Search

Lipid-associated macrophages (LAMs) occur in a broad range of diseased structures and lesions in tissues important for metabolic homeostasis. LAMs can be distinguished from other tissue-resident macrophages by their lipid-handling capacity and expression of specific marker genes (e.g., Trem2 , Gpnmb , and CD36). LAMs exhibit a functional spectrum (with respect to inflammation, lipid handling, and efferocytosis) that can vary depending on metabolic and disease state, location, and microenvironmental needs. LAM pools emerge largely from monocyte-derived precursors, but may also increase in abundance through (re-)polarization and self-renewal. Evidence for the importance of LAMs in metabolic disease justifies ventures into therapeutics that manipulate LAM abundance and phenotypes. Lipid-associated macrophages (LAMs) are phagocytic cells with lipid-handling capacity identified in various metabolic derangements. During disease development, they locate to atherosclerotic plaques, adipose tissue (AT) of individuals with obesity, liver lesions in steatosis and steatohepatitis, and the intestinal lamina propria. LAMs can also emerge in the metabolically demanding microenvironment of certain tumors. In this review, we discuss major questions regarding LAM recruitment, differentiation, and self-renewal, and, ultimately, their acute and chronic functional impact on the development of metabolic diseases. Further studies need to clarify whether and under which circumstances LAMs drive disease progression or resolution and how their phenotype can be modulated to ameliorate metabolic disorders. [ABSTRACT FROM AUTHOR]

Background: Recurrent pregnancy loss (RPL) affects women's reproductive health seriously, with immune dysfunction playing a key role in its cause, yet the exact mechanisms remain elusive. We aim to investigate potential mechanisms and identify biomarkers linked to RPL. Methods: Immune cytokine testing and metabolomic profiling were conducted on the serum of 34 RPL patients and 30 healthy individuals. The metabolic pathways of the differential metabolites were analyzed, and specific metabolites were validated through targeted profiling. Potential biomarkers were identified, and the relationships between immune cytokines and differential metabolites were explored. Results: In the RPL group, serum interleukin-6 and interleukin-10 levels were significantly higher, while interleukin-2 and interferon-g were significantly lower. A total of 296 differential metabolites were detected by untargeted metabolomic profiling between the RPL and control groups, with most linked to amino acid metabolism. Targeted metabolomic profiling of amino acid metabolism revealed upregulation of indole-3-acetic acid, tyrosine, glycine, isoleucine, tryptophan, lysine, aspartic acid, arginine, leucine, threonine, glutamic acid, cystine, and phenylpyruvic acid (PPA) in the RPL group. Moreover, PPA and 5-hydroxy-Ltryptophan showed great potential in predicting RPL in a diagnostic model. Cystine and tyrosine were associated with immune cytokines in correlation analysis. Conclusion: The study highlights the role of amino acid metabolism in RPL pathogenesis, suggesting that PPA and 5-HTP may be potential predictive indicators, while cystine and tyrosine may potentially regulate immune responses related to RPL. Further investigation into the molecular mechanisms underlying these findings could potentially result in the creation of novel diagnostic and therapeutic approaches for RPL. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis. Here, a macrophage infection model was used to unravel the role of the histone deacetylase sirtuin 6 (SIRT6) in Mtb‐triggered regulation of the innate immune response. Mtb infection downregulated microRNA‐26a and upregulated its target SIRT6. SIRT6 suppressed glycolysis and expression of HIF‐1α‐dependent glycolytic genes during infection. In addition, SIRT6 regulated the levels of intracellular succinate which controls stabilization of HIF‐1α, as well as the release of interleukin (IL)‐1β. Furthermore, SIRT6 inhibited inducible nitric oxide synthase (iNOS) and proinflammatory IL‐6 but augmented anti‐inflammatory arginase expression. The miR‐26a/SIRT6/HIF‐1α axis therefore regulates glycolysis and macrophage immune responses during Mtb infection. Our findings link SIRT6 to rewiring of macrophage signaling pathways facilitating dampening of the antibacterial immune response. [ABSTRACT FROM AUTHOR]

Type 2 diabetes (T2D) is associated with insulin resistance and progressive dysfunction of β-pancreatic cells, leading to persistent hyperglycemia. Macrophages play a crucial role in this context, influencing both the development and progression of insulin resistance. These innate immune cells respond to inflammatory stimuli and reprogram their metabolism, directly impacting the pathophysiology of T2D. Macrophages are highly plastic and can adopt either pro-inflammatory or pro-resolutive phenotypic profiles. In T2D, pro-inflammatory macrophages, which rely on glycolysis, exacerbate insulin resistance through increased production of pro-inflammatory cytokines and nitric oxide. In contrast, pro-resolutive macrophages, which prioritize fatty acid metabolism, have different effects on glucose homeostasis. Metaflammation, a chronic low-grade inflammation, is induced by pro-inflammatory macrophages and significantly contributes to the progression of T2D, creating an environment conducive to metabolic dysfunction. This review aims to clarify the contribution of macrophages to the progression of T2D by detailing how their inflammatory responses and metabolic reprogramming influence insulin resistance and the disease's pathophysiology. The review seeks to deepen the understanding of the biochemical and metabolic mechanisms involved, offering broader insights into the impact on the quality of life for millions of patients worldwide. [ABSTRACT FROM AUTHOR]

The pathogenesis of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains unclear, though increasing evidence suggests inflammatory processes play key roles. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) was used to decipher the immunometabolic profile in 4 ME/CFS patients and 4 heathy controls. We analyzed changes in the composition of major PBMC subpopulations and observed an increased frequency of total T cells and a significant reduction in NKs, monocytes, cDCs and pDCs. Further investigation revealed even more complex changes in the proportions of cell subpopulations within each subpopulation. Gene expression patterns revealed upregulated transcription factors related to immune regulation, as well as genes associated with viral infections and neurodegenerative diseases.CD4+ and CD8+ T cells in ME/CFS patients show different differentiation states and altered trajectories, indicating a possible suppression of differentiation. Memory B cells in ME/CFS patients are found early in the pseudotime, indicating a unique subtype specific to ME/CFS, with increased differentiation to plasma cells suggesting B cell overactivity. NK cells in ME/CFS patients exhibit reduced cytotoxicity and impaired responses, with reduced expression of perforin and CD107a upon stimulation. Pseudotime analysis showed abnormal development of adaptive immune cells and an enhanced cell-cell communication network converging on monocytes in particular. Our analysis also identified the estrogen-related receptor alpha (ESRRA)-APP-CD74 signaling pathway as a potential biomarker for ME/CFS in peripheral blood. In addition, data from the GSE214284 database confirmed higher ESRRA expression in the monocyte cell types of male ME/CFS patients. These results suggest a link between immune and neurological symptoms. The results support a disease model of immune dysfunction ranging from autoimmunity to immunodeficiency and point to amyloidotic neurodegenerative signaling pathways in the pathogenesis of ME/CFS. While the study provides important insights, limitations include the modest sample size and the evaluation of peripheral blood only. These findings highlight potential targets for diagnostic biomarkers and therapeutic interventions. Further research is needed to validate these biomarkers and explore their clinical applications in managing ME/CFS. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are multifaceted innate effector cells that critically influence antiviral immunity, and several protective NK cell features that modulate HIV-1 acquisition and viral control have been described. Chronic HIV-1 infection leads to NK cell impairment that has been associated with metabolic dysregulations. Therapeutic approaches targeting cellular immune metabolism represent potential novel interventions to reverse defective NK cell function in people living with HIV. [ABSTRACT FROM AUTHOR]

Purpose: Ketogenic diets are proposed as a therapeutic approach for type 1 and type 2 diabetes due to their low glucose intake. However, their potential effects on the immune system need investigation. This study aims to explore how glucose concentration and beta-hydroxybutyrate (BHB) impact T cell phenotype, metabolism, and function, with a focus on systemic inflammatory response (T2D) and autoimmunity (T1D). Methods: T cells from healthy donors were cultured in vitro under varying glucose concentrations with or without BHB. Flow cytometry was employed to analyze changes in T cell phenotype, while proliferation was evaluated through a CFSE dilution assay. Additionally, we used a novel flow cytometry method allowing a direct assessment of T cell metabolism. Results: Culturing T cells in low glucose concentrations revealed their dependency on glucose metabolism, leading to reduced proliferation rates, overexpression of exhaustion markers and increased susceptibility to Treg suppression and the influence of immune-modulating drugs such as rapamycin, FK506, and MMF. Notably, T cells cultured in low glucose concentrations increased the expression of BDH1 to utilize BHB as an alternative fuel source. Finally, the addition of BHB to the culture effectively rescued T cell impairments caused by insufficient glucose levels. Conclusions: T cells display limited capacity to adapt to low glucose levels, resulting in profound functional impairment. However, T cell functions can be efficiently recovered by the presence of 2mM BHB. [ABSTRACT FROM AUTHOR]

The list of standard abbreviations for JDS is available at adsa.org/jds-abbreviations-24. Nonstandard abbreviations are available in the Notes. The inability of dairy calves to fully respond to immune stimuli until they reach maturity at 6 mo of age severely limits the use of parenteral vaccines to protect calves against disease. Immune responses are metabolically demanding, and immune cells rely on mitochondrial metabolites for their functionality. Due to the essential role of mitochondria in driving T-cell responses necessary for vaccine efficacy, we hypothesized that the mitochondrial function of dairy calf lymphocytes changes with age, from birth to immunologic maturity. In this cross-sectional study, groups of dairy calves (n = 4/group) were blood sampled at birth before colostrum intake and at 1, 2, 3, 4, 6, 8, 16, and 24 wk of age. Mid-lactation adult cows (n = 4) were also sampled to reference fully mature immune cell populations. B, CD4+, CD8+, and γδ T lymphocytes were enriched using magnetic-activated cell sorting, and their mitochondrial function was assessed with an extracellular flux analyzer. Nonmitochondrial oxygen consumption, basal respiration, maximal respiration, spare respiratory capacity, proton leak, and the oxygen consumption rate (OCR) to extracellular acidification rate (ECAR) ratio were reported. Results were compared among groups using a Kruskal-Wallis test. The OCR to ECAR ratio is an indicator of the relative proportions of oxidative phosphorylation and aerobic glycolysis which is associated with effector functions in lymphocytes. The ratio was lower in 0 wk than adults in CD4+ T-cells. For CD8+ T-cells, the OCR to ECAR ratio for the 2-wk group was lower than the 3-wk group. A lower OCR to ECAR ratio indicates more reliance on glycolytic metabolism than oxidative phosphorylation. Maximal respiration is an indication of mitochondrial efficiency and is often associated with mitochondrial mass. For γδ T-cells, the 3-wk group had higher maximal respiration than the 16-wk group, whereas for B-cells maximal respiration was higher in the 1 wk compared with the 16-wk group. Basal respiration indicates all cell functions that require oxygen and was lower in the 0-wk group than the 1- and 3-wk groups for CD4+ T-cells. γδ T-cells exhibited lower basal respiration in the 2-wk group than the 24-wk one. Although we found minimal differences in the mitochondrial outcomes reported from nonstimulated lymphocytes from birth through 6 mo of age and mid-lactation adults who served as mature immune cell populations, these results align with previous reports from weaning aged calf and adult CD4+ T-cells. In conclusion, insufficient evidence exists to suggest that the mitochondria in the lymphocytes of dairy calves from birth through immunologic maturity had functional changes associated with age. The capacity of unstimulated calf mitochondria to perform oxidative phosphorylation is not associated with age. [ABSTRACT FROM AUTHOR]

Background: Environmental lipopolysaccharide (LPS) and microbial component-enriched organic dusts cause significant lung disease. These environmental exposures induce the recruitment and activation of distinct lung monocyte/macrophage subpopulations involved in disease pathogenesis. Aconitate decarboxylase 1 (Acodl) was one of the most upregulated genes following LPS (vs. saline) exposure of murine whole lungs with transcriptomic profiling of sorted lung monocyte/macrophage subpopulations also highlighting its significance. Given monocyte/macrophage activation can be tightly linked to metabolism, the objective of these studies was to determine the role of the immunometabolic regulator ACOD1 in environmental exposure-induced lung inflammation. Methods: Wild-type (WT) mice were intratracheally (i.t.) instilled with 10 mg of LPS or saline. Whole lungs were profiled using bulk RNA sequencing or sorted to isolate monocyte/macrophage subpopulations. Sorted subpopulations were then characterized transcriptomically using a NanoString innate immunity multiplex array 48 h post-exposure. Next, WT and Acod1-/- mice were instilled with LPS, 25% organic dust extract (ODE), or saline, whereupon serum, bronchoalveolar lavage fluid (BALF), and lung tissues were collected. BALF metabolites of the tricarboxylic acid (TCA) cycle were quantified by mass spectrometry. Cytokines/chemokines and tissue remodeling mediators were quantitated by ELISA. Lung immune cells were characterized by flow cytometry. Invasive lung function testing was performed 3 h post-LPS with WT and Acodl-/- mice. Results: Acod1-/- mice treated with LPS demonstrated decreased BALF levels of itaconate, TCA cycle reprogramming, decreased BALF neutrophils, increased lung CD4+ T cells, decreased BALF and lung levels of TNF-α, and decreased BALF CXCL1 compared to WT animals. In comparison, Acod1-/- mice treated with ODE demonstrated decreased serum pentraxin-2, BALF levels of itaconate, lung total cell, neutrophil, monocyte, and B-cell infiltrates with decreased BALF levels of TNF-α and IL-6 and decreased lung CXCL1vs. WT animals. Mediators of tissue remodeling (TIMP1, MMP-8, MMP-9) were also decreased in the LPS-exposed Acod1-/- mice, with MMP-9 also reduced in ODE-exposed Acod1-/- mice. Lung function assessments demonstrated a blunted response to LPS-induced airway hyperresponsiveness in Acod1-/- animals. Conclusion: Acodl is robustly upregulated in the lungs following LPS exposure and encodes a key immunometabolic regulator. ACOD1 mediates the proinflammatory response to acute inhaled environmental LPS and organic dust exposure-induced lung inflammation. [ABSTRACT FROM AUTHOR]

Lung diseases triggered by endogenous or exogenous factors have become a major concern, with high morbidity and mortality rates, especially after the coronavirus disease 2019 (COVID-19) pandemic. Inflammation and an over-activated immune system can lead to a cytokine cascade, resulting in lung dysfunction and injury. Itaconate, a metabolite produced by macrophages, has been reported as an effective anti-inflammatory and anti-oxidative stress agent with significant potential in regulating immunometabolism. As a naturally occurring metabolite in immune cells, itaconate has been identified as a potential therapeutic target in lung diseases through its role in regulating inflammation and immunometabolism. This review focuses on the origin, regulation, and function of itaconate in lung diseases, and briefly discusses its therapeutic potential. [ABSTRACT FROM AUTHOR]

Atherosclerosis is a complex pathological process that results from the chronic inflammatory reaction of the blood vessel wall and involves various immune cells and cytokines. An imbalance in the proportion and function of the effector CD4+ T-cell (Teff) and regulatory T-cell (Treg) subsets is an important cause of the occurrence and development of atherosclerotic plaques. Teff cells depend on glycolytic metabolism and glutamine catabolic metabolism for energy, while Treg cells mainly rely on fatty acid oxidation (FAO), which is crucial for determining the fate of CD4+ T cells during differentiation and maintaining their respective immune functions. Here, we review recent research achievements in the field of immunometabolism related to CD4+ T cells, focusing on the cellular metabolic pathways and metabolic reprogramming involved in the activation, proliferation, and differentiation of CD4+ T cells. Subsequently, we discuss the important roles of mTOR and AMPK signaling in regulating CD4+ T-cell differentiation. Finally, we evaluated the links between CD4+ T-cell metabolism and atherosclerosis, highlighting the potential of targeted modulation of CD4+ T-cell metabolism in the prevention and treatment of atherosclerosis in the future. [ABSTRACT FROM AUTHOR]

Background: Mitochondria play a crucial role in shaping the macrophage inflammatory response during bacterial infections. Spinster homolog 2 (Spns2), responsible for sphingosine-1-phosphate (S1P) secretion, acts as a key regulator of mitochondrial dynamics in macrophages. However, the link between Spns2/S1P signaling and mitochondrial functions remains unclear. Methods: Peritoneal macrophages were isolated from both wild-type and Spns2 knockout rats, followed by non-targeted metabolomics and RNA sequencing analysis to identify the potential mediators through which Spns2/S1P signaling influences the mitochondrial functions in macrophages. Various agonists and antagonists were used to modulate the activation of Spns2/S1P signaling and its downstream pathways, with the underlying mechanisms elucidated through western blotting. Mitochondrial functions were assessed using flow cytometry and oxygen consumption assays, as well as morphological analysis. The impact on inflammatory response was validated through both in vitro and in vivo sepsis models, with the specific role of macrophage-expressed Spns2 in sepsis evaluated using Spns2flox/floxLyz2-Cre mice. Additionally, the regulation of mitochondrial functions by Spns2/S1P signaling was confirmed using THP-1 cells, a human monocyte-derived macrophage model. Results: In this study, we unveil prostaglandin E2 (PGE2) as a pivotal mediator involved in Spns2/S1P-mitochondrial communication. Spns2/S1P signaling suppresses PGE2 production to support malate-aspartate shuttle activity. Conversely, excessive PGE2 resulting from Spns2 deficiency impairs mitochondrial respiration, leading to intracellular lactate accumulation and increased reactive oxygen species (ROS) generation through E-type prostanoid receptor 4 activation. The overactive lactate-ROS axis contributes to the early-phase hyperinflammation during infections. Prolonged exposure to elevated PGE2 due to Spns2 deficiency culminates in subsequent immunosuppression, underscoring the dual roles of PGE2 in inflammation throughout infections. The regulation of PGE2 production by Spns2/S1P signaling appears to depend on the coordinated activation of multiple S1P receptors rather than any single one. Conclusions: These findings emphasize PGE2 as a key effector of Spns2/S1P signaling on mitochondrial dynamics in macrophages, elucidating the mechanisms through which Spns2/S1P signaling balances both early hyperinflammation and subsequent immunosuppression during bacterial infections. [ABSTRACT FROM AUTHOR]

Neutrophils utilize a variety of metabolic sources to support their crucial functions as the first responders in innate immunity. Here, through in vivo and ex vivo isotopic tracing, we examined the contributions of different nutrients to neutrophil metabolism under specific conditions. Human peripheral blood neutrophils, in contrast to a neutrophil-like cell line, rely on glycogen storage as a major metabolic source under resting state but rapidly switch to primarily using extracellular glucose upon activation with various stimuli. This shift is driven by a substantial increase in glucose uptake, enabled by rapidly increased GLUT1 on cell membrane, that dominates the simultaneous increase in gross glycogen cycling capacity. Shifts in nutrient utilization impact neutrophil functions in a function-specific manner: oxidative burst depends on glucose utilization, whereas NETosis and phagocytosis can be flexibly supported by either glucose or glycogen, and neutrophil migration and fungal control are enhanced by the shift from glycogen utilization to glucose utilization. This work provides a quantitative and dynamic understanding of fundamental features in neutrophil metabolism and elucidates how metabolic remodeling shapes neutrophil functions, which has broad health relevance. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB), caused by Mycobacterium tuberculosis (M.tb), is a major global health concern, particularly affecting those with weakened immune systems, including the elderly. CD4+ T cell response is crucial for immunity against M.tb, but chronic infections and aging can lead to T cell exhaustion and senescence, worsening TB disease. Mitochondrial dysfunction, prevalent in aging and chronic diseases, disrupts cellular metabolism, increases oxidative stress, and impairs T‐cell functions. This study investigates the effect of mitochondrial transplantation (mito‐transfer) on CD4+ T cell differentiation and function in aged mouse models and human CD4+ T cells from elderly individuals. Mito‐transfer in naïve CD4+ T cells is found to promote protective effector and memory T cell generation during M.tb infection in mice. Additionally, it improves elderly human T cell function by increasing mitochondrial mass and altering cytokine production, thereby reducing markers of exhaustion and senescence. These findings suggest mito‐transfer as a novel approach to enhance aged CD4+ T cell functionality, potentially benefiting immune responses in the elderly and chronic TB patients. This has broader implications for diseases where mitochondrial dysfunction contributes to T‐cell exhaustion and senescence. [ABSTRACT FROM AUTHOR]

The tumour microenvironment (TME) is a dynamic nexus where cancer cell metabolism and the immune system intricately converge, with nucleotide metabolism (NM) playing a pivotal role. This review explores the critical function of NM in cancer cell proliferation and its profound influence on the TME and immune landscape. NM is essential for DNA and RNA synthesis and is markedly upregulated in cancer cells to meet the demands of rapid growth. This metabolic rewiring fuels cancer progression, but also shapes the TME, impacting the function and viability of immune cells. The altered nucleotide milieu in the TME can suppress immune response, aiding cancer cell evasion from immune surveillance. Drug discoveries in the field of NM have revealed different therapeutic strategies, including inhibitors of nucleotide synthesis and drugs targeting salvage pathways, which are discussed thoroughly in this review. Furthermore, the emerging strategy of combining NM‐targeted therapies with immunotherapies is emphasised, particularly their effect on sensitising tumours to immune checkpoint inhibitors and enhancing overall treatment efficacy. The Human Genome Project paved the way for personalised medicine, countering the established ‘one size fits all’ approach to cancer treatment. Advances in understanding the TME and NM have spurred interest in personalised therapeutic strategies. This review highlights the potential of leveraging individual tumour metabolic profiles to guide treatment selection, aiming to optimise efficacy and minimise adverse effects. The strategic importance of targeting NM in cancer therapy and its synergistic potential with immunotherapies offers a path towards more effective and personalised cancer treatments. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming drives the development of an immunosuppressive tumor microenvironment (TME) through various pathways, contributing to cancer progression and reducing the effectiveness of anticancer immunotherapy. However, our understanding of the metabolic landscape within the tumor-immune context has been limited by conventional metabolic measurements, which have not provided comprehensive insights into the spatiotemporal heterogeneity of metabolism within TME. The emergence of single-cell, spatial, and in vivo metabolomic technologies has now enabled detailed and unbiased analysis, revealing unprecedented spatiotemporal heterogeneity that is particularly valuable in the field of cancer immunology. This review summarizes the methodologies of metabolomics and metabolic regulomics that can be applied to the study of cancer-immunity across single-cell, spatial, and in vivo dimensions, and systematically assesses their benefits and limitations. [ABSTRACT FROM AUTHOR]

Background Objective Methods Results Conclusions Peripheral immune cells critically contribute to the clinical‐pathological progression of neurodegenerative diseases and also represent a reliable frame for translational applications. However, data on progressive supranuclear palsy (PSP) are almost scarce in this regard.Our goal is to provide a broad biological characterization of peripheral immune cells in a selected PSP cohort.Seventy‐one PSP patients scored on the PSP Rating Scale (PSPRS), and 59 controls were enrolled. The blood cell count was collected, together with the neutrophil‐to‐lymphocyte ratio (NLR) calculation. In a subgroup of patients and controls, the peripheral blood mononuclear cells (PBMCs) were analyzed by the mitochondrial bioenergetic performance and the western blot assay of the nuclear factor erythroid 2‐related factor (NRF2)/heme oxygenase 1 (HO‐1) pathway and the total tau (t‐tau) and phosphorylated tau (p‐tau) proteins. Case–control comparison and correlation analyses were performed.PSP patients had a NLR higher than controls, with increased circulating neutrophils. The leukocyte metabolism was also globally increased and the NRF2/HO‐1 pathway activated in patients. P‐tau, but not t‐tau, significantly accumulated in PSP PBMCs and inversely correlated with the PSPRS.PSP displays a systemic inflammatory shift of the peripheral immunity, which may justify a metabolic reprogramming of the blood leukocytes. Consistently, the NRF2/HO‐1 pathway, a master regulator of inflammatory and metabolic response, was activated. PBMCs also engulf tau proteins, especially p‐tau, in a way inverse to the disease severity, allowing for a peripheral tracking of tauopathy in patients. Immunometabolic targets may, therefore, gain relevance to PSP in biomarker or therapeutic purposes. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

AbstractIn recent years, mostly spanning the past decade, the concept of immunometabolism has ushered with a novel perspective on carcinogenesis, tumor progression, and tumor response to therapy. It has become clear that the metabolic state of immune cells plays a significant role in shaping their antitumor or protumor activities within the cancer microenvironment. Consequently, the examination of tumor metabolic heterogeneity, including an exploration of immunometabolism, proves indispensable for enhancing prognostic tools and advancing the quest for personalized treatments. Here we have delved into how metabolic reprogramming profoundly influences the acquisition and maintenance of functional states, spanning from effector and cytotoxic profiles to regulatory and immunosuppressive phenotypes in both innate and adaptive immunity. These alterations wield considerable influence over tumor evolution and affect the outcome of cancer. Furthermore, we explore some of the cellular signaling mechanisms that underpin the metabolic and phenotypic flexibility of immune cells in response to external stimuli. [ABSTRACT FROM AUTHOR]

This article explores the role of O-GlcNAcylation in regulating the immune system. O-GlcNAcylation is a post-translational modification that affects cell signaling, metabolism, and development. It has been linked to immune dysfunction and the development of autoimmune, inflammatory, and allergic diseases, as well as immune cell malignancies. The article includes original research articles and comprehensive reviews that cover various aspects of O-GlcNAcylation in the immune system, such as its impact on leukemia, immune cell infiltration, and inflammation. The collection of articles provides a comprehensive overview of O-GlcNAcylation's role in the immune system, highlighting the potential for therapeutic interventions and improved disease diagnoses. [Extracted from the article]

Stimulation of mammalian cells with inflammatory inducers such as lipopolysaccharide (LPS) leads to alterations in activity of central cellular metabolic pathways. Interestingly, these metabolic changes seem to be important for subsequent release of pro‐inflammatory cytokines. This has become particularly clear for enzymes of tricarboxylic acid (TCA) cycle such as succinate dehydrogenase (SDH). LPS leads to inhibition of SDH activity and accumulation of succinate to enhance the LPS‐induced formation of IL‐1β. If enzymes involved in beta‐oxidation of fatty acids are important for sufficient responses to LPS is currently not clear. Using cells from various patients with inborn long‐chain fatty acid oxidation disorders (lcFAOD), we report that disease‐causing deleterious variants of Electron Transfer Flavoprotein Dehydrogenase (ETFDH) and of Very Long Chain Acyl‐CoA Dehydrogenase (ACADVL), both cause insufficient inflammatory responses to stimulation with LPS. The insufficiencies included reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro‐inflammatory cytokines such as IL‐6. The insufficient responses to LPS were reproduced in cells from healthy controls by targeted loss‐of‐function of either ETFDH or ACADVL, supporting that the deleterious ETFDH and ACADVL variants cause the attenuated responses to LPS. ETFDH and ACADVL encode two distinct enzymes both involved in fatty acid beta‐oxidation, and patients with these deficiencies cannot sufficiently metabolize long‐chain fatty acids. We report that genes important for beta‐oxidation of long‐chain fatty acids are also important for inflammatory responses to an acute immunogen trigger like LPS, which may have important implications for understanding infection and other metabolic stress induced disease pathology in lcFAODs. [ABSTRACT FROM AUTHOR]

The establishment of effective antiviral responses within host cells is intricately related to their metabolic status, shedding light on immunometabolism. In this study, we investigated the hypothesis that cellular reliance on glutamine metabolism contributes to the development of a potent antiviral response. We evaluated the antiviral response in the presence or absence of L-glutamine in the culture medium, revealing a bivalent response hinging on cellular metabolism. While certain interferon-stimulated genes (ISGs) exhibited higher expression in an oxidative phosphorylation (OXPHOS)-dependent manner, others were surprisingly upregulated in a glycolytic-dependent manner. This metabolic dichotomy was influenced in part by variations in interferon-β (IFN-β) expression. We initially demonstrated that the presence of L-glutamine induced an enhancement of OXPHOS in A549 cells. Furthermore, in cells either stimulated by poly:IC or infected with dengue virus and Zika virus, a marked increase in ISGs expression was observed in a dose-dependent manner with L-glutamine supplementation. Interestingly, our findings unveiled a metabolic dependency in the expression of specific ISGs. In particular, genes such as ISG54, ISG12 and ISG15 exhibited heightened expression in cells cultured with L-glutamine, corresponding to higher OXPHOS rates and IFN-β signaling. Conversely, the expression of viperin and 2′-5′-oligoadenylate synthetase 1 was inversely related to L-glutamine concentration, suggesting a glycolysis-dependent regulation, confirmed by inhibition experiments. This study highlights the intricate interplay between cellular metabolism, especially glutaminergic and glycolytic, and the establishment of the canonical antiviral response characterized by the expression of antiviral effectors, potentially paving the way for novel strategies to modulate antiviral responses through metabolic interventions. [ABSTRACT FROM AUTHOR]

Glutamine is a critical amino acid that serves as an energy source, building block, and signaling molecule for the heart tissue and the immune system. However, the role of glutamine metabolism in regulating cardiac remodeling following myocardial infarction (MI) is unknown. In this study, we show in adult male mice that glutamine metabolism is altered both in the remote (contractile) area and in infiltrating macrophages in the infarct area after permanent left anterior descending artery occlusion. We found that metabolites related to glutamine metabolism were differentially altered in macrophages at days 1, 3, and 7 after MI using untargeted metabolomics. Glutamine metabolism in live cells was increased after MI relative to no MI controls. Gene expression in the remote area of the heart indicated a loss of glutamine metabolism. Glutamine administration improved left ventricle (LV) function at days 1, 3, and 7 after MI, which was associated with improved contractile and metabolic gene expression. Conversely, administration of BPTES, a pharmacological inhibitor of glutaminase-1, worsened LV function after MI. Neither glutamine nor BPTES administration impacted gene expression or bioenergetics of macrophages isolated from the infarct area. Our results indicate that glutamine metabolism plays a critical role in maintaining LV contractile function following MI and that glutamine administration improves LV function. Glutamine metabolism may also play a role in regulating macrophage function, but macrophages are not responsive to exogenous pharmacological manipulation of glutamine metabolism. NEW & NOTEWORTHY: Glutamine metabolism is altered in both infarct macrophages and the remote left ventricle (LV) following myocardial infarction (MI). Supplemental glutamine improves LV function following MI while inhibiting glutamine metabolism with BPTES worsens LV function. Supplemental glutamine or BPTES does not impact macrophage immunometabolic phenotypes after MI. [ABSTRACT FROM AUTHOR]

Objectives Increasing studies demonstrated the importance of C5a and anti-neutrophil cytoplasmic antibody (ANCA)-induced neutrophil activation in the pathogenesis of ANCA-associated vasculitis (AAV). Sphingosine-1-phosphate (S1P) acts as a downstream effector molecule of C5a and enhances neutrophil activation induced by C5a and ANCA. The current study investigated the role of a S1P receptor modulator, FTY720, in experimental autoimmune vasculitis (EAV) and explored the immunometabolism-related mechanisms of FTY720 in modulating ANCA-induced neutrophil activation. Methods The effects of FTY720 in EAV were evaluated by quantifying haematuria, proteinuria, crescent formation, tubulointerstitial injury and pulmonary haemorrhage. RNA sequencing of renal cortex and gene enrichment analysis were performed. The proteins of key identified pathways were analysed in neutrophils isolated from peripheral blood of patients with active AAV and normal controls. We assessed the effects of FTY720 on ANCA-induced neutrophil respiratory burst and neutrophil extracellular traps formation (NETosis). Results FTY720 treatment significantly attenuated renal injury and pulmonary haemorrhage in EAV. RNA sequencing analyses of renal cortex demonstrated enhanced fatty acid oxidation (FAO) and peroxisome proliferator-activated receptor (PPAR) signalling in FTY720-treated rats. Compared with normal controls, patients with active AAV showed decreased FAO in neutrophils. FTY720-treated differentiated HL-60 cells showed increased expression of carnitine palmitoyltransferase 1a (CPT1a) and PPARα. Blocking or knockdown of CPT1a or PPARα in isolated human neutrophils and HL-60 cells reversed the inhibitory effects of FTY720 on ANCA-induced neutrophil respiratory burst and NETosis. Conclusion FTY720 attenuated renal injury in EAV through upregulating FAO via the PPARα–CPT1a pathway in neutrophils, offering potential immunometabolic targets in AAV treatment. [ABSTRACT FROM AUTHOR]

Myocardial infarction (MI), a severe outcome of cardiovascular disease, poses a serious threat to human health. Uncontrolled inflammation and excessive cardiomyocyte death, following an infarction event, significantly contribute to both the mortality rate and complications associated with MI. The protein IL-4-induced gene 1 (IL4I1 or FIG1) serves as a natural inhibitor of innate and adaptive immunity, playing a crucial role in CD4+ T cell differentiation, macrophage polarization, and ferroptosis inhibition. Previous studies have linked IL4I1 to acute MI. This review summarizes evidence from both basic and clinical research, highlighting IL4I1 as a critical immunoregulatory enzyme that not only regulates inflammatory responses, but also potentially mitigates MI-induced damage. [ABSTRACT FROM AUTHOR]

The mammalian immune system is constantly surveying our tissues to clear pathogens and maintain tissue homeostasis. In order to fulfill these tasks, immune cells take up nutrients to supply energy for survival and for directly regulating effector functions via their cellular metabolism, a process now known as immunometabolism. Neutrophilic granulocytes, the most abundant leukocytes in the human body, have a short half-life and are permanently needed in the defense against pathogens. According to a long-standing view, neutrophils were thought to primarily fuel their metabolic demands via glycolysis. Yet, this view has been challenged, as other metabolic pathways recently emerged to contribute to neutrophil homeostasis and effector functions. In particular during neutrophilic development, the pentose phosphate pathway, glycogen synthesis, oxidative phosphorylation, and fatty acid oxidation crucially promote neutrophil maturation. At steady state, both glucose and lipid metabolism sustain neutrophil survival and maintain the intracellular redox balance. This review aims to comprehensively discuss how neutrophilic metabolism adapts during development, which metabolic pathways fuel their functionality, and how these processes are reconfigured in case of various diseases. We provide several examples of hereditary diseases, in which mutations in metabolic enzymes validate their critical role for neutrophil function. [ABSTRACT FROM AUTHOR]

Itaconate is one of the most studied immunometabolites produced by myeloid cells during inflammatory response. It mediates a wide range of anti-inflammatory and immunoregulatory effects and plays a role in a number of pathological states, including autoimmunity and cancer. Itaconate and its derivatives are considered potential therapeutic agents for the treatment of inflammatory diseases. While immunoregulatory effects of itaconate have been extensively studied in vitro and using knockout mouse models, less is known about how therapeutic administration of this metabolite regulates inflammatory response in vivo. Here, we investigate the immunoregulatory properties of exogenous administration of itaconate and its derivative dimethyl itaconate in a mouse model of lipopolysaccharide-induced inflammation. The data show that administration of itaconate or dimethyl itaconate controls systemic production of multiple cytokines, including increased IL-10 production. However, only dimethyl itaconate was able to suppress systemic production of IFNγ and IL-1β. In contrast to in vitro data, administration of itaconate or dimethyl itaconate in vivo resulted in systemic upregulation of IL-6 in the blood. Electrophilic stress due to itaconate or dimethyl itaconate was not responsible for IL-6 upregulation. However, inhibition of succinate dehydrogenase with dimethyl malonate also resulted in elevated systemic levels of IL-6 and IL-10. Taken together, our study reports a novel effect of exogenous itaconate and its derivative dimethyl itaconate on the production of IL-6 in vivo, with important implications for the development of itaconate-based anti-inflammatory therapies. [ABSTRACT FROM AUTHOR]

Neutrophils are the most abundant leukocytes in humans and play a role in the innate immune response by being the first cells attracted to the site of infection. While early studies presented neutrophils as almost exclusively glycolytic cells, recent advances show that these cells use several metabolic pathways other than glycolysis, such as the pentose phosphate pathway, oxidative phosphorylation, fatty acid oxidation, and glutaminolysis, which they modulate to perform their functions. Metabolism shifts from fatty acid oxidation–mediated mitochondrial respiration in immature neutrophils to glycolysis in mature neutrophils. Tissue environments largely influence neutrophil metabolism according to nutrient sources, inflammatory mediators, and oxygen availability. Inhibition of metabolic pathways in neutrophils results in impairment of certain effector functions, such as NETosis, chemotaxis, degranulation, and reactive oxygen species generation. Alteration of these neutrophil functions is implicated in certain human diseases, such as antiphospholipid syndrome, coronavirus disease 2019, and bronchiectasis. Metabolic regulators such as AMPK, HIF-1α, mTOR, and Arf6 are linked to neutrophil metabolism and function and could potentially be targeted for the treatment of diseases associated with neutrophil dysfunction. This review details the effects of alterations in neutrophil metabolism on the effector functions of these cells. [ABSTRACT FROM AUTHOR]

Macrophages represent primary players of the innate immune system. Macrophage activation triggers several signaling pathways and is tightly associated with metabolic changes, which drive different immune subsets. Recent studies unveil the role of various metabolic enzymes in macrophage activation. Here, we show that malic enzyme 1 (ME1) is overexpressed in LPS-induced macrophages. Through chromatin immunoprecipitation, we demonstrate that ME1 transcriptional regulation is under control of NF-κB. Furthermore, ME1 activity is also increased in activated human PBMC-derived macrophages. Notably, ME1 gene silencing decreases nitric oxide as well as reactive oxygen species and prostaglandin E2 inflammatory mediators. Therefore, modulating ME1 provides a potential approach for immunometabolic regulation and in turn macrophage function. [ABSTRACT FROM AUTHOR]

Immune cells undergo metabolic reprogramming to meet the demands associated with immune responses. The effects of aging on these pathways and on the metabolic phenotype of the immune cells participating in antibody responses to vaccines are still largely unknown. Here we used a vaccine for SARS-CoV-2 that utilizes the cellular heat shock chaperone glycoprotein 96 (gp96), engineered to co-express SARS-CoV-2 Spike (spike) protein (gp96-Ig-S). Results show that this vaccine induces comparable B cell primary responses in young and old mice at later time points, but a significantly lesser secondary response in old as compared to young mice, with the antibodies generated in the secondary response being also of lower avidity. This occurs because aging changes the B cell metabolic phenotype and induces hyper-metabolic B cells that are associated with higher intrinsic inflammation and decreased protective antibody responses. However, the gp96-Ig-S vaccine was found to be effective in significantly reducing the metabolic/inflammatory status of B cells from old mice, suggesting the possibility that targeting metabolic pathways may improve immune function in old mice that do not respond adequately to the vaccine. [ABSTRACT FROM AUTHOR]

Abstract Type 2 diabetes (T2D) is associated with insulin resistance and progressive dysfunction of β-pancreatic cells, leading to persistent hyperglycemia. Macrophages play a crucial role in this context, influencing both the development and progression of insulin resistance. These innate immune cells respond to inflammatory stimuli and reprogram their metabolism, directly impacting the pathophysiology of T2D. Macrophages are highly plastic and can adopt either pro-inflammatory or pro-resolutive phenotypic profiles. In T2D, pro-inflammatory macrophages, which rely on glycolysis, exacerbate insulin resistance through increased production of pro-inflammatory cytokines and nitric oxide. In contrast, pro-resolutive macrophages, which prioritize fatty acid metabolism, have different effects on glucose homeostasis. Metaflammation, a chronic low-grade inflammation, is induced by pro-inflammatory macrophages and significantly contributes to the progression of T2D, creating an environment conducive to metabolic dysfunction. This review aims to clarify the contribution of macrophages to the progression of T2D by detailing how their inflammatory responses and metabolic reprogramming influence insulin resistance and the disease’s pathophysiology. The review seeks to deepen the understanding of the biochemical and metabolic mechanisms involved, offering broader insights into the impact on the quality of life for millions of patients worldwide.

Abstract The pathogenesis of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains unclear, though increasing evidence suggests inflammatory processes play key roles. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) was used to decipher the immunometabolic profile in 4 ME/CFS patients and 4 heathy controls. We analyzed changes in the composition of major PBMC subpopulations and observed an increased frequency of total T cells and a significant reduction in NKs, monocytes, cDCs and pDCs. Further investigation revealed even more complex changes in the proportions of cell subpopulations within each subpopulation. Gene expression patterns revealed upregulated transcription factors related to immune regulation, as well as genes associated with viral infections and neurodegenerative diseases.CD4+ and CD8+ T cells in ME/CFS patients show different differentiation states and altered trajectories, indicating a possible suppression of differentiation. Memory B cells in ME/CFS patients are found early in the pseudotime, indicating a unique subtype specific to ME/CFS, with increased differentiation to plasma cells suggesting B cell overactivity. NK cells in ME/CFS patients exhibit reduced cytotoxicity and impaired responses, with reduced expression of perforin and CD107a upon stimulation. Pseudotime analysis showed abnormal development of adaptive immune cells and an enhanced cell-cell communication network converging on monocytes in particular. Our analysis also identified the estrogen-related receptor alpha (ESRRA)-APP-CD74 signaling pathway as a potential biomarker for ME/CFS in peripheral blood. In addition, data from the GSE214284 database confirmed higher ESRRA expression in the monocyte cell types of male ME/CFS patients. These results suggest a link between immune and neurological symptoms. The results support a disease model of immune dysfunction ranging from autoimmunity to immunodeficiency and point to amyloidotic neurodegenerative signaling pathways in the pathogenesis of ME/CFS. While the study provides important insights, limitations include the modest sample size and the evaluation of peripheral blood only. These findings highlight potential targets for diagnostic biomarkers and therapeutic interventions. Further research is needed to validate these biomarkers and explore their clinical applications in managing ME/CFS.

ABSTRACT: The inability of dairy calves to fully respond to immune stimuli until they reach maturity at 6 mo of age severely limits the use of parenteral vaccines to protect calves against disease. Immune responses are metabolically demanding, and immune cells rely on mitochondrial metabolites for their functionality. Due to the essential role of mitochondria in driving T-cell responses necessary for vaccine efficacy, we hypothesized that the mitochondrial function of dairy calf lymphocytes changes with age, from birth to immunologic maturity. In this cross-sectional study, groups of dairy calves (n = 4/group) were blood sampled at birth before colostrum intake and at 1, 2, 3, 4, 6, 8, 16, and 24 wk of age. Mid-lactation adult cows (n = 4) were also sampled to reference fully mature immune cell populations. B, CD4+, CD8+, and γδ T lymphocytes were enriched using magnetic-activated cell sorting, and their mitochondrial function was assessed with an extracellular flux analyzer. Nonmitochondrial oxygen consumption, basal respiration, maximal respiration, spare respiratory capacity, proton leak, and the oxygen consumption rate (OCR) to extracellular acidification rate (ECAR) ratio were reported. Results were compared among groups using a Kruskal-Wallis test. The OCR to ECAR ratio is an indicator of the relative proportions of oxidative phosphorylation and aerobic glycolysis which is associated with effector functions in lymphocytes. The ratio was lower in 0 wk than adults in CD4+ T-cells. For CD8+ T-cells, the OCR to ECAR ratio for the 2-wk group was lower than the 3-wk group. A lower OCR to ECAR ratio indicates more reliance on glycolytic metabolism than oxidative phosphorylation. Maximal respiration is an indication of mitochondrial efficiency and is often associated with mitochondrial mass. For γδ T-cells, the 3-wk group had higher maximal respiration than the 16-wk group, whereas for B-cells maximal respiration was higher in the 1 wk compared with the 16-wk group. Basal respiration indicates all cell functions that require oxygen and was lower in the 0-wk group than the 1- and 3-wk groups for CD4+ T-cells. γδ T-cells exhibited lower basal respiration in the 2-wk group than the 24-wk one. Although we found minimal differences in the mitochondrial outcomes reported from nonstimulated lymphocytes from birth through 6 mo of age and mid-lactation adults who served as mature immune cell populations, these results align with previous reports from weaning aged calf and adult CD4+ T-cells. In conclusion, insufficient evidence exists to suggest that the mitochondria in the lymphocytes of dairy calves from birth through immunologic maturity had functional changes associated with age. The capacity of unstimulated calf mitochondria to perform oxidative phosphorylation is not associated with age.

Abstract Lung diseases triggered by endogenous or exogenous factors have become a major concern, with high morbidity and mortality rates, especially after the coronavirus disease 2019 (COVID-19) pandemic. Inflammation and an over-activated immune system can lead to a cytokine cascade, resulting in lung dysfunction and injury. Itaconate, a metabolite produced by macrophages, has been reported as an effective anti-inflammatory and anti-oxidative stress agent with significant potential in regulating immunometabolism. As a naturally occurring metabolite in immune cells, itaconate has been identified as a potential therapeutic target in lung diseases through its role in regulating inflammation and immunometabolism. This review focuses on the origin, regulation, and function of itaconate in lung diseases, and briefly discusses its therapeutic potential.

Composite biomaterials comprising polylactide (PLA) and hydroxyapatite (HA) are applied in bone, cartilage and dental regenerative medicine, where HA confers osteoconductive properties. However, after surgical implantation, adverse immune responses to these composites can occur, which have been attributed to size and morphology of HA particles. Approaches to effectively modulate these adverse immune responses have not been described. PLA degradation products have been shown to alter immune cell metabolism (immunometabolism), which drives the inflammatory response. Accordingly, to modulate the inflammatory response to composite biomaterials, inhibitors were incorporated into composites comprised of amorphous PLA (aPLA) and HA (aPLA + HA) to regulate glycolytic flux. Inhibition at specific steps in glycolysis reduced proinflammatory (CD86+CD206-) and increased pro-regenerative (CD206+) immune cell populations around implanted aPLA + HA. Notably, neutrophil and dendritic cell (DC) numbers along with proinflammatory monocyte and macrophage populations were decreased, and Arginase 1 expression among DCs was increased. Targeting immunometabolism to control the proinflammatory response to biomaterial composites, thereby creating a pro-regenerative microenvironment, is a significant advance in tissue engineering where immunomodulation enhances osseointegration and angiogenesis, which could lead to improved bone regeneration.

Abstract Stimulation of mammalian cells with inflammatory inducers such as lipopolysaccharide (LPS) leads to alterations in activity of central cellular metabolic pathways. Interestingly, these metabolic changes seem to be important for subsequent release of pro‐inflammatory cytokines. This has become particularly clear for enzymes of tricarboxylic acid (TCA) cycle such as succinate dehydrogenase (SDH). LPS leads to inhibition of SDH activity and accumulation of succinate to enhance the LPS‐induced formation of IL‐1β. If enzymes involved in beta‐oxidation of fatty acids are important for sufficient responses to LPS is currently not clear. Using cells from various patients with inborn long‐chain fatty acid oxidation disorders (lcFAOD), we report that disease‐causing deleterious variants of Electron Transfer Flavoprotein Dehydrogenase (ETFDH) and of Very Long Chain Acyl‐CoA Dehydrogenase (ACADVL), both cause insufficient inflammatory responses to stimulation with LPS. The insufficiencies included reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro‐inflammatory cytokines such as IL‐6. The insufficient responses to LPS were reproduced in cells from healthy controls by targeted loss‐of‐function of either ETFDH or ACADVL, supporting that the deleterious ETFDH and ACADVL variants cause the attenuated responses to LPS. ETFDH and ACADVL encode two distinct enzymes both involved in fatty acid beta‐oxidation, and patients with these deficiencies cannot sufficiently metabolize long‐chain fatty acids. We report that genes important for beta‐oxidation of long‐chain fatty acids are also important for inflammatory responses to an acute immunogen trigger like LPS, which may have important implications for understanding infection and other metabolic stress induced disease pathology in lcFAODs.

Abstract Metabolic reprogramming drives the development of an immunosuppressive tumor microenvironment (TME) through various pathways, contributing to cancer progression and reducing the effectiveness of anticancer immunotherapy. However, our understanding of the metabolic landscape within the tumor-immune context has been limited by conventional metabolic measurements, which have not provided comprehensive insights into the spatiotemporal heterogeneity of metabolism within TME. The emergence of single-cell, spatial, and in vivo metabolomic technologies has now enabled detailed and unbiased analysis, revealing unprecedented spatiotemporal heterogeneity that is particularly valuable in the field of cancer immunology. This review summarizes the methodologies of metabolomics and metabolic regulomics that can be applied to the study of cancer-immunity across single-cell, spatial, and in vivo dimensions, and systematically assesses their benefits and limitations.

Abstract Background Mitochondria play a crucial role in shaping the macrophage inflammatory response during bacterial infections. Spinster homolog 2 (Spns2), responsible for sphingosine-1-phosphate (S1P) secretion, acts as a key regulator of mitochondrial dynamics in macrophages. However, the link between Spns2/S1P signaling and mitochondrial functions remains unclear. Methods Peritoneal macrophages were isolated from both wild-type and Spns2 knockout rats, followed by non-targeted metabolomics and RNA sequencing analysis to identify the potential mediators through which Spns2/S1P signaling influences the mitochondrial functions in macrophages. Various agonists and antagonists were used to modulate the activation of Spns2/S1P signaling and its downstream pathways, with the underlying mechanisms elucidated through western blotting. Mitochondrial functions were assessed using flow cytometry and oxygen consumption assays, as well as morphological analysis. The impact on inflammatory response was validated through both in vitro and in vivo sepsis models, with the specific role of macrophage-expressed Spns2 in sepsis evaluated using Spns2 flox/flox Lyz2-Cre mice. Additionally, the regulation of mitochondrial functions by Spns2/S1P signaling was confirmed using THP-1 cells, a human monocyte-derived macrophage model. Results In this study, we unveil prostaglandin E2 (PGE2) as a pivotal mediator involved in Spns2/S1P-mitochondrial communication. Spns2/S1P signaling suppresses PGE2 production to support malate-aspartate shuttle activity. Conversely, excessive PGE2 resulting from Spns2 deficiency impairs mitochondrial respiration, leading to intracellular lactate accumulation and increased reactive oxygen species (ROS) generation through E-type prostanoid receptor 4 activation. The overactive lactate-ROS axis contributes to the early-phase hyperinflammation during infections. Prolonged exposure to elevated PGE2 due to Spns2 deficiency culminates in subsequent immunosuppression, underscoring the dual roles of PGE2 in inflammation throughout infections. The regulation of PGE2 production by Spns2/S1P signaling appears to depend on the coordinated activation of multiple S1P receptors rather than any single one. Conclusions These findings emphasize PGE2 as a key effector of Spns2/S1P signaling on mitochondrial dynamics in macrophages, elucidating the mechanisms through which Spns2/S1P signaling balances both early hyperinflammation and subsequent immunosuppression during bacterial infections.

Immunotherapy is currently the main treatment for malignant tumors by activating immune cell. Metabolic reprogramming in tumor microenvironment can greatly affect the function of immune cell, and T cell is the main anti-tumor effector cell. Therefore, the T cell-based immunometabolic therapy can improve clinical efficacy. In T cell-based immunometabolic therapy, regular agents in conventional forms are difficult to achieve the intended efficacy due to poor tumor permeability and low cellular uptake. Nanoparticle-based strategy can serve as the optimal targeted drug delivery system due to co-encapsulation of multiple therapeutic agents and stable loading. Here, we intend to summarize examples of nanoparticles in the T cell-based immunometabolic therapy, and provide a comprehensive and helpful review by covering notable and vital applications of nanotechnology-based strategies for T cell-based immunometabolic therapy.

The aim of this study was to evaluate the effects of supplementing OC enriched in polyphenols (EOC) to mid-lactating Holstein cows on milk quality, metabolic response, and rumen fermentation and microbiota. Twenty multiparous Holstein dairy cows (10 cows/group) were enrolled for 30 d in two homogeneous groups according to milk yield, days in milking, parity, and body condition score. The control group (CTR) received no supplemented concentrate, whereas the EOC group received concentrate with a 7% inclusion of EOC. Milk and blood samples were collected at 0 d and 30 d of treatment, while rumen fluid samples were collected after 30 d of treatment. Overall, the dietary supplementation of EOC did not affect milk yield and its quality, rumen pH, and rumen VFA. However, milk of EOC cows had lower C10:0, C12:0, C14:0, and C16:0 content, and greater C18:0, C18:1 cis-9, and C18:2 n6 content, compared with CTR cows. Regarding the rumen microbiota composition, EOC diet increased the relative abundance of Bacteroidales_RF16_group, Absconditabacteriales_(SR1), and Fibrobacteracea in the rumen. On cow’s metabolism, EOC cows showed lower blood haptoglobin and greater ferric reducing antioxidant power (FRAP), cholesterol, and Zn levels compared with CTR cows. The supplementation of EOC led to a milder low-grade inflammatory response of cows and a positive modulation of cholesterol synthesis (probably at both intestinal and hepatic level). Supplementing EOC modulated rumen microbiota and improved the lipid profile of milk. Thereby, OC may be considered a valid feed to be included in the dairy cow’s diet leading to a positive effects on dairy cattle metabolism (less low-grade inflammatory response and oxidative stress) and at the same time giving an added value to the milk with a better profile of the fatty acids.

The control of the immune system, neuroendocrine system, and energy metabolism is essential for the physiological process of male reproduction. The hypothalamic-pituitary-testicular (HPT) axis regulates the generation of gonadal steroid hormones in the testes, which in turn controls spermatogenesis. For the growth and maturation of germ cells, the immune cells and cytokines in the testes offer a safe microenvironment. The cellular reactions and metabolic activities in the testes produce energy and biosynthetic precursors that control the growth of germ cells, as well as testicular immunology and inflammation. Both inflammatory and anti-inflammatory responses depend on immune cell metabolism, which is thought to influence testicular spermatogenesis. The significance of immunometabolism in male reproduction will be underlined in this review.

Abstract Background Peritoneal metastases frequently occur in epithelial ovarian cancer (EOC), resulting in poor prognosis and survival rates. Tumor-associated-macrophages (TAMs) massively infiltrate into ascites spheroids and are multi-polarized as protumoral M2-like phenotype, orchestrating the immunosuppression and promoting tumor progression. However, the impact of omental conditioned medium/ascites (OCM/AS) on TAM polarization and its function in tumor progression remains elusive. Methods The distribution and polarization of TAMs in primary and omental metastatic EOC patients’ tumors and ascites were examined by m-IHC, FACS analysis, and immunofluorescence. QPCR, immunofluorescence, FACS analysis, lipid staining assay, ROS assay, and Seahorse real-time cell metabolic assay characterized TAMs as being polarized in the ascites microenvironment. The oncogenic role of TAMs in tumor cells was demonstrated by co-cultured migration/invasion, proliferation, and spheroid formation assays. Mechanistic studies of the regulations of TAM polarization were performed by using RNA-Seq, GTPase pull-down, G-LISA activation assays, and other biochemical assays. A Yap1 macrophages (MФs) conditional knockout (cKO) mouse model demonstrated the roles of YAP1 in TAM polarization status and its pro-metastatic function. Finally, the anti-metastatic potential of targeting TAMs through restoring YAP1 by pharmacological agonist XMU MP1 was demonstrated in vitro and in vivo. Results Abundant polyunsaturated fatty acids (PUFAs) in OCM/AS suppressed RhoA-GTPase activities, which, in turn, downregulated nuclear YAP1 in MФs, leading to increased protumoral TAM polarization accompanied by elevated OXPHOS metabolism. Abolishment of YAP1 in MФs further confirmed that a higher M2/M1 ratio of TAM polarization could alleviate CD8+ T cell infiltration and cytotoxicity in vivo. Consistently, the loss of YAP1 has been observed in EOC metastatic tissues, suggesting its clinical relevance. On the contrary, restoration of YAP1 expression by pharmaceutical inhibition of MST1/2 induced conversion of M2-to-M1-like polarized MФs, elevating the infiltration of CD8+ T cells and attenuating tumor growth. Conclusion This study revealed that PUFAs-enriched OCM/AS of EOC promotes M2-like TAM polarization through RhoA-YAP1 inhibition, where YAP1 downregulation is required for accelerating protumoral M2-like TAM polarization, thereby causing immunosuppression and enhancing tumor progression. Conversion of M2-to-M1-like polarized MФs through Yap1 activation inhibits tumor progression and contributes to developing potential TAMs-targeted immunotherapies in combating EOC peritoneal metastases.

Abstract Danggui Buxue (DGBX) decoction is a classical prescription composed of Astragali Radix (AR) and Angelicae Sinensis Radix (ASR), used to enrich blood, and nourish Qi in Chinese medicine, with the potential to recover energy and stimulate metabolism. Chronic inflammation is a risk factor in the development of inflammatory bowel disease (IBD)-related colorectal cancer (CRC). More importantly, AR and ASR have anti-inflammatory and anti-cancer activities, as well as prefiguring a potential effect on inflammation-cancer transformation. We, therefore, aimed to review the immunometabolism potential of DGBX decoction and its components in this malignant transformation, to provide a helpful complement to manage the risk of IBD-CRC. The present study investigates the multifaceted roles of DGBX decoction and its entire components AR and ASR, including anti-inflammation effects, anti-cancer properties, immune regulation, and metabolic regulation. This assessment is informed by a synthesis of scholarly literature, with more than two hundred articles retrieved from PubMed, Web of Science, and Scopus databases within the past two decades. The search strategy employed utilized keywords such as “Danggui Buxue”, “Astragali Radix”, “Angelicae Sinensis Radix”, “Inflammation”, and “Metabolism”, alongside the related synonyms, with a particular emphasis on high-quality research and studies yielding significant findings. The potential of DGBX decoction in modulating immunometabolism holds promise for the treatment of IBD-related CRC. It is particularly relevant given the heterogeneity of CRC and the growing trend towards personalized medicine, but the precise and detailed mechanism necessitate further in vivo validation and extensive clinical studies to substantiate the immunometabolic modulation and delineate the pathways involved. Graphical Abstract

Macrophages are innate immune cells that play key roles during both homeostasis and disease. Depending on the microenvironmental cues sensed in different tissues, macrophages are known to acquire specific phenotypes and exhibit unique features that, ultimately, orchestrate tissue homeostasis, defense, and repair. Within the tumor microenvironment, macrophages are referred to as tumor‐associated macrophages (TAMs) and constitute a heterogeneous population. Like their tissue resident counterpart, TAMs are plastic and can switch function and phenotype according to the niche‐derived stimuli sensed. While changes in TAM phenotype are known to be accompanied by adaptive alterations in their cell metabolism, it is reported that metabolic reprogramming of macrophages can dictate their activation state and function. In line with these observations, recent research efforts have been focused on defining the metabolic traits of TAM subsets in different tumor malignancies and understanding their role in cancer progression and metastasis formation. This knowledge will pave the way to novel therapeutic strategies tailored to cancer subtype‐specific metabolic landscapes. This review outlines the metabolic characteristics of distinct TAM subsets and their implications in tumorigenesis across multiple cancer types.

Tumor‐infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells have demonstrated remarkable success in the treatment of relapsed/refractory melanoma and hematological malignancies, respectively. These treatments have marked a pivotal shift in cancer management. However, as “living drugs,” their effectiveness is dependent on their ability to proliferate and persist in patients. Recent studies indicate that the mechanisms regulating these crucial functions, as well as the T cell's differentiation state, are conditioned by metabolic shifts and the distinct utilization of metabolic pathways. These metabolic shifts, conditioned by nutrient availability as well as cell surface expression of metabolite transporters, are coupled to signaling pathways and the epigenetic landscape of the cell, modulating transcriptional, translational, and post‐translational profiles. In this review, we discuss the processes underlying the metabolic remodeling of activated T cells, the impact of a tumor metabolic environment on T cell function, and potential metabolic‐based strategies to enhance T cell immunotherapy.

Metabolism plays a crucial role in regulating the function of immune cells in both health and disease, with altered metabolism contributing to the pathogenesis of cancer and many inflammatory diseases. The local microenvironment has a profound impact on the metabolism of immune cells. Therefore, immunological and metabolic heterogeneity as well as the spatial organization of cells in tissues should be taken into account when studying immunometabolism. Here, we highlight challenges of investigating metabolic communication. Additionally, we review the capabilities and limitations of current technologies for studying metabolism in inflamed microenvironments, including single‐cell omics techniques, flow cytometry‐based methods (Met‐Flow, single‐cell energetic metabolism by profiling translation inhibition (SCENITH)), cytometry by time of flight (CyTOF), cellular indexing of transcriptomes and epitopes by sequencing (CITE‐Seq), and mass spectrometry imaging. Considering the importance of metabolism in regulating immune cells in diseased states, we also discuss the applications of metabolomics in clinical research, as well as some hurdles to overcome to implement these techniques in standard clinical practice. Finally, we provide a flowchart to assist scientists in designing effective strategies to unravel immunometabolism in disease‐relevant contexts.

Metformin and IACS‐010759 are two distinct antimetabolic agents. Metformin, an established antidiabetic drug, mildly inhibits mitochondrial complex I, while IACS‐010759 is a new potent mitochondrial complex I inhibitor. Mitochondria is pivotal in the energy metabolism of cells by providing adenosine triphosphate through oxidative phosphorylation (OXPHOS). Hence, mitochondrial metabolism and OXPHOS become a vulnerability when targeted in cancer cells. Both drugs have promising antitumoral effects in diverse cancers, supported by preclinical in vitro and in vivo studies. We present evidence of their direct impact on cancer cells and their immunomodulatory effects. In clinical studies, while observational epidemiologic studies on metformin were encouraging, actual trial results were not as expected. However, IACS‐01075 exhibited major adverse effects, thereby causing a metabolic shift to glycolysis and elevated lactic acid concentrations. Therefore, the future outlook for these two drugs depends on preventive clinical trials for metformin and investigations into the plausible toxic effects on normal cells for IACS‐01075.

In recent years, the field of immunometabolism has solidified its position as a prominent area of investigation within the realm of immunological research. An expanding body of scientific literature has unveiled the intricate interplay between energy homeostasis, signalling molecules, and metabolites in relation to fundamental aspects of our immune cells. It is now widely accepted that disruptions in metabolic equilibrium can give rise to a myriad of pathological conditions, ranging from autoimmune disorders to cancer. Emerging evidence, although sometimes fragmented and anecdotal, has highlighted the indispensable role of lipids in modulating the behaviour of immune cells, including B cells. In light of these findings, this review aims to provide a comprehensive overview of the current state of knowledge regarding lipid metabolism in the context of B cell biology.

Tuberculosis (TB) remains a significant threat to human health. Tuberculous granuloma is a typical pathological feature of TB and also a "refuge" for Mycobacterium tuberculosis (Mtb) to escape host immune defense and achieve long-term survival and latent infection. Mtb exploits these granulomas to spread and propagate within the body, leading to persistent infections that are difficult to eradicate. The metabolic cascade reactions and metabolites produced by immune cells in the granuloma environment are crucial for disease progression and the induction of protective anti-tuberculosis immunity. Mtb can use its virulence factors to target key host metabolic pathways, resist immune defenses, achieve long-term survival, and promote granuloma progression. This paper discusses the key immunometabolism pathways and the regulation mechanism of Mtbhost interaction in granuloma. It provides insights for developing new tuberculosis prevention and treatment strategies targeting granuloma pathogenesis.

Abstract Microglia, brain-resident macrophages, can acquire distinct functional phenotypes, which are supported by differential reprogramming of cell metabolism. These adaptations include remodeling in glycolytic and mitochondrial metabolic fluxes, potentially altering energy substrate availability at the tissue level. This phenomenon may be highly relevant in the brain, where metabolism must be precisely regulated to maintain appropriate neuronal excitability and synaptic transmission. Direct evidence that microglia can impact on neuronal energy metabolism has been widely lacking, however. Combining molecular profiling, electrophysiology, oxygen microsensor recordings and mathematical modeling, we investigated microglia-mediated disturbances in brain energetics during neuroinflammation. Our results suggest that proinflammatory microglia showing enhanced nitric oxide release and decreased CX3CR1 expression transiently increase the tissue lactate/glucose ratio that depends on transcriptional reprogramming in microglia, not in neurons. In this condition, neuronal network activity such as gamma oscillations (30–70 Hz) can be fueled by increased ATP production in mitochondria, which is reflected by elevated oxygen consumption. During dysregulated inflammation, high energy demand and low glucose availability can be boundary conditions for neuronal metabolic fitness as revealed by kinetic modeling of single neuron energetics. Collectively, these findings indicate that metabolic flexibility protects neuronal network function against alterations in local substrate availability during moderate neuroinflammation.

Danggui Buxue (DGBX) decoction is a classical prescription composed of Astragali Radix (AR) and Angelicae Sinensis Radix (ASR), used to enrich blood, and nourish Qi in Chinese medicine, with the potential to recover energy and stimulate metabolism. Chronic inflammation is a risk factor in the development of inflammatory bowel disease (IBD)-related colorectal cancer (CRC). More importantly, AR and ASR have anti-inflammatory and anti-cancer activities, as well as prefiguring a potential effect on inflammation-cancer transformation. We, therefore, aimed to review the immunometabolism potential of DGBX decoction and its components in this malignant transformation, to provide a helpful complement to manage the risk of IBD-CRC. The present study investigates the multifaceted roles of DGBX decoction and its entire components AR and ASR, including anti-inflammation effects, anti-cancer properties, immune regulation, and metabolic regulation. This assessment is informed by a synthesis of scholarly literature, with more than two hundred articles retrieved from PubMed, Web of Science, and Scopus databases within the past two decades. The search strategy employed utilized keywords such as “Danggui Buxue”, “Astragali Radix”, “Angelicae Sinensis Radix”, “Inflammation”, and “Metabolism”, alongside the related synonyms, with a particular emphasis on high-quality research and studies yielding significant findings. The potential of DGBX decoction in modulating immunometabolism holds promise for the treatment of IBD-related CRC. It is particularly relevant given the heterogeneity of CRC and the growing trend towards personalized medicine, but the precise and detailed mechanism necessitate further in vivo validation and extensive clinical studies to substantiate the immunometabolic modulation and delineate the pathways involved.Highlights: Danggui Buxue decoction is a classical prescription consisting of Astragali Radix and Angelicae Sinensis Radix with the efficacy of tonifying blood and invigorating qi in traditional Chinese medicine. Astragali Radix and Angelicae Sinensis Radix, both have a variety of pharmacological activities, including anti-inflammation and anti-cancer effects. In view of inflammation and malignant transformation in inflammatory bowel disease-related colorectal cancer and the curative effects of Astragali Radix and Angelicae Sinensis Radix, immunometabolism modulation potential of DGBX were reviewed and discussed in the present study. [ABSTRACT FROM AUTHOR]