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Glucose metabolic profiles of M1 and M2 macrophages. (A) Glucose metabolic profile of M1 macrophages. Classically activated macrophages induce aerobic glycolysis that results in lactate production and increased synthesis and secretion of inflammatory cytokines. (B) Glucose metabolic profile of M2 macrophages. Alternatively activated macrophages trigger a metabolic profile predominated by oxidative phosphorylation (OxPhos).
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Activation of the immune system occurs in response to the recognition of foreign antigens and receipt of optimal stimulatory signals by immune cells, a process that requires energy. Energy is also needed to support cellular growth, differentiation, proliferation, and effector functions of immune cells. In HIV-infected individuals, persistent viral...
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... Freemerman and co-authors illustrated convincingly that Glut1 is the primary rate limiting glucose transporter on pro-inflammatory M1 macrophages (Freemerman et al., 2014). Macrophages that expressed Glut1 secreted high levels of pro- inflammatory mediators such as G-CSF, CXCL1, CXCL2, IL-6, RANTES, TNF and IL-1RA, and reactive oxygen species (Fig. 3) (Freemerman et al., 2014). Independent work demonstrates that aerobic glycolysis positively regulates IL-6, IL1β and TNF mRNA expression in pro-inflammatory GM-CSF macrophages likely via HIF-1α/HIF-2α regulated genes ( Izquierdo et al., 2015). Because the CCL2/CCR2 axis regulates monocyte recruitment to inflammatory sites ...
Citations
... As HIV-infected individuals display dysfunctional glucose metabolism in monocytes and T cells, which is linked to immune activation and inflammatory disease progression [35], we next assessed the effect of Oxidized low-density lipoprotein (Ox-LDL) on aerobic (which was not certified by peer review) is the author/funder. All rights reserved. ...
HIV-induced persistent immune activation is a key mediator of inflammatory comorbidities such as cardiovascular disease (CVD) and neurocognitive disorders. While a preponderance of data indicate that gut barrier disruption and microbial translocation are drivers of chronic immune activation, the molecular mechanisms of this persistent inflammatory state remain poorly understood. Here, utilizing the nonhuman primate model of HIV infection with suppressive antiretroviral therapy (ART), we investigated activation of inflammasome pathways and their association with intestinal epithelial barrier disruption and CVD pathogenesis. Longitudinal blood samples obtained from rhesus macaques with chronic SIV infection and long-term suppressive ART were evaluated for biomarkers of intestinal epithelial barrier disruption (IEBD), inflammasome activation (IL-1β and IL-18), inflammatory cytokines, and triglyceride (TG) levels. Activated monocyte subpopulations and glycolytic potential were investigated in peripheral blood mononuclear cells (PBMCs). Higher plasma levels of IL-1β and IL-18 were observed following the hallmark increase in IEBD biomarkers, intestinal fatty acid-binding protein (IFABP) and LPS-binding pro-tein (LBP), during the chronic phase of treated SIV infection. Further, significant correlations of plasma IFABP levels with IL-1β and IL-18 were observed between 10-12 months of ART. Higher levels of sCD14, IL-6, and GM-CSF, among other inflammatory mediators, were also observed only during the long-term SIV+ART phase along with a trend of increase in frequencies of activated CD14+CD16+ intermediate monocyte subpopulations. Lastly, we found elevated levels of blood TG and higher glycolytic capacity in PBMCs of chronic SIV-infected macaques with long-term ART. The increase in circulating IL-18 and IL-1β following IEBD and their significant positive correlation with IFABP suggest a connection between gut barrier disruption and inflammasome activation during chronic SIV infection, despite viral suppression with ART. Additionally, the increase in markers of monocyte activation, along with elevated TG and enhanced glycolytic pathway activity, indicates metabolic remodeling that could accelerate CVD pathogenesis. Further research is needed to understand mechanisms by which gut dysfunction and inflammasome activation contribute to HIV-associated CVD and metabolic complications, enabling targeted interventions in people with HIV.
... Glycometabolism stands as a pivotal aspect of virus-host interactions, serving dual critical roles in the battle between viral survival strategies and host defense mechanisms. On the one hand, glycolysis is closely linked to the activation of natural immunity in the host cell [33]. Various glycometabolic enzymes and products are instrumental in triggering innate immune responses [34,35]. ...
The lumpy skin disease virus (LSDV), a member of the Poxviridae family, is primarily characterized by the formation of skin nodules in cattle. In our study, RNA sequencing was employed to investigate LSDV-infected Madin-Darby bovine kidney (MDBK) cells. At 4 hours post-infection (hpi), 108 differentially expressed long non-coding RNAs (delncRNAs) were identified. A co-expressed functional analysis indicated that lncRNAs may influence cellular glycometabolic processes. Additionally, we observed 798 differentially expressed mRNAs (demRNAs), predominantly associated with lipopeptide-induced immune response pathways in enrichment analyses. These findings indicate an active cellular defense against the poxvirus at this early stage. At 24 hpi, 1101 delncRNAs were identified, impacting cell metabolism, especially glycometabolism. Notably, two LncRNAs, which interacted with MAPK3, emerged as potential central regulators in the lncRNA-mRNA cis-regulation network. The number of demRNAs surged to 5295, with KEGG pathway enrichment analysis revealing associations with various diseases. This late phase marked a critical juncture, as the virus inflicted near-total cellular destruction, resulting in severe pathological conditions. Moreover, two of the demRNAs at 4 hpi, AV5191 and AV15574, were shown to inhibit LSDV replication in MDBK cells. The LSDV-induced host lncRNA/mRNA profiles reveal intricate regulatory dynamics, providing a foundational and robust public resource for understanding the nuanced mechanisms in poxvirus-host interactions.
... During oxidative phosphorylation mitochondria produce ATP, reactive oxygen species and free radicals necessary for the monocyte to function [9]. In turn, aerobic glycolysis provides cells with ATP and intermediates used for the nucleotide and amino acid synthesis [1]. The data on the pGO and monocyte interactions are limited. ...
Graphene oxide (GO) is a lightweight two-dimensional material with unique properties. It is being actively studied for use in biomedical research. However, there are limited data on the interaction of GO with immune cells, particularly its effects on cellular metabolism are unknown. In our work, we investigated the effect of GO particles on the activity of mitochondrial respiration and the intensity of aerobic glycolysis in human monocytes. We used GO nanoparticles (Ossila, UK) functionalized with linear polyethylene glycol (PEG, pGO) in two sizes ("small" – S 0.1-0.2 µm and "large" – L 1-5 µm). It was found that in untreated cells and monocytes incubated with low concentration (5 µg/mL) of either small or large pGO nanoparticles basal oxygen consumption rate was comparable. However, at high concentration (25 µg/mL) both small and large pGO nanoparticles caused a significant increase in monocytes respiration rate. Interestingly, in monocytes treated with pGO nanoparticles an increase in mitochondrial respiration was not accompanied by an increase in glycolytic activity. Moreover, treatment with large particles was shown to attenuate glycolysis at both low and high concentration. Hence, GO nanoparticles functionalized with linear PEG differently affect mitochondrial respiration and glycolysis in human monocytes.
... 22,23 Inactivated monocytes have low basal metabolic activity and the adenosine triphosphate (ATP) in them is mainly produced through OXPHOS. 24 Upon activation, monocytes have been shown to increase glucose uptake and glycolysis, and differentiated macrophages have higher energy metabolism than monocytes. 24,25 Macrophages induce different phenotypes depending on the energy metabolism they use. ...
... 24 Upon activation, monocytes have been shown to increase glucose uptake and glycolysis, and differentiated macrophages have higher energy metabolism than monocytes. 24,25 Macrophages induce different phenotypes depending on the energy metabolism they use. 22 Macrophages acquire a proinflammatory phenotype, which primarily uses glycolysis as a source of energy in an inflammatory environment. ...
... Normally, inactive monocytes are metabolically quiescent and primarily rely on OXPHOS to produce ATP. 24 However, in this study, G6PT −/− THP-1 monocytes undergo a metabolic shift from OXPHOS to glycolysis, which is accompanied by increased glucose uptake and altered expression of GLUT3, HKs, PFKFB3, and PKM. Notably, G6PT −/− THP-1 monocytes exhibit a significant decrease in glycolytic reserve, which represents the potential of cells to increase ATP production through glycolysis under conditions of stress or high energy demand. ...
Glycogen storage disease type Ib (GSD‐Ib) is an autosomal recessive disorder caused by a deficiency in the glucose‐6‐phosphate (G6P) transporter (G6PT) that is responsible for transporting G6P into the endoplasmic reticulum. GSD‐Ib is characterized by disturbances in glucose homeostasis, neutropenia, and neutrophil dysfunction. Although some studies have explored neutrophils abnormalities in GSD‐Ib, investigations regarding monocytes/macrophages remain limited so far. In this study, we examined the impact of G6PT deficiency on monocyte‐to‐macrophage differentiation using bone marrow‐derived monocytes from G6pt−/− mice as well as G6PT‐deficient human THP‐1 monocytes. Our findings revealed that G6PT‐deficient monocytes exhibited immature differentiation into macrophages. Notably, the impaired differentiation observed in G6PT‐deficient monocytes seemed to be associated with abnormal glucose metabolism, characterized by enhanced glucose consumption through glycolysis, even under quiescent conditions with oxidative phosphorylation. Furthermore, we observed a reduced secretion of inflammatory cytokines in G6PT‐deficient THP‐1 monocytes during the inflammatory response, despite their elevated glucose consumption. In conclusion, this study sheds light on the significance of G6PT in monocyte‐to‐macrophage differentiation and underscores its importance in maintaining glucose homeostasis and supporting immune response in GSD‐Ib. These findings may contribute to a better understanding of the pathogenesis of GSD‐Ib and potentially pave the way for the development of targeted therapeutic interventions.
... Favoring this less efficient but rapid process of ATP production is a conserved metabolic feature that platelets share with different developmentally related lineages of blood cells including, dendritic cells, monocytes, T cells, and macrophages. [87][88][89][90][91][92][93] Besides aerobic glycolysis, it has also been shown that fatty acids, and glutamine oxidation can also be therapeutically targeted for antiplatelet effects (Figure 3). ...
Current antithrombotic therapies used in clinical settings either target the coagulation pathways or platelet activation receptors (P2Y12 or GPIIb/IIIa), as well as the cyclooxygenase (COX) enzyme through aspirin. However, they are associated with bleeding risk and are not suitable for long-term use. Thus, novel strategies which provide broad protection against platelet activation with minimal bleeding risks are required. Regardless of the nature of agonist stimulation, platelet activation is an energy-intensive and ATP-driven process characterized by metabolic switching towards a high rate of aerobic glycolysis, relative to oxidative phosphorylation (OXPHOS). Consequently, there has been considerable interest in recent years in investigating whether targeting metabolic pathways in platelets, especially aerobic glycolysis and OXPHOS, can modulate their activation, thereby preventing thrombosis. This review briefly discusses the choices of metabolic substrates available to platelets that drive their metabolic flexibility. We have comprehensively elucidated the relevance of aerobic glycolysis in facilitating platelet activation and the underlying molecular mechanisms that trigger this switch from OXPHOS. We have provided a detailed account of the antiplatelet effects of targeting vital metabolic checkpoints such as pyruvate dehydrogenase kinases (PDKs) and pyruvate kinase M2 (PKM2) that preferentially drive the pyruvate flux to aerobic glycolysis. Furthermore, we discuss the role of fatty acids, and glutamine oxidation in mitochondria and their subsequent role in driving OXPHOS and platelet activation. While the approach of targeting metabolic regulatory mechanisms in platelets to prevent their activation is still in a nascent stage, accumulating evidence highlights its beneficial effects as a potentially novel antithrombotic strategy.
... This leads to metabolic dysfunction in the host, a condition that becomes particularly prominent if the immune response fails to eliminate the pathogen and the infection becomes chronic. This is the result of a continuously active immune response, forcing the host to adapt to long periods of higher energy and biosynthetic demand [11]. ...
... The ten metabolites with the most significant p-values in this comparison, in order of significance, were 3,4-dihydroxybutyric acid (DHBA), tetrahydrofuran, phenylalanine, 1-deoxypentitol, 2,4-di-tert-butyl-phenol, glycerol-3-phosphate, alpha-linolenic acid, lysine, dimethylaminoethyl acrylate and 3-hydroxyisovaleric acid. This profile is mainly suggestive of inflammation and elevated catabolism to supply intermediates to comply with the increased energy demands, which is typical during infection [11]. It also indicates that multiple areas of metabolism are significantly affected during co-infection, as five of the seven chemical classes represented by the ANOVA results are represented in the ten most significant metabolites here. ...
Background:
The synergy between the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis during co-infection of a host is well known. While this synergy is known to be driven by immunological deterioration, the metabolic mechanisms that contribute to the associated disease burden experienced during HIV/tuberculosis (TB) co-infection remain poorly understood. Furthermore, while anti-HIV treatments suppress viral replication, these therapeutics give rise to host metabolic disruption and adaptations beyond that induced by only infection or disease.
Methods:
In this study, the serum metabolic profiles of healthy controls, untreated HIV-negative TB-positive patients, untreated HIV/TB co-infected patients, and HIV/TB co-infected patients on antiretroviral therapy (ART), were measured using two-dimensional gas chromatography time-of-flight mass spectrometry. Since no global metabolic profile for HIV/TB co-infection and the effect of ART has been published to date, this pilot study aimed to elucidate the general areas of metabolism affected during such conditions.
Results:
HIV/TB co-infection induced significant changes to the host's lipid and protein metabolism, with additional microbial product translocation from the gut to the blood. The results suggest that HIV augments TB synergistically, at least in part, contributing to increased inflammation, oxidative stress, ART-induced mitochondrial damage, and its detrimental effects on gut health, which in turn, affects energy availability. ART reverses these trends to some extent in HIV/TB co-infected patients but not to that of healthy controls.
Conclusion:
This study generated several new hypotheses that could direct future metabolic studies, which could be combined with other research techniques or methodologies to further elucidate the underlying mechanisms of these changes.
... Metabolic profiling is an important determinant of CD8+ T cell anti-HIV-1 function 14 . Long-term HIV-1 infection and prolonged ART use often cause metabolic-related diseases 15 and significantly impact the immune system 16,17 . An in vitro study compared the metabolic profile of CD8 + T cells in PLWH on ART with that of CD8+ T cells from elite controllers (ECs) and found that the former is characterized by less metabolic plasticity and antiviral function but more susceptible to metabolic intervention 18 . ...
CD8 + T cells are essential for long-lasting HIV-1 control and have been harnessed to develop therapeutic and preventive approaches for people living with HIV-1 (PLWH). HIV-1 infection induces marked metabolic alterations. However, it is unclear whether these changes affect the anti-HIV function of CD8 + T cells. Here, we show that PLWH exhibit higher levels of plasma glutamate than healthy controls. In PLWH, glutamate levels positively correlate with HIV-1 reservoir and negatively correlate with the anti-HIV function of CD8 + T cells. Single-cell metabolic modeling reveals glutamate metabolism is surprisingly robust in virtual memory CD8 + T cells (TVM). We further confirmed that glutamate inhibits TVM cells function via the mTORC1 pathway in vitro. Our findings reveal an association between metabolic plasticity and CD8 + T cell-mediated HIV control, suggesting that glutamate metabolism can be exploited as a therapeutic target for the reversion of anti-HIV CD8 + T cell function in PLWH.
... However, the way glucose is utilised during its breakdown may be of greater importance for cellular function. Glycolysis could be creating substrates for DNA (via the PPP) and cell membrane (via lipid metabolism) synthesis to facilitate cell growth and differentiation (17). Alternatively, glucose breakdown could be directed towards the TCA cycle, where fumarate and alpha-ketoglutarate can alter DNA methylation and gene expression (18). ...
Introduction
Immunometabolism examines the links between immune cell function and metabolism. Dysregulation of immune cell metabolism is now an established feature of innate immune cell activation. Advances in liquid chromatography mass spectrometry (LC-MS) technologies have allowed discovery of unique insights into cellular metabolomics. Here we have studied and compared different sample preparation techniques and data normalisation methods described in the literature when applied to metabolomic profiling of human monocytes.
Methods
Primary monocytes stimulated with lipopolysaccharide (LPS) for four hours was used as a study model. Monocytes (n=24) were freshly isolated from whole blood and stimulated for four hours with lipopolysaccharide (LPS). A methanol-based extraction protocol was developed and metabolomic profiling carried out using a Hydrophilic Interaction Liquid Chromatography (HILIC) LC-MS method. Data analysis pipelines used both targeted and untargeted approaches, and over 40 different data normalisation techniques to account for technical and biological variation were examined. Cytokine levels in supernatants were measured by ELISA.
Results
This method provided broad coverage of the monocyte metabolome. The most efficient and consistent normalisation method was measurement of residual protein in the metabolite fraction, which was further validated and optimised using a commercial kit. Alterations to the monocyte metabolome in response to LPS can be detected as early as four hours post stimulation. Broad and profound changes in monocyte metabolism were seen, in line with increased cytokine production. Elevated levels of amino acids and Krebs cycle metabolites were noted and decreases in aspartate and β-alanine are also reported for the first time. In the untargeted analysis, 154 metabolite entities were significantly altered compared to unstimulated cells. Pathway analysis revealed the most prominent changes occurred to (phospho-) inositol metabolism, glycolysis, and the pentose phosphate pathway.
Discussion
These data report the emergent changes to monocyte metabolism in response to LPS, in line with reports from later time points. A number of these metabolites are reported to alter inflammatory gene expression, which may facilitate the increases in cytokine production. Further validation is needed to confirm the link between metabolic activation and upregulation of inflammatory responses.
... Increased mitochondrial oxidative stress and cell death in Treg have been observed in CVD (16,17). Moreover, chronic inflammation in HIV can lead to an increased production of ROS (18). Oxidative stress has been mainly described to affect CD4+ T cells, monocytes, dendritic cells and neutrophils in PWH (19,20). ...
Cardiovascular disease (CVD) is a leading cause of enhanced morbidity and mortality in persons with HIV (PWH) in the era of highly active antiretroviral therapy (AART). However, the underlying mechanisms are not fully understood. Regulatory T cells (Treg), notably the highly suppressive memory subset, have been shown to limit CVD. Importantly, memory Treg cell numbers remain low in many treated PWH. High density lipoproteins (HDL) also protect from CVD, and we previously found that Treg-HDL interactions reduce oxidative stress in these cells. Here, we evaluated Treg-HDL interactions in PWH and whether they were operative in those higher CVD risk. To do that, we recruited a cohort of PWH with intermediate/high CVD risk (median ASCVD risk score of 13.2%, n=15) or low/borderline risk (median ASCVD risk score of 3.6%, n=14), as well as a group of statins treated PWH with intermediate/high CVD risk (median ASCVD risk score of 12.7%, n=14). We evaluated Treg frequency, phenotype and response to HDL. PWH with Int/High CVD risk had a significantly lower number of memory Treg, but memory Treg were more activated and displayed an inflammatory phenotype, versus those with Low/BL CVD risk. In untreated patients, Treg absolute numbers were negatively correlated with ASCVD score. Although HDL decreased oxidative stress in memory Treg in all subjects, memory Treg from PWH with Int/High CVD risk were significantly less responsive to HDL than those from PWH with Low/BL CVD risk. The level of oxidative stress in memory Treg positively correlated with ASCVD scores. In contrast, plasma HDL from PWH, regardless of CVD risk, retained their anti-oxidative properties, suggesting that the defect in memory Treg response to HDL is intrinsic. Statin treatment partially ameliorated the memory Treg defect. In conclusion, the defective HDL-Treg interactions may contribute to the inflammation-induced increased CVD risk observed in many AART-treated PWH.
... HIV infection also leads to deregulated oxidative stress, as well as abnormalities in tryptophan levels, glucose metabolism, and lipid metabolism (12,13). Studies have reported significant changes in plasma metabolites, including glucose, lipids, and amino acids, at different stages of HIV infection, and these changes are accompanied by alterations in nutrient transport receptors on immune cells (14,15). However, whether immunometabolism plays a role in HIV disease progression (especially in rapid progression) has not been fully elucidated. ...
The complex mechanism of immune-system damage in HIV infection is incompletely understood. HIV-infected “rapid progressors” (RPs) have severe damage to the immune system early in HIV infection, which provides a “magnified” opportunity to study the interaction between HIV and the immune system. In this study, forty-four early HIV-infected patients (documented HIV acquisition within the previous 6 months) were enrolled. By study the plasma of 23 RPs (CD4⁺ T-cell count < 350 cells/µl within 1 year of infection) and 21 “normal progressors” (NPs; CD4⁺ T-cell count > 500 cells/μl after 1 year of infection), eleven lipid metabolites were identified that could distinguish most of the RPs from NPs using an unsupervised clustering method. Among them, the long chain fatty acid eicosenoate significantly inhibited the proliferation and secretion of cytokines and induced TIM-3 expression in CD4⁺ and CD8⁺ T cells. Eicosenoate also increased levels of reactive oxygen species (ROS) and decreased oxygen consumption rate (OCR) and mitochondrial mass in T cells, indicating impairment in mitochondrial function. In addition, we found that eicosenoate induced p53 expression in T cells, and inhibition of p53 effectively decreased mitochondrial ROS in T cells. More importantly, treatment of T cells with the mitochondrial-targeting antioxidant mito-TEMPO restored eicosenoate-induced T-cell functional impairment. These data suggest that the lipid metabolite eicosenoate inhibits immune T-cell function by increasing mitochondrial ROS by inducing p53 transcription. Our results provide a new mechanism of metabolite regulation of effector T-cell function and provides a potential therapeutic target for restoring T-cell function during HIV infection.
