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Immune cell trafficking in obesity. (A) In lean adipose tissue, adipocytes store triglycerides in a large unilocular droplet. Insulinmediated repression of lipolysis is present along with little hypoxia, absence of inflammation, and physiologic levels of NEFA, glucose, and ROS. In lean adipose, alternatively activated 'M2' macrophages are resident and their phenotype is maintained by the presence of T-regulatory (Treg) cells, Th2 cells, and eosinophils. Lean adipose secretes adipokines such as adiponectin, IL-4, and IL-10, which act to maintain insulin sensitivity. (B) As obesity progresses and adipose tissue expands, hypertrophy and hyperplasia ensues: adipocytes accumulate triglycerides and grow large, while pre-adipocytes are differentiated to mature adipocytes. Alterations in adipokines are prognostic: leptin rises and adiponectin falls with increasing obesity. Chemokines are released, such as MCP1, which recruit monocytes that polarize to pro-inflammatory M1 macrophages. M1 macrophages surround dying adipocytes in classic 'crown-like structures' and release many pro-inflammatory mediators. The loss of eosinophils, Tregs, and Th2 T cells as obesity progresses is paired with the infiltration of CD4 + Th1 cells, CD8 + T cells, NK cells, and other granulocytes such as neutrophils, mast cells, and basophils. Elevated cytokines, such as TNFa and IL-1b, levels of NEFA, acylcarnitines, and ROS release contribute to the pro-inflammatory microenvironment.
Source publication
Glucose is a critical component in the pro-inflammatory response of macrophages (MФs). However, the contribution of glucose transporters (GLUTs) and the mechanisms regulating subsequent glucose metabolism in the inflammatory response are not well understood. Since MФs contribute to obesity-induced inflammation, it is important to understand how sub...
Contexts in source publication
Context 1
... formation of choles- terol-laden foam cells and expanding atherosclerotic plaques (37)(38)(39)(40)(41)(42)(43). Similarly, as obesity progresses, immune cells infiltrate either transiently (neutrophils) or continuously over time (innate and adaptive cells) while other beneficial immune cells decrease in number or are functionally over- shadowed (Fig. 2). As macrophages disperse into adipose tis- sue and accumulate triglycerides, they become activated and subsequently cause tissue damage in a fashion reminiscent to the formation of an atherosclerotic lesion (12,13,44). Therefore, lessons may be learned from considering other immune-linked metabolic diseases like atherosclerosis, which ...
Context 2
... M1 polariza- tion (75,76,(84)(85)(86). In obese adipose, chronic inflamma- tion ensues with pro-inflammatory release of TNFa, IL-1b, PAI-1, and ROS (12,13,15,35). Lumeng et al. (75, 84) demonstrated that M2 macrophages are dispersed in adi- pose tissue, whereas infiltrating M1 macrophages form 'crown-like structures' around dying adipocytes (Fig. 2B). Through the use of genetic alteration and bone marrow transplant models, M2 'anti-inflammatory' macrophages are demonstrated to maintain insulin sensitivity in liver and adipose, whereas M1 macrophages have been shown to inhibit insulin sensitivity, which can lead to systemic insulin resistance and the promotion of an 'obesogenic' ...
Context 3
... to macrophages, B cells and T cells play dynamic roles in the transition from metabolic homeostasis in lean adipose to a state of chronic inflammation and insulin resis- tance in the obese (95-97) (Fig. 2). B and T lymphocytes can influence obesity and insulin resistance. B lymphocytes have been shown to infiltrate adi- pose with onset of weight gain (98) and contribute to insu- lin resistance (99), but have been studied to a much lesser extent then adipose-resident T cells. T cells were first identi- fied in visceral fat, and secretion ...
Citations
... Moreover, increased levels of glucose transporters in macrophages can result in more efficient glucose uptake and glycolysis, as well as the promotion of (Freemerman et al. 2014). Empagliflozin, an inhibitor of sodium-glucose co-transporter 2 (SGLT2), can reduce glucose uptake and decrease glycolysis levels, thereby reducing the levels of M1 macrophages, inducing proliferation of M2 macrophages, and alleviating tissue inflammation (Xu et al. 2019). ...
... [4][5][6] Metabolic reprogramming in cancer cells push them into aerobic glycolysis, although energetic efficiency of glycolysis is much less than oxidative phosphorylation (OX-PHOS). [7] This is compensated by over-expression of glucose transporters [8] and very fast conversion of glucose to lactic acid. ...
Cancer cells change their glucose metabolism towards lactic acid production for various defensive and proliferative advantages. Dichloroacetate (DCA) is an inhibitor of a key enzyme and thus, changes back the OX‐PHOS to glycolysis ratio. We designed and synthesized a singlet oxygen triggered source of dichloroacetate which releases this inhibitor during photodynamic singlet oxygen generation. Synergistic action of DCA and singlet oxygen results in significant enhancement of photocytotoxicity. The results suggest that this approach could offer significant improvement in the therapeutic outcome of PDT.
... Multiple studies have supported a growing appreciation for the metabolic require ments of phagocyte activity during a typical immune response. Neutrophil production of free radicals ex vivo has been shown to be inhibited when treated with Rapa (37,48), and GLUT1 overexpression in macrophages increases the production of reactive oxygen species (49). A recent article has connected eosinophil-mediated inflammation with S. aureus infection (50), and we observed a minor but significantly increased eosinophil population during S. aureus infection in Rapa-treated mice. ...
... While both mTOR and NF-κB can be activated through the PI3K/Akt pathway in response to bacterial and host factors, our results suggest a separate, parallel function in the immune response to S. aureus SSTI where mTOR signaling supports metabolic functions of the phagocyte and NF-κB signaling controls cytokine production. Indeed, others have shown that GLUT1 knockout in phagocytes does not greatly impact cytokine production upon activation (49,57). Crosstalk between mTOR and NF-κB signaling has been described, especially in tumor cells (58), and several studies have observed an increase in IL-12 production from Rapa-treated phagocytes upon activation (59-61), though we did not observe a significant difference in IL-12 production in the lesions of Rapa-treated animals. ...
Mammalian target of rapamycin (mTOR) is a key regulator of metabolism in the mammalian cell. Here, we show the essential role for mTOR signaling in the immune response to bacterial infection. Inhibition of mTOR during infection with Staphylococcus aureus revealed that mTOR signaling is required for bactericidal free radical production by phagocytes. Mechanistically, mTOR supported glucose transporter GLUT1 expression, potentially through hypoxia-inducible factor 1α, upon phagocyte activation. Cytokine and chemokine signaling, inducible nitric oxide synthase, and p65 nuclear translocation were present at similar levels during mTOR suppression, suggesting an NF-κB-independent role for mTOR signaling in the immune response during bacterial infection. We propose that mTOR signaling primarily mediates the metabolic requirements necessary for phagocyte bactericidal free radical production. This study has important implications for the metabolic requirements of innate immune cells during bacterial infection as well as the clinical use of mTOR inhibitors.
IMPORTANCE
Sirolimus, everolimus, temsirolimus, and similar are a class of pharmaceutics commonly used in the clinical treatment of cancer and the anti-rejection of transplanted organs. Each of these agents suppresses the activity of the mammalian target of rapamycin (mTOR), a master regulator of metabolism in human cells. Activation of mTOR is also involved in the immune response to bacterial infection, and treatments that inhibit mTOR are associated with increased susceptibility to bacterial infections in the skin and soft tissue. Infections caused by Staphylococcus aureus are among the most common and severe. Our study shows that this susceptibility to S. aureus infection during mTOR suppression is due to an impaired function of phagocytic immune cells responsible for controlling bacterial infections. Specifically, we observed that mTOR activity is required for phagocytes to produce antimicrobial free radicals. These results have important implications for immune responses during clinical treatments and in disease states where mTOR is suppressed.
... Although the glycolytic pathway is inefficient for producing ATP, it is the fastest way to obtain energy. It promotes a high production of ROS, which constitutes one of the leading defense mechanisms of M1 macrophages against pathogens and increases the release of chemokines that exacerbate the inflammatory response 37 . ...
Excess body weight has become a global epidemic and a significant risk factor for developing chronic diseases, which are the leading causes of worldwide morbidities. Adipose tissue (AT), primarily composed of adipocytes, stores substantial amounts of energy and plays a crucial role in maintaining whole-body glucose and lipid metabolism. This helps prevent excessive body fat accumulation and lipotoxicity in peripheral tissues. In addition, AT contains endothelial cells and a substantial population of immune cells (constituting 60-70% of non-adipocyte cells), including macrophages, T and B lymphocytes, and natural killer cells. These resident immune cells engage in crosstalk with adipocytes, contributing to the maintenance of metabolic and immune homeostasis in AT. An exacerbated inflammatory response or inadequate immune resolution can lead to chronic systemic low-grade inflammation, triggering the development of metabolic alterations and the onset of chronic diseases. This review aims to elucidate the regulatory mechanisms through which immune cells influence AT function and energy homeostasis. We also focus on the interactions and functional dynamics of immune cell populations, highlighting their role in maintaining the delicate balance between metabolic health and obesity-related inflammation. Finally, understanding immunometabolism is crucial for unraveling the pathogenesis of metabolic diseases and developing targeted immunotherapeutic strategies. These strategies may offer innovative avenues in the rapidly evolving field of immunometabolism. (Rev Invest Clin. 2024;76(2):65-79).
... Numerous studies have highlighted the substantial involvement of aerobic glycolysis in the inflammatory process [36]. In instances of inflammation, immune cells exhibit a preference for glycolysis to fulfill their elevated energy requirements [37]. In TNBC, glycolysis has been documented to enhance the malignant characteristics of cancer cells through the involvement of glycolytic enzymes and the abundance of related products and substrates [38]. ...
Our study aims to find the relevant mechanism of Mume Fructus in the treatment of triple-negative breast cancer (TNBC) by network pharmacology analysis and experimental validation. The effective compounds of Mume Fructus and TNBC-related target genes were imported into Cytoscape to construct a Mume Fructus-effective compounds-disease target network. The common targets of Mume Fructus and TNBC were determined by drawing Venn diagrams. Then, the intersection targets were transferred to the STRING database to construct a protein–protein interaction (PPI) network. To investigate the mechanism of Mume Fructus in treatment of TNBC, breast cancer cell (MDA-MB-231) was treated with Mume Fructus and/or transfected with small interference RNA-PKM2(siPKM2). CCK-8 assay, cell clonal formation assay, transwell, flow cytometry, qRT-PCR, and western blotting were performed. Eight effective compounds and 145 target genes were obtained, and the Mume Fructus- effective compounds-disease target network was constructed. Then through the analysis of the PPI network, we obtained 10 hub genes including JUN, MAPK1, RELA, AKT1, FOS, ESR1, IL6, MAPK8, RXRA, and MYC. KEGG enrichment analysis showed that JUN, MAPK1, RELA, FOS, ESR1, IL6, MAPK8, and RXRA were enriched in the Th17 cell differentiation signaling pathway. Loss of PKM2 and Mume Fructus both inhibited the malignant phenotype of MDA-MB-231 cells. And siPKM2 further aggravated the Mume Fructus inhibition of malignancy of breast cancer cells. Network pharmacology analysis suggests that Mume Fructus has multiple therapeutic targets for TNBC and may play a therapeutic role by modulating the immune microenvironment of breast cancer.
... UCP2 is a mitochondrial anion carrier protein that is crucially involved in energy metabolic regulation in various cells [46][47][48]. GLUT1 mainly contributes to basal glucose uptake and enhances glycolysis [49,50], which is crucial in energy metabolism and is related to the metabolic reprogramming of macrophages [51,52]. ...
Background: Brown rice (BR) has various beneficial effects. Recently, functional ingredient derived from processed BR (Kinmemai rice extract [KR-ex.]) has been developed in Japan, which reportedly decreases subjects’ “susceptibility to catching colds.” However, the effects of KR-ex. on the immune system remain unclear. Objective: This study aimed to examine the immunostimulant effects of KR-ex., focusing on the expression of activation markers and intracellular energy metabolic activity using human monocyte (U937)-derived macrophage cells. Methods: Cell activity was assessed using the gene expression of interleukin-1β and cyclooxygenase-2 as activation markers. The energy metabolic activity in mitochondria was evaluated using the expression of uncoupling protein 2 and the oxygen consumption rate, whereas that in glycolysis was evaluated using the expression of glucose transporter 1 and the amount of lactate released. Results: The results showed that the KR-ex. group had significantly higher expression of activation markers than the control group. Moreover, the KR-ex. group showed decreased mitochondrial metabolic activity and increased glycolytic metabolic activity compared to the control group. Conclusions: These results suggest that KR-ex. activates human macrophages and promotes the shifting of the intracellular energy metabolism from the mitochondria to glycolysis. Keywords: Brown rice; Functional ingredient; Immunostimulant effect; Macrophage; Intracellular energy metabolism; Mitochondria; Glycolysis
... [27] Studies have shown that M2 macrophages predict poor prognosis in HNSCC, [28] whereas the molecular subtype associated with a better prognosis showed lower infiltration of M2 macrophages. Although M1 macrophages exhibit anti-tumor properties through their inflammatory response to cancer cells, [29] no difference was observed among molecular subtypes in this study. Generally, HNSCC subgroups with worse prognoses exhibit a more immunosuppressive TME. ...
The dysregulation of lipid metabolism is a critical factor in the initiation and progression of tumors. In this investigation, we aim to characterize the molecular subtypes of head and neck squamous cell carcinoma (HNSCC) based on their association with fatty acid metabolism and develop a prognostic risk model. The transcriptomic and clinical data about HNSCC were obtained from public databases. Clustering analysis was conducted on fatty acid metabolism genes (FAMG) associated with prognosis, utilizing the non-negative matrix factorization algorithm. The immune infiltration, response to immune therapy, and drug sensitivity between molecular subtypes were evaluated. Differential expression genes were identified between subtypes, and a prognostic model was constructed using Cox regression analyses. A nomogram for HNSCC was constructed and evaluated. Thirty FAMGs have been found to exhibit differential expression in HNSCC, out of which three are associated with HNSCC prognosis. By performing clustering analysis on these 3 genes, 2 distinct molecular subtypes of HNSCC were identified that exhibit significant heterogeneity in prognosis, immune landscape, and treatment response. Using a set of 7778 genes that displayed differential expression between the 2 molecular subtypes, a prognostic risk model for HNSCC was constructed comprising 11 genes. This model has the ability to stratify HNSCC patients into high-risk and low-risk groups, which exhibit significant differences in prognosis, immune infiltration, and immune therapy response. Moreover, our data suggest that this risk model is negatively correlated with B cells and most T cells, but positively correlated with macrophages, mast cells, and dendritic cells. Ultimately, we constructed a nomogram incorporating both the risk signature and radiotherapy, which has demonstrated exceptional performance in predicting prognosis for HNSCC patients. A molecular classification system and prognostic risk models were developed for HNSCC based on FAMGs. This study revealed the potential involvement of FAMGs in modulating tumor immune microenvironment and response to treatment.
... Considering that GLUT1 functions as a key glucose transporter and upregulation acts as a marker for aerobic glycolysis in metabolically active cells [62], we speculate that the regulation of GLUT1 in microglial inflammation might be associated with metabolic reprogramming. This hypothesis is corroborated by previous findings that the overexpression or increased expression of GLUT1 could decrease macrophage oxygen consumption, increase cellular glucose uptake, and enhance glycolytic capacity, leading to excessive activation and increased secretion of inflammatory mediators [63]. Conversely, GLUT1 antagonists have been found to decrease glycolytic levels in microglia and inhibit their inflammatory activation [33]. ...
Background
Stress is a recognized risk factor for cognitive decline, which triggers neuroinflammation involving microglial activation. However, the specific mechanism for microglial activation under stress and affects learning and memory remains unclear.
Methods
The chronic stress mouse model was utilized to explore the relationship between microglial activation and spatial memory impairment. The effect of hippocampal hyperglycemia on microglial activation was evaluated through hippocampal glucose-infusion and the incubation of BV2 cells with high glucose. The gain-and loss-of-function experiments were conducted to investigate the role of GLUT1 in microglial proinflammatory activation. An adeno-associated virus (AAV) was employed to specifically knockdown of GLUT1 in hippocampal microglia to assess its impact on stressed-mice.
Results
Herein, we found that chronic stress induced remarkable hippocampal microglial proinflammatory activation and neuroinflammation, which were involved in the development of stress-related spatial learning and memory impairment. Mechanistically, elevated hippocampal glucose level post-stress was revealed to be a key regulator of proinflammatory microglial activation via specifically increasing the expression of microglial GLUT1. GLUT1 overexpression promoted microglial proinflammatory phenotype while inhibiting GLUT1 function mitigated this effect under high glucose. Furthermore, specific downregulation of hippocampal microglial GLUT1 in stressed-mice relieved microglial proinflammatory activation, neuroinflammation, and spatial learning and memory injury. Finally, the NF-κB signaling pathway was demonstrated to be involved in the regulatory effect of GLUT1 on microglia.
Conclusions
We demonstrate that elevated glucose and GLUT1 expression induce microglia proinflammatory activation, contributing to stress-associated spatial memory dysfunction. These findings highlight significant interplay between metabolism and inflammation, presenting a possible therapeutic target for stress-related cognitive disorders.
... Recognition of LPS by TLR4 on the surface of myeloid cells activates numerous signaling cascades via the recruitment of MyD88 and Toll/IL-1R domain-containing adaptorinducing IFN-β (TRIF) [79]. This subsequently leads to a shift in the metabolic profile of activated pro-inflammatory macrophages, driven by increased GLUT1 glucose uptake and increased activity of glycolytic enzymes (i.e., HK, glucose-6-phosphate dehydrogenase) [80,81]. The metabolic reprogramming of activated macrophages by TLR4 also heavily employs the action of HIF-1α, as PKM2 expression induced by LPS recognition drives HIF-1α activation and IL-1β secretion [82]. ...
Mammalian cells utilize glucose as a primary carbon source to produce energy for most cellular functions. However, the bioenergetic homeostasis of cells can be perturbed by environmental alterations, such as changes in oxygen levels which can be associated with bacterial infection. Reduction in oxygen availability leads to a state of hypoxia, inducing numerous cellular responses that aim to combat this stress. Importantly, hypoxia strongly augments cellular glycolysis in most cell types to compensate for the loss of aerobic respiration. Understanding how this host cell metabolic adaptation to hypoxia impacts the course of bacterial infection will identify new anti-microbial targets. This review will highlight developments in our understanding of glycolytic substrate channeling and spatiotemporal enzymatic organization in response to hypoxia, shedding light on the integral role of the hypoxia-inducible factor (HIF) during host–pathogen interactions. Furthermore, the ability of intracellular and extracellular bacteria (pathogens and commensals alike) to modulate host cellular glucose metabolism will be discussed.
... Along with the known inflammatory and anti-inflammatory regulators of functional plasticity carried out by mononuclear phagocytes, recent shreds of evidence depict the role of sugar, amino acid, and lipid metabolic pathways reprogramming in modulating their immune response under diverse tissue microenvironments [77,107,108]. The M1 subtype is marked by a high glycolysis rate, fatty acid synthesis, and truncated TCA cycle, with flux through the pentose phosphate pathway [109,110]. Along with this, inflammatory functions of this phenotype are also mediated by certain intermediates. For example, LPS/IFN-γ stimulation act on succinate dehydrogenase (SDH) and isocitrate dehydrogenase (IDH) enzymes (an enzyme responsible for the conversion of isocitrate to alpha-ketoglutarate) of the TCA cycle due to which citrate and succinate accumulate (TCA break) in these mononuclear cells having inflammatory roles [111]. ...
Background
Monocytes and macrophages are essential components of innate immune system and have versatile roles in homeostasis and immunity. These phenotypically distinguishable mononuclear phagocytes play distinct roles in different stages, contributing to the pathophysiology in various forms making them a potentially attractive therapeutic target in inflammatory conditions. Several pieces of evidence have supported the role of different cell surface receptors expressed on these cells and their downstream signaling molecules in initiating and perpetuating the inflammatory response. In this review, we discuss the current understanding of the monocyte and macrophage biology in inflammation, highlighting the role of chemoattractants, inflammasomes, and integrins in the function of monocytes and macrophages during events of inflammation. This review also covers the recent therapeutic interventions targeting these mononuclear phagocytes at the cellular and molecular levels.
