely to suffer from heart muscle enlargement a sign of heart failure. The animals also had better blood pressure numbers. In one study of eleven infertile men, glutathione had a significant positive effect on sperm motility after 2 months of treatment Atherosclerosis is a condition caused by a build-up of plaque in the arteries that can lead to heart disease and stroke.
In one study, ten patients with atherosclerosis were administered glutathione. Researchers noted a significant increase in blood filtration, in addition to a significant decrease in blood thickness Adopting healthy habits like getting enough sleep, exercising, and cutting back on alcohol use can keep glutathione levels healthy 29 , 30 , Research around oral glutathione is mixed on whether supplements are an effective way to boost your levels 32 , 33 since the antioxidant is poorly absorbed during digestion.
Milk thistle and N-acetyl cysteine NAC are supplements that can boost glutathione in the body. Milk thistle supports liver function, while NAC provides cysteine, a precursor for glutathione synthesis. A more effective route is glutathione injections. Injections bypass the gut and deliver glutathione directly into the bloodstream.
The antioxidant is injected directly into the muscle usually your glutes or upper arm or subcutaneously. You can ask your physician about glutathione injections. You can also work with Hone. Then, a healthcare professional who is licensed in your state will review your request, and, if he or she thinks that you might benefit from glutathione injections, a prescription for the shots will be sent to the pharmacy.
Good question. In some cases, you could have itching, irritation, or redness at the injection site. You should seek medical attention if you develop swelling of the lips, throat or tongue, hives, difficulty breathing, fever, chills, or if lumps under the skin are raised, red, draining pus, warm to the touch, or severely painful.
By Tracy Middleton Medically reviewed by Jack Jeng, M. December 6, What is Glutathione? Glutathione Facts. Glutathione is an important antioxidant that may extend lifespan, boost immunity, improve strength and physical performance, and reduce the risk for age-related diseases.
The primary role of glutathione is to fight against free radicals, which cause oxidative stress. Why Is Glutathione Important? Glutathione in the Body. Glutathione prevents the formation of free radicals.
GSH also helps detoxify the body and keeps your immune system strong. Are You Ready to Meet the Master Antioxidant? Let's Get Started. Boost immunity Want to boost immune function?
CIC is upregulated by several inflammatory mediators such as tumor necrosis factor TNF -α, IFN-γ, or commensal LPS via the upregulation of NF-κB and or STAT-1 [ 92 , 95 ]. In this scenario, citrate exerts a multiplicity of vital roles, enabling macrophage function and inflammatory status such as increasing NO, ROS, and prostaglandin E2 PGE2 production [ 92 , 96 ].
Cytosolic citrate can also act as a source of NADPH, either as a result of malate import into mitochondria via CIC, and the subsequent formation of pyruvate via malic enzyme, or the conversion of citrate into alpha-ketoglutarate via the action of cytosolic IDH [ 97 , 98 ].
Cytosolic citrate is also a substrate of ACLY, producing acetyl-CoA and oxaloacetate and upregulating acetyl-CoA carboxylase ACC stimulating lipid synthesis [ 99 ].
Activated M1 polarized macrophages are characterized by high levels of cytosolic itaconate from cis-aconitate drawn from the Krebs cycle via a significant inflammation-mediated upregulation of macrophage aconitate decarboxylase 1 [ , ]. Itaconate is involved in tolerance and suppression of inflammation [ , ], inhibits mitochondrial respiration, stabilizes HIF1α, and activates Nrf-2 via alkylation of KEAP-1 [ 84 , ].
Finally, itaconate accumulation leads to the inhibition of succinate dehydrogenase, directing the accumulation of succinate and leading to numerous proinflammatory and prooxidative consequences [ , , ].
As a result, large increases in the genesis and release of ROS follow [ , ]. High levels of cytosolic succinate may induce an increase in lysine group succinylation in the cellular proteome, which many influence protein activity via changes in charge and conformation [ ].
The mechanisms involved are beyond the scope of this review, but it is important to note that this post-translational modification offers another route relaying subtle redox-mediated metabolic changes to protein function [ ].
Finally, once externalized, succinate can bind to the G protein-coupled succinate receptor 1 SUCNR1 that is expressed on the surface of activated M1 polarized macrophages [ , ]. This is a mechanism involved in sustaining and amplifying their inflammatory effects [ 12 , ].
The latter then triggers a wide range of M2-associated genes including GATA binding protein 3 GATA3 , CD36, arginase-1 Arg1 , matrix metalloproteases MMPs , FIZZ1, and PPARγ [ , ].
IL-4 and IL also upregulate the activity of transforming growth factor TGF -β, suppressor of cytokine signaling 1 SOCS-1 , and insulin-like growth factor 1 IGF-1 that act to suppress the production of proinflammatory cytokines and promotes tissue repair [ , , ].
Unlike M1 polarization, M2 polarization is associated with a return to OXPHOS and increased FAO [ , ]. In addition, M2 polarized macrophages possess an intact TCA cycle [ , ]. M2 macrophages are also characterized by activation of the nuclear liver X receptor LXR thereby regulating lipid synthesis and cholesterol homeostasis [ ].
Overexpression of LXR inhibits NF-κB and activator protein-1 AP-1 to reduce M1 responses and inflammation [ , ]. One major element reinforcing the transition from M1 to M2 polarization is the change in the metabolism of arginine.
In M1 polarized macrophages, elevated activity of iNOS leads to the metabolism of arginine to produce citrulline and NO. The latter is a major element in maintaining the switch toward aerobic glycolysis as explained above [ 84 ].
However, in M2 polarized macrophages, the increased transcription of arginase-1 metabolizes arginine to ornithine and urea.
They both play a vital role in M2 macrophage survival, proliferation, and tissue repair [ , ]. Glutamine metabolism is also of particular importance in M2 macrophages for two main reasons.
Firstly, oxidation of this amino acid is an essential source of acetyl-CoA in an inflammatory environment leading to depleted extracellular glucose levels thereby maintaining TCA activity [ , , ].
Secondly, glutaminolysis-mediated increase in α-ketoglutarate and the activation of the glutamine—UDP- N -acetylglucosamine GlcNAc pathway reinforce M2 polarization [ ]. There are major differences in the regulation of the metabolic bioenergetic pathways involved in the transition to M2 polarization compared to those governing M1 polarization.
In the case of M2 polarization the main players are AMPK and PPARγ whose activities are briefly described below. AMPK stimulates OXPHOS and FAO while inhibiting NF-κB and mTOR.
This, in turn, decreases inflammation, reduces the levels of HIF1α, and terminates aerobic glycolysis [ , , , ].
AMPK inhibits ACC, increases glycolytic flux, mitogenesis, lipases, autophagy, and lysosomal degradation [ , ]. PPAR-γ upregulates FAO, maintains mitochondrial membrane potential, mitochondrial citrate synthase, and regulates numerous genes involved in mitochondrial function including transcription factor A TFAM , and peroxisome proliferator-activated receptor-gamma PGC -1α [ , , , ].
It also downregulates NF-κB and upregulates Nrf-2 [ , , ]. PPAR stimulates the activity of LXR [ ], which controls cholesterol and lipid homeostasis. Thus, inflammation is reduced and glycolysis is blocked via the inhibition of NF-κB [ , ].
Finally, PPAR-γ promotes the oxidation of glutamine [ ] whose importance in M2 polarization has been discussed above [ ]. Macrophage ROS levels affect the activity of STAT-1, MAPKs, and NF-κB and lead to an overall increase in inflammatory signaling [ ]. ROS levels also affect the assembly of NADPH oxidase subunits and regulate the formation of corrosive RNS species such as peroxynitrite, thereby influencing H 2 O 2- mediated intracellular signaling and macromolecule damage [ ].
Continually high ROS or NO levels are accompanied by the development of macrophage senescence [ , , ]. The mechanisms driving this phenomenon appear to involve the persistent expression of NF-κB, STAT-3, IL, and TGF-β, and potentially the upregulation of PD-1 [ , , ].
There is also ample evidence that macrophage functions and polarization patterns are influenced by GSH levels and the overall activity of the GSH system [ , ]. For example, increased GSH oxidation compromises phagocytosis and macrophage survival [ , ]. The GSH system also plays a key role in regulating M1 inflammatory status and the production of PGE2 and NO, while protecting macromolecules from oxidative damage [ , ].
The antiviral responses initiated following M1 macrophage activation such as increased expression of STAT-1, Irf7, and Irf9 are also dependent on an optimally functioning GSH system and are compromised by GSH depletion [ ]. Thioredoxin TRX -1 affects the inflammatory status of macrophages by modulating the activity of macrophage receptors, and the macrophage migration inhibiting factor MIF [ ].
The latter effect reduces the proinflammatory status of M1 macrophages and encourages M2 polarization by lowering TNF-α and monocyte-chemoattractant protein MCP -1 production [ , , , ]. Nrf-2 upregulation also exerts an anti-inflammatory effect in activated macrophages by attenuating the activity of IL-1β and IL-6 [ , ].
The mechanism involves Nrf-2 binding at the relevant gene promoter sites resulting in inhibition of the recruitment of RNA Polymerase II complex [ ]. Nrf-2 upregulation also rises the expression of CD and Arg1 [ , ]. It affects the transcription of a multitude of genes involved in the switch between M1 and M2 polarization [ , ].
The metabolic reprogramming in macrophages is presented in Fig. Metabolic reprogramming in macrophages Maf. DCs are archetypal antigen presenting cells APCs and play a dominant role in linking innate and humoral immunity [ ].
In physiological conditions, tissue-resident DCs drain to the lymph nodes and, thereafter, present self-antigens to T-cells, thereby maintaining immune tolerance [ ]. However, after pathogen invasion, TLR- mediated activation of DCs is followed by numerous changes in function and phenotype resulting in their active migration to lymph nodes and cytokine production [ ].
Resting-state DCs rely on OXPHOS-driven TCA cycle activity fueled by glutaminolysis and FAO to meet their energy needs [ , ]. Their overall metabolism is regulated by AMPK [ ].
In addition, glycolytic intermediates are shunted into the PPP while increased NO production inhibits the ETC. Moreover, citrate is withdrawn from the TCA acting as a crucial player in FA synthesis that maintains and increases inflammatory cytokines, NO, and ROS production [ , ].
However, chronic aerobic glycolysis is enabled and regulated by mTOR and HIF1α activation [ , ]. In addition, upregulation of mTOR and the subsequent increase in HIF1α activity induces the transcription of iNOS [ , ] leading to NO-mediated suppression of mitochondrial OXPHOS via reversible inhibition of ETC complex I, III, and IV [ 17 , , ].
mTOR activation initiates and controls lipid synthesis and mitochondrial biogenesis via the downstream upregulation of SREBPs and PPAR. It stimulates IL-6, IL-1, and TNF-α production, via the upregulation of AKT, FOXO3, and Myc [ ]. mTOR activation serves as the enabler and master regulator of DC migration, maturation, and endocytosis [ ].
Phagosomal ROS levels are involved in MH1-mediated presentation of digested antigens to CD8 T cells [ , ]. In this context, it is noteworthy that the activation of CD8 T cells requires upregulation of mitochondrial reactive oxygen species mtROS production [ ].
DC production of ROS following TLR activation also plays a major role in the maturation and priming of CD4 T cells [ , ]. Many aspects of DC function are influenced by the GSH system activity. For example, GSH levels regulate DC differentiation and function as APCs [ ].
DC GSH levels also determine T-cell polarization patterns by affecting IL and IL production [ , ]. GSH depletion is associated with the differentiation of naive T cells [ ] and inhibits DC maturation and inflammatory cytokine production leading to profound cellular dysfunction [ ].
Moreover, DCs directly influence the redox state of activated T cells via the transfer of thioredoxin [ ]. Redox homeostasis within activated DCs is regulated by Nrf-2 which acts to restrain T-cell proliferation by repressing IL production and upregulating IL [ , ].
Conversely, DCs that lack Nrf-2 generate increased numbers of activated T helper Th cells and reduced numbers of T regulatory Treg cells [ ]. Moreover, Nrf-2 depletion and the resultant prooxidative state in DCs encourage a Th-2 pattern of differentiation in naive T cells [ , ].
Finally, Nrf-2 also plays an important role in the transition between glycolysis and OXPHOS in tolerogenic DCs that enables their long-term survival [ ].
There is considerable evidence of DC dysfunction in diseases underpinned by chronic inflammation and oxidative stress [ , ]. Such dysfunction may be directly or indirectly driven by increased inflammatory cytokines, RNS, and ROS.
Direct effects involve damage to functional macromolecules and increased activation of apoptotic pathways [ , ]. Indirect effects include enhanced Wnt signaling [ 90 ], epigenetic dysregulation, and compromised TLR activity [ , , , ]. The metabolic reprogramming of DCs is shown in Fig.
Metabolic reprogramming of dendritic cells DCs. OXPHOS oxidative phosphorylation, TCA tricarboxylic acid cycle, FA fatty acid, NF-kB nuclear factor NF-kappa-B, mTOR mechanistic target of rapamycin, HIF1α hypoxia-inducible factor 1-alpha, PPARγ peroxisome proliferator-activated receptor, ROS reactive oxygen species, NO nitric oxide.
Neutrophils are the first line responders of the innate immune system, which play a key role in the destruction of invading pathogens. However, these leucocytes also participate in humoral immunity via a sophisticated cross-talk with other immune cells [ , , ]. Importantly, these regulatory functions extend beyond modulation of the activity of myeloid cells and also involve modifying the function of T-cells, marginal zone B-cells, and NK-cell homeostasis [ , , ].
There is also considerable evidence of functionally distinct subsets and extensive cellular plasticity enabling a range of roles depending on cellular location and inflammatory status [ , ].
Glycolysis is the primary energy source for activated neutrophils under physiological conditions [ ]. This is also true for inflammatory environments [ ]. However, neutrophils adjust their metabolism to carry out their various effector functions such as phagocytosis, degranulation, oxidative burst, neutrophil extracellular traps NET formation, and chemotaxis [ ].
The weight of evidence suggests that NET formation is reliant on glycolysis, with extensive involvement of lactate synthesis, the PPP, and glutamine metabolism as sources of NADPH [ , ]. This metabolic reprogramming also supplies superoxide production, and induces ROS and hypochlorous acid, used in the neutrophil oxidative burst following phagocytosis of invading pathogens [ , , , ].
The metabolic changes underpinning chemotaxis are somewhat more complicated, however, and involve mitochondrial contributions in addition to upregulated glycolysis [ , , ]. This activity supplies ATP which activates membrane-bound P2Y2 receptors following the receipt of chemotactic stimuli — Mitochondrial activity provides the ATP required for neutrophil activity in regions of profound glucose deprivation.
It occurs in an environment of extreme inflammation and also plays a dominant role in neutrophil autophagy and survival via FAO [ ]. These metabolic changes underpinning neutrophil activity in inflammatory environments are primarily regulated by the cooperative action of NF-κB [ 43 , ], HIF1α [ , ], and mTOR [ , ].
The multiple and arguably pivotal roles of the latter include the regulation of NET production, autophagy, oxidative burst, phosphorylation, and stabilization of NOX and HIF1α [ , ].
mTOR also increases the surface expression of GLUT-1 and intensifies mitochondrial biogenesis and FAO via the upregulation of PPARγ and SREBPs [ 72 ]. Elevated mTOR activity increases the production of leukotrienes, prostaglandins, resolving, and proinflammatory cytokines via phosphorylation of AKT [ ].
mTORC1 also exerts an inhibitory effect on OXPHOS by upregulation of IFN-γ and NO which inhibits the activity of enzymes in the ETC [ ]. While mTOR upregulation plays a key role in the optimal function of activated neutrophils, it should be stressed that other enzymes and transcription factors are also important regulatory elements enabling pathogen destruction.
This in turn restrains extreme inflammation and prevents excessive survival. On the other hand, AMPK regulates and restrains NF-κB and the production of proinflammatory cytokines, limiting tissue inflammation and destruction while optimizing chemotaxis and phagocytosis [ , ].
Finally, PPAR-γ also regulates migration and restrains inflammation by inhibiting NF-κB while stimulating IL production [ , ]. For example, excessive ROS fabrication may compromise the initiation and outcome of phagocytosis [ ], resulting in a dysregulated or decreased oxidative burst [ ] and production of NETs [ ].
Chronically upregulated ROS and cytokine production may also result in the internalization of membrane chemokine receptors, most notably CXCR2 [ ], thereby decreasing neutrophil migration.
Upregulated NO inhibits neutrophil migration, crawling, and adhesion [ , , ]. Mechanistically, this is achieved via the downregulation of adhesion factors such as E-selectin, P-selectin, ICAM-1, and VCAM As a result, neutrophil binding to the endothelium is compromised, and subsequent crawling and transmigration to inflammatory centers are damaged [ ].
Neutrophil migration may also be hampered by increased production of peroxynitrite due to the combination of NO and superoxide cations [ , , , ]. There is evidence suggesting that the tyrosine nitration mediates inhibition of P-selectins [ , , ] and upregulation of haem oxygenase HO-1 -1 [ ].
A multitude of neutrophil functions is heavily affected by the cellular antioxidant system. For example, Nrf-2 activity influences the efficiency of neutrophil phagocytosis [ ], recruitment to inflammatory sites [ ], and prolonged survival [ ]. The glutathione system regulates various functions displayed by activated neutrophils most notably the stimulation of glutathione reductase.
It sustains the neutrophil respiratory burst and NET production [ , ] influencing optimal phagocytic activity [ , ]. It is noteworthy that the basal activity of the GSH system in neutrophils appears to be lower than that found in myeloid cells [ ], rendering these immune cells vulnerable to depleted GSH levels [ ].
This may result in compromised cytoskeletal reorganization, affecting chemotaxis and transmigration and leading to reduced recruitment to sites of inflammation, impaired degranulation, and early apoptosis [ , ].
In this context, it should be noted that prolonged neutrophil activity depletes levels of GSH, likely due to excessive production of myeloperoxidase MPO during chronic nitro-oxidative stress and inflammation [ , , ]. This effect appears to be a result of the desensitization of neutrophils toward MCP-1 [ , ], thereby restraining neutrophil recruitment into inflammatory tissues [ ].
The mechanisms involved are not fully understood, but they appear to rely at least in part on the oxidation state of functional cysteine residues within the TRX protein [ ]. Table 3 summarizes the redox mechanisms that affect neutrophil functions, and the metabolic reprogramming of neutrophils is presented in Fig.
Мodulation of effector functions of neutrophils. PRRs pattern-recognition receptors, GPCRs G protein-coupled receptors, NET neutrophil extracellular traps, ROS reactive oxygen species, PPP pentose phosphate pathway, FA fatty acid, ATP adenosine triphosphate, NF-kB nuclear factor NF-kappa-B, HIF1α hypoxia-inducible factor 1-alpha, mTOR mechanistic target of rapamycin, PI3K phosphatidylinositol 3-kinase, AMPK AMP-activated protein kinase, PPARγ peroxisome proliferator-activated receptor.
Activation of T-cells follows the ligation of the T-cell receptor TCR and the major histocompatibility complex molecules by APC.
Nuclear factor of activated T cell 1 NFAT1 , activation protein-1 AP -1, and NF-κB are triggered as a result of this signaling cascade [ ]. When TCRs are ligated, ROS production increases by mitochondria and NOXs [ ], which in turn regulates the signaling pathways required to enable and modulate T-cell activation, proliferation, and differentiation [ ].
Unsurprisingly, T-cell activation and differentiation require extensive metabolic reprogramming [ , , , , ]. However, it should be stressed that the metabolic reprogramming pathways of various T-cell subsets display important differences [ , , ].
The metabolic needs of naive and memory T and Treg cells are relatively modest and are met by reliance on OXPHOS and FAO [ , , ]. However, the differentiation and various effector functions of effector CD4 and CD8 cells require ATP obtained from aerobic glycolysis and NADPH.
They are supplied by increased activity of the PPP and glutaminolysis, which is largely mediated by high levels of HIF1α and mTOR [ , , , , , ]. Important differences exist between subsets when it comes to FA metabolism and T-cell activation and differentiation.
For example, effector T-cell activity relies on FA uptake and FAS while T memory cells utilize stored FA [ , ]. Uniquely, the relative reliance on FA uptake versus FA synthesis exerts a major influence on the differentiation of naive T cells into Tregs or Th cells [ , ].
In particular, uptake of environmental FA is a characteristic feature of Treg development, while Th differentiation counts on ACC-mediated FA synthesis [ , ]. TCR signaling also leads to the upregulation of amino acid transporters, facilitating the uptake of branch chain amino acids such as alanine, cysteine, leucine, glycine, and glutamine [ , , ].
These amino acids, in combination with high PPP activity, promote the rapid increase of GSH needed for T-cell survival and function [ ]. Augmented glutamine catabolism following T-cell activation, mediated by mitochondria-dependent oxidation, is of particular importance as the resultant increase in α-ketoglutarate production stimulates TCA activity and fuels increased OXPHOS [ , ].
TCR-dependent uptake of glutamine, valine, and leucine is implicated in inflammatory T-cell responses, the differentiation of Th-1 and Th cells, and the development of effector and memory CD8 cells [ , , , ].
ROS levels rise rapidly after TCR engagement and are critical in driving T-cell activation, proliferation, and differentiation [ , , , ]. Unsurprisingly, given the information discussed above, ROS influences the differentiation patterns and the disparate effector functions of various T lymphocytes.
For example, the Th-2 polarized phenotype is encouraged by excessive microenvironmental ROS [ ]. Conversely, Th-1 and Th polarizations occur at low microenvironmental levels of ROS [ ].
Excessive ROS resulting from either high production or damaged cellular antioxidant defenses may lead to mitochondrial membrane polarization with fatal consequences for T-cell activation and survival following TCR engagement [ ]. Similarly, prolonged or chronic ROS upregulation may result in T-cell hyperresponsiveness, exhaustion, and anergy [ , , , , ].
Several mechanisms appear to underpin this phenomenon including compromised mitochondrial ETC activity and dynamics [ , ], upregulation of PD-1 [ , ], dysregulated NF-κB signaling, chronic IKKβ signaling [ , , ], and oxidation of functional cysteine groups in proteins [ , , ].
Finally, excessive ROS production may lead to dysregulated T-cell homeostasis by differential modulation of T-cell homeostasis as effector T cells are more susceptible to ROS-mediated cell death than Tregs [ , , ]. Nrf-2 transcription is upregulated following TCR engagement on naive T cells and restrains inflammatory T-cell activity.
Thus, a Th-2 pattern is activated following TCR stimulation [ , ]. Animal studies show that the upregulation of Nrf-2 increases the proliferation of Tregs [ ] and amplifies their immunosuppressive and cytotoxic functions [ ]. As previously discussed, GSH synthesis rapidly escalates following TCR activation and affects T-cell survival and function [ ].
Increased de novo GSH synthesis also suppresses Th differentiation while encouraging the production of Tregs. Conversely, GSH depletion or loss of de novo GSH synthesis in a state of chronic nitro-oxidative stress [ ] compromises mTOR, NFAT, and N-Myc function.
Thus, the metabolic reprogramming is abrogated enabling the maintenance of aerobic glycolysis and leading to the termination of T-cell activation [ , , ]. Tregs also appear to exert at least some of their cytotoxic and immunosuppressive functions on effector T cells by decreasing GSH synthesis [ ].
The TRX system activity exerts a range of influences on T-cell proliferation and activation via increased TRX-1 production. This restrains their stimulation and encourages the development of Tregs from naive T cells, decreasing their differentiation down the Th-1 and Th pathways [ ].
TRX-1 upregulation is important in enabling T effector and Treg cell survival and function during chronic nitro-oxidative stress by protecting membrane protein thiols from oxidation [ , ]. Increased TRX-1 activity is needed to maintain the production of IL-2 [ ] and Th-mediated activation of B cells [ ].
The metabolic reprogramming of T cells is depicted in Fig. Metabolic reprogramming of T and B cells. B-cell receptor BCR or cytokine-associated activation of naive B cells results in PI3K phospholipase C gamma 1 expression, leading to calcium mobilization and NF-κB activation and upregulation of c-Myc, HIF1α, AKT, mTOR, and STAT-6 [ ].
Once activated, these lymphocytes migrate to germinal centers and display high rates of glycolysis and OXPHOS [ , , ]. The short-term metabolic reprogramming and increased glycolysis are controlled by PI3K, HIF1α, AKT, and STAT-6 signaling [ , , ].
The role of mTOR appears to be confined to the upregulation of GLUT-1 [ ]. It is noteworthy that GSK-3 has a key role in regulating glycolysis in activated B cells and may also adjust ROS production and changes in mitochondrial dynamics [ , ].
However, while mTOR may not be the primary player in the regulation of glycolysis, sustained germinal center B-cell BCR signaling requires activation of mTOR [ , ]. mTOR is also involved in somatic hypermutation and in the formation of memory B cells [ , , ]. The relative levels of OXPHOS and glycolysis differ in plasmablasts and memory B cells, with glycolysis being dominant in the former and OXPHOS being dominant in the latter to enable their long-term survival [ ].
B1 and B2 subsets appear to display differing metabolic profiles, with PPP, FAO, and aerobic glycolysis being more active in B1 compared to B2 cells [ ]. The production of high-affinity antibodies by plasmablasts is an energetically demanding process and requires rapid increases in glucose consumption and mitochondrial mass accompanied by significant changes in mitochondrial dynamics [ , , ], reviewed in [ ].
Unsurprisingly, functional mitochondria are an indispensable element in B-cell differentiation and effector functions [ ].
The process of antibody synthesis is also regulated by AMPK, which enables memory B-cell formation and survival in part by regulating mitochondrial dynamics and suppressing the activation of mTOR [ , , ]. High levels of hydrogen peroxide are required to initiate and maintain BCR signaling [ , ].
This is primarily provided by the activity of NOX-2 [ ], but in the longer term, the source of hydrogen peroxide is mtROS [ , ].
In addition, the cellular redox state and mtROS release play a major role in B-cell survival and differentiation and IgM synthesis [ , ]. However, excessive mitochondrial mtROS synthesis may inhibit B-cell activation and the differentiation of B cells into antibody-producing plasmablasts [ ].
Increased concentrations of mtROS may also inhibit the production of antibodies by downregulating CD19 expression [ ]. Finally, chronically upregulated ROS can upregulate the consumption of IgM antibodies [ , ].
In this context, it is noteworthy that B-cell activation is accompanied by a concomitant stimulation of the TRX and GSH system, with the latter involving triggering of the cystine transporter xCT and higher uptake of cysteine [ ].
The intensive function of both systems correlates with elevated production of IgM [ ]. Finally, there is evidence associating increased Nrf-2 expression in activated B cells with prolonged survival and resistance to ROS-mediated apoptosis [ , , ].
Table 4 summarizes the redox mechanisms that affect B-cell functions, and the metabolic reprogramming of B cells is depicted in Fig. The signaling mechanisms involved in NK-cell activation [ , ] entail the engagement of multiple activation receptors such as natural cytotoxicity receptors [ , , ] leading to the stimulation of AP-1, NFAT, and NF-κB [ , ].
Cytoskeletal reorganization and release of chemokines, inflammatory cytokines, and lytic granules containing granzyme A, B, and perforin follows [ , , ]. Unsurprisingly, the various effector and regulatory functions of activated NK-cells are enabled by metabolic programming, which is underpinned by the upregulation of glucose-driven glycolysis, OXPHOS, increased FA synthesis, and glutamine metabolism [ , , , ].
Metabolic reprogramming, glycolysis, and mitochondrial activity are controlled by mTOR that is upregulated in NK cells following stimulation by IL and IL-3 [ , , ]. The high expression of this kinase is also responsible for increased FA synthesis and glutamine metabolism by activated NK cells via the upregulation of SREBPs and N-Myc [ , ].
The importance of mTOR and HIF1α in NK-cell proliferation and function is difficult to overemphasize as reduced HIF1α and mTOR activity are associated with loss of cytotoxic effects. It is evidenced by decreased production of perforin and granzyme B, and premature apoptosis [ , , ].
Increased ROS production enables NK-cell-mediated cytolysis by promoting the release of perforin and granzyme B [ ] and NK-cell division and proliferation after pathogen invasion [ ].
Nrf-2 activation serves as an immunological checkpoint following NK-cell activation [ , ]. The upregulation of GSH synthesis may enable the proliferation and cytotoxic functions of NK-cells and, conversely, GSH downregulation results in compromised functions and recruitment to sites of inflammation [ , , ].
In an inflammatory environment, the upregulation of TRX-1 plays a role in NK-cell survival by maintaining membrane cytoprotective sulfhydryl residues in a reduced state [ , ]. This phenomenon may protect those cells from hydrogen peroxide-mediated NK-cell dysfunctions [ , ].
However, this level of protection is clearly limited as chronic nitro-oxidative stress may result in NK-cell hypofunction and loss of cytotoxic activity [ , , , ]. There is evidence suggesting that this is due to compromised hydrogen peroxide signaling following NOX-2 hyperactivity [ ].
However, there is also proof that NK-cell function may be impaired by excessive production of NO [ ]. Table 4 summarizes the redox mechanisms that affect NK-cell functions, while Fig.
Metabolic reprograming in NK-cells. AP-1 activator protein-1, NFAT nuclear factor of activated T cell, NF-kB nuclear factor NF-kappa-B, OXPHOS oxidative phosphorylation, FA fatty acid.
In brief, HDL attenuates the activation of TLR-4 by stimulating cholesterol efflux from membrane lipid rafts MLR , NF-κB activity, DC maturation and activation, and antigen presentation to T lymphocytes. It also affects Th-1 and Th differentiation, T-cell and BCR activation, the complement system, and monocyte and macrophage chemotaxis [ 13 , 41 , 79 , 90 , ].
HDL-mediated MLR disruption underpins anti-inflammatory and immunosuppressive effects. HDL exerts a unique immunoregulatory role by activating pentraxin 3, an immunosensory molecule.
ApoA1 regulates the balance between Th and Tregs, improves mitochondrial functions, increases the activity of the ETC, and stabilizes PON1 within the HDL particle, thereby maintaining PON1 activity.
The latter protects against immune cell membrane lipid peroxidation, circulating oxidized lipoproteins, and oxidative damage to mitochondria. It positively affects glucose metabolism, PPP, FAO, PPAR-γ activity, and aerobic glycolysis via upregulation of GLUT-1 [ 41 , 90 ].
Evidence suggests that the bulk of oxidized phospholipids present in the circulation exists as immune complexes with natural IgM and IgG due to their status as oxidation-specific epitopes or neoantigens [ , ].
It is also proposed that oxidized phospholipid complexes are proinflammatory [ , ] using several routes, which include recruitment of the complement cascade [ ] and production of inflammatory responses in human macrophages largely by engagement of the Fc gamma receptor 1 [ , ].
These complexes may activate mature DCs leading to a primed inflammasome thereby exaggerating IFN-γ and IL-1 production [ , , ]. Moreover, DCs activated and primed via this mechanism may trigger naive T cells and induce Th polarization [ , , ]. As a result of activating neutrophil PRR, oxidized phospholipids contribute significantly to inflammation and oxidative stress and the formation of NETs [ , ].
The process effectively endows these leucocytes with a de facto memory, resulting in an amplified inflammatory or anergic response to future antigenic challenges [ , ]. The mechanisms driving the metabolic and epigenetic changes described above appear to depend, at least in part, on mTOR-induced assembly of NADPH oxidase and subsequent increases in ROS-mediated signaling [ , ].
The final part of this review deals with the detrimental effects of chronic oxidative and nitrosative stress on the immune response as a whole.
In physiological conditions, NOX-derived cytosolic hydrogen peroxide regulates redox-sensitive intracellular signaling pathways [ , , , , ]. However, in conditions of excessive ROS production, hyperoxidation of thiolate anions to sulfonic acid essentially incapacitates reversible cysteine oxidation.
It is an effective signaling mechanism, locking functional cysteines in the oxidized mode [ 90 , ]. The other signaling system involved in regulating the activity of redox-sensitive proteins and enzymes is reversible S-nitrosylation [ 17 , ]. However, pathological levels of ROS disable the mechanisms responsible for maintaining the reversibility of S-nitrosylation inducing a cellular state described as protein hypernitrosylation [ ].
Hyperoxidation and S-nitrosylation can result in impaired function of the redox-sensitive transcription factors and enzymes regulating metabolic reprogramming in immune cells.
Compromised mitochondrial functions and seriously suppressed immune cell activation and function may follow. Chronic nitro-oxidative stress also affects the activity of HDL, apoA1, and PON1 whilst increasing the density of oxidized phospholipids further dysregulates the immune response [ 41 ].
Finally, chronic nitro-oxidative stress and inflammation also stimulate IDO that may result in a state of profound immune suppression [ ]. The section below deals with these processes, beginning with the effects of hypernitrosylation and hyperoxidation on transcription factors and enzymes.
S-nitrosylation exerts a significant inhibition of NF-κB function by reducing the binding of its subunits to DNA thereby decreasing the activity of the complex as a transcription factor [ , , ], as well as the expression of target effector genes [ , ].
The outcomes involve decreased levels of IL [ ], IL-1β [ ], IL-6, IL-8, and iNOS [ , ]. Moreover, S-nitrosylation may inhibit TLR-4 [ , ] and TLR-2 signaling [ ]. S-nitrosylation is additionally involved in Nrf-2 triggering, which appears to be affected via the conformational modification of crucial thiol groups [ , , ].
Moreover, mTOR may be directly activated following S -nitrosylation of the tuberous sclerosis complex 2 [ ] and the nitrosylation of small GTPases [ ]. Prolonged nitrosylation may also compromise immune cells via the chronic upregulation of GSK-3 [ ].
In addition, in an environment of chronic nitro-oxidative stress, mTOR may be inactivated by oxidation of Cys [ ] and AMPK activation [ , ]. In an environment of increased ROS, several enzymes involved in regulating metabolic reprogramming in immune cells are triggered most notably via PPAR-γ [ , ].
The most prominent results are damage to the enzymes of the ETC [ , , , ] and a range of structural and functional phospholipids, basically cardiolipin [ , , ].
This ultimately leads to altered ATP production and accelerated ROS, provoking further impairement of macromolecules, forming the basis of self-amplifying pathology [ , , , ]. Increased NO production by mitochondria in an environment of nitrosative stress may also be a source of dysfunction and damage [ , , ].
In essence, two pathways are implicated. The first involves reversible inhibition of ETC enzymes by NO-mediated S-nitrosylation [ 17 , , ]. The second comprises irreversible nitration of functional enzymes and structural proteins by ONOO - [ , ].
This pattern of pathology leads to a vicious circle of bioenergetic failure and elevated mtROS production [ , , , ].
Clearly compromised mitochondrial function has many direct adverse effects on the activity of immune cells, as discussed above.
However, mitochondrial dysfunction may also lead to numerous indirect negative consequences related to depleted levels of NADPH, which results from the distorted activity of this organelle [ , , ].
Lowered levels of malic enzyme 2 and IDH may affect the TCA cycle [ , ]. Chronic nitro-oxidative stress may cause nitrosylation and hyperoxidation of the key cysteine residues within TRX and thioredoxin reductase thereby compromising or abrogating TRX activity [ , , , ].
Mechanistically, this is achieved via the oxidation and nitrosylation or tyrosine nitration or via inhibiting the activity of GSH, glutathione peroxidase, and glutathione reductase [ 13 , , ].
Increased production of radical species also raises the activity of multidrug resistance-associated proteins, resulting in extrusion of GSH and GSSH into the intercellular environment.
The decreased importation of cysteine, which follows, leads to reduced synthesis of replacement GSH [ , , , ].
A state of persistent nitro-oxidative stress may also cause Nrf-2 inhibition via several mechanisms, including activation of MAPK kinase, decreased DJ-1 [ , ], and reduced TRX system activity [ , ]. Such inactivated enzymes are α-ketoglutarate dehydrogenase [ , , ] and conitase, which catalyze the conversion of citrate to isocitrate [ , ], IDH [ , , ], ME2 [ , ], and pyruvate dehydrogenase kinase [ ].
The negative consequences of lowered α-ketoglutarate dehydrogenase and aconitase are of particular importance, and may lead to reduced TCA cycle activity and NADPH synthesis [ , ] and accumulation of citrate [ ].
The inactivation of pyruvate dehydrogenase kinase also results in adverse metabolic consequences by attenuating the conversion of pyruvate to acetyl-CoA [ ]. Chronic oxidative stress induces HDL [ , , ] and ApoA1 [ , , ] dysfunctions. PON1 is rendered dysfunctional in such an environment, which appears to be mediated by the high activity of MPO [ , , ].
The mechanisms underpinning the development of a dysfunctional HDL particle and reduced activity of ApoA1 are complex and readers are referred to the work of Morris et al. Chronic nitro-oxidative stress can induce the development of endotoxin tolerance by provoking IDO activation [ , ].
Increased IDO activity upregulates the tryptophan catabolite TRYCAT pathway, as well as TGF-β1 and IL [ , ], which exert multiple inhibitory effects on TLR signaling [ , ].
Neutrophils with endotoxin tolerance are characterized by decreased oxidative burst, downregulated TLR-4 receptors, and impaired cell adhesion, rolling, and migration [ , , ]. Macrophages with endotoxin tolerance display significant dysregulation of their function as APCs [ ].
Impaired antigen presentation is also seen in DCs following IDO activation [ ]. In this state, DC activation of naive T cells leads to Th-2 polarization [ , ]. DCs may inhibit T memory and T effector cells and induce CD4 and CD8 T-cell anergy and activation of Tregs [ , ].
This explains that prolonged endotoxin tolerance is typified by impaired proliferation and anergy of CD4 T and CD8 T cells and increased Treg cell numbers [ , , ]. Finally, endotoxin tolerance is characterized by a reduced number and cytolytic function of NK cells [ , , ].
Hypernitrosylation and chronic nitro-oxidative stress may inhibit these antioxidant systems, thereby decreasing the activity levels of the TCA cycle, mitochondrial functions, and immune cell metabolism.
As such, redox mechanisms regulate and modulate many different immune functions, including but not limited to macrophage and Th cell polarization, phagocytosis, production of pro- and anti-inflammatory cytokines, metabolic reprogramming of immune cells, immune training and tolerance, chemotaxis, pathogen sensing, antiviral and antibacterial effects, TLR activity, and endotoxin tolerance.
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Wink DA, Hines HB, Cheng RYS, Switzer CH, Flores-Santana W, Vitek MP, et al. This powerful compound supports the cells that keep you healthy. Cytokines are communication proteins released by white blood cells to communicate information to other cells for an appropriate immune response.
For example, cytokines activate B cells, which secrete antibodies. Mast cells line the respiratory system, from the nasal passage through the throat to the lungs. Because these pathways are the primary means of entry into the body, mast cells are under constant attack.
They need high levels of glutathione to perform. Lymphocytes are a class of white blood cells. Three forms of T cells, a smaller type of lymphocyte, work together to defend your body against invaders. Helper T cells identify targets for destruction by killer T cells.
After eliminating the threat, suppressor T cells suppress the immune system. Glutathione is essential for T-cell growth. In recent studies, researchers have found that T cells can be activated but cannot reproduce.
The scientists noted that GSH-deficient T cells did not increase in size. While T cells can technically function, glutathione deficiency severely impairs their performance, limiting their expansion in individual cell sizes and numbers.
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