bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2023‒06‒11
nineteen papers selected by
Dylan Ryan
University of Cambridge
  1. Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity.
  2. Identification of host regulators of Mycobacteriumtuberculosis phenotypes uncovers a role for the MMGT1-GPR156 lipid droplet axis in persistence.
  3. The Drosophila tumor necrosis factor receptor, Wengen, couples energy expenditure with gut immunity.
  4. A Treg-specific long noncoding RNA maintains immune-metabolic homeostasis in aging liver.
  5. Uptake of long-chain fatty acids from the bone marrow suppresses CD8+ T-cell metabolism and function in multiple myeloma.
  6. Reshaping immunometabolism in the tumour microenvironment to improve cancer immunotherapy.
  7. A ketogenic diet substantially reshapes the human metabolome.
  8. Resolvin D1 reprograms energy metabolism to promote microglia to phagocytize neutrophils after ischemic stroke.
  9. Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose limitation.
  10. Metabolic alterations upon SARS-CoV-2 infection and potential therapeutic targets against coronavirus infection.
  11. Effects of T cell leptin signaling on systemic glucose tolerance and T cell responses in obesity.
  12. Amino acid metabolism in immune cells: essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy.
  13. Modulating Copper Reactivity: A New Approach to Reprogram Mitochondrial Retrograde Signaling.
  14. Fumarate disarms CD8+ T cells against cancer.
  15. The role of adiponectin for immune cell function in metabolic diseases.
  16. Retraction Notice to: mTORC1-Induced HK1-Dependent Glycolysis Regulates NLRP3 Inflammasome Activation.
  17. Immunometabolic changes of β-glucan-trained immunity induction and inhibition on neonatal calf immune innate cells.
  18. Understanding glycosylation: Regulation through the metabolic flux of precursor pathways.
  19. The CH24H metabolite, 24HC, blocks viral entry by disrupting intracellular cholesterol homeostasis.
  1. Nat Commun. 2023 Jun 03. 14(1): 3214
    Lysophosphatidic acid modulates CD8 T cell immunosurveillance and metabolism to impair anti-tumor immunity.
    Jacqueline A Turner, Malia A Fredrickson, Marc D'Antonio, Elizabeth Katsnelson, Morgan MacBeth, Robert Van Gulick, Tugs-Saikhan Chimed, Martin McCarter, Angelo D'Alessandro, William A Robinson, Kasey L Couts, Roberta Pelanda, Jared Klarquist, Richard P Tobin, Raul M Torres.
      Lysophosphatidic acid (LPA) is a bioactive lipid which increases in concentration locally and systemically across different cancer types. Yet, the exact mechanism(s) of how LPA affects CD8 T cell immunosurveillance during tumor progression remain unknown. We show LPA receptor (LPAR) signaling by CD8 T cells promotes tolerogenic states via metabolic reprogramming and potentiating exhaustive-like differentiation to modulate anti-tumor immunity. We found LPA levels predict response to immunotherapy and Lpar5 signaling promotes cellular states associated with exhausted phenotypes on CD8 T cells. Importantly, we show that Lpar5 regulates CD8 T cell respiration, proton leak, and reactive oxygen species. Together, our findings reveal that LPA serves as a lipid-regulated immune checkpoint by modulating metabolic efficiency through LPAR5 signaling on CD8 T cells. Our study offers key insights into the mechanisms governing adaptive anti-tumor immunity and demonstrates LPA could be exploited as a T cell directed therapy to improve dysfunctional anti-tumor immunity.
    DOI:  https://doi.org/10.1038/s41467-023-38933-4
  2. Cell Host Microbe. 2023 May 29. pii: S1931-3128(23)00201-9. [Epub ahead of print]
    Identification of host regulators of Mycobacteriumtuberculosis phenotypes uncovers a role for the MMGT1-GPR156 lipid droplet axis in persistence.
    Haroon Kalam, Chih-Hung Chou, Motohiko Kadoki, Daniel B Graham, Jacques Deguine, Deborah T Hung, Ramnik J Xavier.
      The ability of Mycobacterium tuberculosis (Mtb) to establish latency affects disease and response to treatment. The host factors that influence the establishment of latency remain elusive. We engineered a multi-fluorescent Mtb strain that reports survival, active replication, and stressed non-replication states and determined the host transcriptome of the infected macrophages in these states. Additionally, we conducted a genome-wide CRISPR screen to identify host factors that modulated the phenotypic state of Mtb. We validated hits in a phenotype-specific manner and prioritized membrane magnesium transporter 1 (MMGT1) for a detailed mechanistic investigation. Mtb infection of MMGT1-deficient macrophages promoted a switch to persistence, upregulated lipid metabolism genes, and accumulated lipid droplets during infection. Targeting triacylglycerol synthesis reduced both droplet formation and Mtb persistence. The orphan G protein-coupled receptor GPR156 is a key inducer of droplet accumulation in ΔMMGT1 cells. Our work uncovers the role of MMGT1-GPR156-lipid droplets in the induction of Mtb persistence.
    Keywords:  CRISPR screen; Mycobacterium tuberculosis; RNA-seq; fatty acid biosynthesis; host response to infection; lipid droplets; macrophages; phenotype switching; phenotypic states
    DOI:  https://doi.org/10.1016/j.chom.2023.05.009
  3. Sci Adv. 2023 Jun 09. 9(23): eadd4977
    The Drosophila tumor necrosis factor receptor, Wengen, couples energy expenditure with gut immunity.
    Rihab Loudhaief, Rouba Jneid, Christian Fokdal Christensen, Duncan J Mackay, Ditte S Andersen, Julien Colombani.
      It is well established that tumor necrosis factor (TNF) plays an instrumental role in orchestrating the metabolic disorders associated with late stages of cancers. However, it is not clear whether TNF/TNF receptor (TNFR) signaling controls energy homeostasis in healthy individuals. Here, we show that the highly conserved Drosophila TNFR, Wengen (Wgn), is required in the enterocytes (ECs) of the adult gut to restrict lipid catabolism, suppress immune activity, and maintain tissue homeostasis. Wgn limits autophagy-dependent lipolysis by restricting cytoplasmic levels of the TNFR effector, TNFR-associated factor 3 (dTRAF3), while it suppresses immune processes through inhibition of the dTAK1/TAK1-Relish/NF-κB pathway in a dTRAF2-dependent manner. Knocking down dTRAF3 or overexpressing dTRAF2 is sufficient to suppress infection-induced lipid depletion and immune activation, respectively, showing that Wgn/TNFR functions as an intersection between metabolism and immunity allowing pathogen-induced metabolic reprogramming to fuel the energetically costly task of combatting an infection.
    DOI:  https://doi.org/10.1126/sciadv.add4977
  4. Nat Aging. 2023 Jun 05.
    A Treg-specific long noncoding RNA maintains immune-metabolic homeostasis in aging liver.
    Chenbo Ding, Zhibin Yu, Esen Sefik, Jing Zhou, Eleanna Kaffe, Gaoyang Wang, Bin Li, Richard A Flavell, Weiguo Hu, Youqiong Ye, Hua-Bing Li.
      Regulatory T (Treg) cells modulate several aging-related liver diseases. However, the molecular mechanisms regulating Treg function in this context are unknown. Here we identified a long noncoding RNA, Altre (aging liver Treg-expressed non-protein-coding RNA), which was specifically expressed in the nucleus of Treg cells and increased with aging. Treg-specific deletion of Altre did not affect Treg homeostasis and function in young mice but caused Treg metabolic dysfunction, inflammatory liver microenvironment, liver fibrosis and liver cancer in aged mice. Depletion of Altre reduced Treg mitochondrial integrity and respiratory capacity, and induced reactive oxygen species accumulation, thus increasing intrahepatic Treg apoptosis in aged mice. Moreover, lipidomic analysis identified a specific lipid species driving Treg aging and apoptosis in the aging liver microenvironment. Mechanistically, Altre interacts with Yin Yang 1 to orchestrate its occupation on chromatin, thereby regulating the expression of a group of mitochondrial genes, and maintaining optimal mitochondrial function and Treg fitness in the liver of aged mice. In conclusion, the Treg-specific nuclear long noncoding RNA Altre maintains the immune-metabolic homeostasis of the aged liver through Yin Yang 1-regulated optimal mitochondrial function and the Treg-sustained liver immune microenvironment. Thus, Altre is a potential therapeutic target for the treatment of liver diseases affecting older adults.
    DOI:  https://doi.org/10.1038/s43587-023-00428-8
  5. Blood Adv. 2023 Jun 05. pii: bloodadvances.2023009890. [Epub ahead of print]
    Uptake of long-chain fatty acids from the bone marrow suppresses CD8+ T-cell metabolism and function in multiple myeloma.
    Nancy Gudgeon, Hannah Victoria Giles, Emma Louise Bishop, Taylor Fulton-Ward, Cristina Escribano-Gonzalez, Haydn Munford, Anna James-Bott, Kane Foster, Farheen Karim, Dedunu Abeysekara Jayawardana, Ansar Mahmood, Adam Cribbs, Daniel A Tennant, Supratik Basu, Guy Pratt, Sarah Dimeloe.
      T cells demonstrate impaired function in Multiple Myeloma (MM), but suppressive mechanisms in the bone marrow microenvironment remain poorly defined. We observe that bone marrow CD8+ T-cell function is decreased in MM patients compared to controls, and also is consistently lower within bone marrow samples than matched peripheral blood. These changes are accompanied by decreased mitochondrial mass and markedly elevated long-chain fatty acid uptake. In vitro modelling confirmed that uptake of bone marrow lipids suppresses CD8+ T function, which is impaired in autologous bone marrow plasma, but rescued by lipid removal. Analysis of single-cell RNA-sequencing data identified expression of fatty acid transport protein 1 (FATP1) in bone marrow CD8+ T cells in MM, and FATP1 blockade also rescued CD8+ T-cell function, thereby identifying this as a novel target to augment T cell activity in MM. Finally, analysis of samples from treated patient cohorts identified that CD8+ T cell metabolic dysfunction resolves in treatment-responsive but not relapsed MM patients and is associated with substantial T cell functional restoration.
    DOI:  https://doi.org/10.1182/bloodadvances.2023009890
  6. Biomed Pharmacother. 2023 Jun 01. pii: S0753-3322(23)00753-9. [Epub ahead of print]164 114963
    Reshaping immunometabolism in the tumour microenvironment to improve cancer immunotherapy.
    Shuchen Chen, He Duan, Gongping Sun.
      The evolving understanding of cellular metabolism has revealed a the promise of strategies aiming to modulate anticancer immunity by targeting metabolism. The combination of metabolic inhibitors with immune checkpoint blockade (ICB), chemotherapy and radiotherapy may offer new approaches to cancer treatment. However, it remains unclear how these strategies can be better utilized despite the complex tumour microenvironment (TME). Oncogene-driven metabolic changes in tumour cells can affect the TME, limiting the immune response and creating many barriers to cancer immunotherapy. These changes also reveal opportunities to reshape the TME to restore immunity by targeting metabolic pathways. Further exploration is required to determine how to make better use of these mechanistic targets. Here, we review the mechanisms by which tumour cells reshape the TME and cause immune cells to transition into an abnormal state by secreting multiple factors, with the ultimate goal of proposing targets and optimizing the use of metabolic inhibitors. Deepening our understanding of changes in metabolism and immune function in the TME will help advance this promising field and enhance immunotherapy.
    Keywords:  Diet; Immunometabolism; Immunotherapy; Lactate; Tumour microenvironment
    DOI:  https://doi.org/10.1016/j.biopha.2023.114963
  7. Clin Nutr. 2023 May 04. pii: S0261-5614(23)00141-3. [Epub ahead of print]
    A ketogenic diet substantially reshapes the human metabolome.
    David Effinger, Simon Hirschberger, Polina Yoncheva, Annika Schmid, Till Heine, Patrick Newels, Burkhard Schütz, Chen Meng, Michael Gigl, Karin Kleigrewe, Lesca-Miriam Holdt, Daniel Teupser, Simone Kreth.
      BACKGROUND: Western dietary habits (WD) have been shown to promote chronic inflammation, which favors the development of many of today's non-communicable diseases. Recently, ketogenic diets (KD) have emerged as an immune-regulating countermeasure for WD-induced metaflammation. To date, beneficial effects of KD have been solely attributed to the production and metabolism of ketone bodies. Given the drastic change in nutrient composition during KD, it is reasonable to assume that there are widespread changes in the human metabolome also contributing to the impact of KD on human immunity. The current study was conducted to gain insight into the changes of the human metabolic fingerprint associated with KD. This could allow to identify metabolites that may contribute to the overall positive effects on human immunity, but also help to recognize potential health risks of KD.METHODS: We conducted a prospective nutritional intervention study enrolling 40 healthy volunteers to perform a three-week ad-libitum KD. Prior to the start and at the end of the nutritional intervention serum metabolites were quantified, untargeted mass spectrometric metabolome analyses and urine analyses of the tryptophan pathway were performed.
    RESULTS: KD led to a marked reduction of insulin (-21.45% ± 6.44%, p = 0.0038) and c-peptide levels (-19.29% ± 5.45%, p = 0.0002) without compromising fasting blood glucose. Serum triglyceride concentration decreased accordingly (-13.67% ± 5.77%, p = 0.0247), whereas cholesterol parameters remained unchanged. LC-MS/MS-based untargeted metabolomic analyses revealed a profound shift of the human metabolism towards mitochondrial fatty acid oxidation, comprising highly elevated levels of free fatty acids and acylcarnitines. The serum amino acid (AA) composition was rearranged with lower abundance of glucogenic AA and an increase of BCAA. Furthermore, an increase of anti-inflammatory fatty acids eicosatetraenoic acid (p < 0.0001) and docosahexaenoic acid (p = 0.0002) was detected. Urine analyses confirmed higher utilization of carnitines, indicated by lower carnitine excretion (-62.61% ± 18.11%, p = 0.0047) and revealed changes to the tryptophan pathway depicting reduced quinolinic acid (-13.46% ± 6.12%, p = 0.0478) and elevated kynurenic acid concentrations (+10.70% ± 4.25%, p = 0.0269).
    CONCLUSIONS: A KD fundamentally changes the human metabolome even after a short period of only three weeks. Besides a rapid metabolic switch to ketone body production and utilization, improved insulin and triglyceride levels and an increase in metabolites that mediate anti-inflammation and mitochondrial protection occurred. Importantly, no metabolic risk factors were identified. Thus, a ketogenic diet could be considered as a safe preventive and therapeutic immunometabolic tool in modern medicine.
    TRIAL REGISTRATION: German Clinical Trials Register; DRKS-ID: DRKS00027992 (www.drks.de).
    Keywords:  Immunometabolism; Ketogenic diet; Metabolomics; Metaflammation; T-cell immunity; Western diet
    DOI:  https://doi.org/10.1016/j.clnu.2023.04.027
  8. Cell Rep. 2023 Jun 06. pii: S2211-1247(23)00628-9. [Epub ahead of print]42(6): 112617
    Resolvin D1 reprograms energy metabolism to promote microglia to phagocytize neutrophils after ischemic stroke.
    Lei Li, Shu-Qi Cheng, Yu-Qin Sun, Jian-Bing Yu, Xin-Xin Huang, Yin-Feng Dong, Juan Ji, Xi-Yue Zhang, Gang Hu, Xiu-Lan Sun.
      Neutrophil aggregation and clearance are important factors affecting neuroinflammatory injury during acute ischemic stroke. Emerging evidence suggests that energy metabolism is essential for microglial functions, especially microglial phagocytosis, which determines the degree of brain injury. Here, we demonstrate that Resolvin D1 (RvD1), a lipid mediator derived from docosahexaenic acid (DHA), promotes the phagocytosis of neutrophils by microglia, thereby reducing neutrophil accumulation in the brain and alleviating neuroinflammation in the ischemic brain. Further studies reveal that RvD1 reprograms energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS), providing sufficient energy for microglial phagocytosis. Moreover, RvD1 enhances microglial glutamine uptake and stimulates glutaminolysis to support OXPHOS to boost ATP production depending on adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activation. Overall, our results reveal that RvD1 reprograms energy metabolism to promote the microglial phagocytosis of neutrophils after ischemic stroke. These findings may guide perspectives for stroke therapy from modulating microglial immunometabolism.
    Keywords:  CP: Immunology; Resolvin D1; immunometabolism; ischemic stroke; microglia; neutrophil; phagocytosis; reprogram energy metabolism
    DOI:  https://doi.org/10.1016/j.celrep.2023.112617
  9. bioRxiv. 2023 May 17. pii: 2023.05.17.541212. [Epub ahead of print]
    Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose limitation.
    Matthew H Raymonda, Irene Rodríguez-Sánchez, Xenia L Schafer, Leonid Smorodintsev-Schiller, Isaac S Harris, Joshua Munger.
      Human cytomegalovirus (HCMV) modulates cellular metabolism to support productive infection, and the HCMV U L 38 protein drives many aspects of this HCMV-induced metabolic program. However, it remains to be determined whether virally-induced metabolic alterations might induce novel therapeutic vulnerabilities in virally infected cells. Here, we explore how HCMV infection and the U L 38 protein modulate cellular metabolism and how these changes alter the response to nutrient limitation. We find that expression of U L 38, either in the context of HCMV infection or in isolation, sensitizes cells to glucose limitation resulting in cell death. This sensitivity is mediated through U L 38's inactivation of the TSC complex subunit 2 (TSC2) protein, a central metabolic regulator that possesses tumor-suppressive properties. Further, expression of U L 38 or the inactivation of TSC2 results in anabolic rigidity in that the resulting increased levels of fatty acid biosynthesis are insensitive to glucose limitation. This failure to regulate fatty acid biosynthesis in response to glucose availability sensitizes cells to glucose limitation, resulting in cell death unless fatty acid biosynthesis is inhibited. These experiments identify a regulatory circuit between glycolysis and fatty acid biosynthesis that is critical for cell survival upon glucose limitation and highlight a metabolic vulnerability associated with viral infection and the inactivation of normal metabolic regulatory controls.Importance: Viruses modulate host cell metabolism to support the mass production of viral progeny. For Human Cytomegalovirus, we find that the viral U L 38 protein is critical for driving these pro-viral metabolic changes. However, our results indicate that these changes come at a cost, as U L 38 induces an anabolic rigidity that leads to a metabolic vulnerability. We find that U L 38 decouples the link between glucose availability and fatty acid biosynthetic activity. Normal cells respond to glucose limitation by down-regulating fatty acid biosynthesis. Expression of U L 38 results in the inability to modulate fatty acid biosynthesis in response to glucose limitation, which results in cell death. We find this vulnerability in the context of viral infection, but this linkage between fatty acid biosynthesis, glucose availability, and cell death could have broader implications in other contexts or pathologies that rely on glycolytic remodeling, for example, oncogenesis.
    DOI:  https://doi.org/10.1101/2023.05.17.541212
  10. Signal Transduct Target Ther. 2023 Jun 07. 8(1): 237
    Metabolic alterations upon SARS-CoV-2 infection and potential therapeutic targets against coronavirus infection.
    Peiran Chen, Mandi Wu, Yaqing He, Binghua Jiang, Ming-Liang He.
      The coronavirus disease 2019 (COVID-19) caused by coronavirus SARS-CoV-2 infection has become a global pandemic due to the high viral transmissibility and pathogenesis, bringing enormous burden to our society. Most patients infected by SARS-CoV-2 are asymptomatic or have mild symptoms. Although only a small proportion of patients progressed to severe COVID-19 with symptoms including acute respiratory distress syndrome (ARDS), disseminated coagulopathy, and cardiovascular disorders, severe COVID-19 is accompanied by high mortality rates with near 7 million deaths. Nowadays, effective therapeutic patterns for severe COVID-19 are still lacking. It has been extensively reported that host metabolism plays essential roles in various physiological processes during virus infection. Many viruses manipulate host metabolism to avoid immunity, facilitate their own replication, or to initiate pathological response. Targeting the interaction between SARS-CoV-2 and host metabolism holds promise for developing therapeutic strategies. In this review, we summarize and discuss recent studies dedicated to uncovering the role of host metabolism during the life cycle of SARS-CoV-2 in aspects of entry, replication, assembly, and pathogenesis with an emphasis on glucose metabolism and lipid metabolism. Microbiota and long COVID-19 are also discussed. Ultimately, we recapitulate metabolism-modulating drugs repurposed for COVID-19 including statins, ASM inhibitors, NSAIDs, Montelukast, omega-3 fatty acids, 2-DG, and metformin.
    DOI:  https://doi.org/10.1038/s41392-023-01510-8
  11. PLoS One. 2023 ;18(6): e0286470
    Effects of T cell leptin signaling on systemic glucose tolerance and T cell responses in obesity.
    Kaitlin Kiernan, Amanda G Nichols, Yazan Alwarawrah, Nancie J MacIver.
      BACKGROUND/OBJECTIVES: Leptin is an adipokine secreted in proportion to adipocyte mass and is therefore increased in obesity. Leptin signaling has been shown to directly promote inflammatory T helper 1 (Th1) and T helper 17 (Th17) cell number and function. Since T cells have a critical role in driving inflammation and systemic glucose intolerance in obesity, we sought to determine the role of leptin signaling in this context.METHODS: Male and female T cell-specific leptin receptor knockout mice and littermate controls were placed on low-fat diet or high-fat diet to induce obesity for 18 weeks. Weight gain, serum glucose levels, systemic glucose tolerance, T cell metabolism, and T cell differentiation and cytokine production were examined.
    RESULTS: In both male and female mice, T cell-specific leptin receptor deficiency did not reverse impaired glucose tolerance in obesity, although it did prevent impaired fasting glucose levels in obese mice compared to littermate controls, in a sex dependent manner. Despite these minimal effects on systemic metabolism, T cell-specific leptin signaling was required for changes in T cell metabolism, differentiation, and cytokine production observed in mice fed high-fat diet compared to low-fat diet. Specifically, we observed increased T cell oxidative metabolism, increased CD4+ T cell IFN-γ expression, and increased proportion of T regulatory (Treg) cells in control mice fed high-fat diet compared to low-fat diet, which were not observed in the leptin receptor conditional knockout mice, suggesting that leptin receptor signaling is required for some of the inflammatory changes observed in T cells in obesity.
    CONCLUSIONS: T cell-specific deficiency of leptin signaling alters T cell metabolism and function in obesity but has minimal effects on obesity-associated systemic metabolism. These results suggest a redundancy in cytokine receptor signaling pathways in response to inflammatory signals in obesity.
    DOI:  https://doi.org/10.1371/journal.pone.0286470
  12. J Hematol Oncol. 2023 Jun 05. 16(1): 59
    Amino acid metabolism in immune cells: essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy.
    Luming Yang, Zhaole Chu, Meng Liu, Qiang Zou, Jinyang Li, Qin Liu, Yazhou Wang, Tao Wang, Junyu Xiang, Bin Wang.
      Amino acids are basic nutrients for immune cells during organ development, tissue homeostasis, and the immune response. Regarding metabolic reprogramming in the tumor microenvironment, dysregulation of amino acid consumption in immune cells is an important underlying mechanism leading to impaired anti-tumor immunity. Emerging studies have revealed that altered amino acid metabolism is tightly linked to tumor outgrowth, metastasis, and therapeutic resistance through governing the fate of various immune cells. During these processes, the concentration of free amino acids, their membrane bound transporters, key metabolic enzymes, and sensors such as mTOR and GCN2 play critical roles in controlling immune cell differentiation and function. As such, anti-cancer immune responses could be enhanced by supplement of specific essential amino acids, or targeting the metabolic enzymes or their sensors, thereby developing novel adjuvant immune therapeutic modalities. To further dissect metabolic regulation of anti-tumor immunity, this review summarizes the regulatory mechanisms governing reprogramming of amino acid metabolism and their effects on the phenotypes and functions of tumor-infiltrating immune cells to propose novel approaches that could be exploited to rewire amino acid metabolism and enhance cancer immunotherapy.
    Keywords:  Amino acids; Immune cells; SLC transporters; Tumor microenvironment; mTOR
    DOI:  https://doi.org/10.1186/s13045-023-01453-1
  13. ACS Chem Biol. 2023 Jun 08.
    Modulating Copper Reactivity: A New Approach to Reprogram Mitochondrial Retrograde Signaling.
    Emmanouil Zacharioudakis.
      The crosstalk between mitochondria and the nucleus regulates cell plasticity and innate immune response. A new study shows that copper(II) accumulates in mitochondria of activated macrophages in response to pathogen infection and induces metabolic and epigenetic reprogramming that promotes inflammation. Pharmacologic targeting of mitochondrial copper(II) uncovers a new therapeutic strategy to combat aberrant inflammation and regulate cell plasticity.
    DOI:  https://doi.org/10.1021/acschembio.3c00298
  14. Cell Metab. 2023 Jun 06. pii: S1550-4131(23)00182-1. [Epub ahead of print]35(6): 907-909
    Fumarate disarms CD8+ T cells against cancer.
    Luigi Nezi, Teresa Manzo.
      The composition of nutrients in the tumor microenvironment is a key determinant of anti-tumor CD8+ T cell response. In this issue of Cell Metabolism, Jiang and colleagues unveil that tumor-derived fumarate dampens TCR signaling in CD8+ T cells, resulting in defective activation, loss of effector functions, and associated failure of tumor control.
    DOI:  https://doi.org/10.1016/j.cmet.2023.05.005
  15. Diabetes Obes Metab. 2023 Jun 05.
    The role of adiponectin for immune cell function in metabolic diseases.
    Mingyue Gao, Dawei Cui, Jue Xie.
      Adiponectin, as an indispensable regulator of the immune system, is the most abundant adipokine and is mainly produced by white adipose tissue. Adiponectin mediates the positive effects on systemic metabolism by regulating associated downstream signalling pathways; however, accumulating evidence shows that adiponectin plays an important role in regulating the function of innate and adaptive immune cells in the development of obesity and its related diseases. In this review, we focus on the biological function of adiponectin in regulating innate and adaptive immunity and outline the key role of adiponectin in various metabolic diseases, which will highlight a potential direction for adiponectin-based therapeutic interventions for metabolic diseases.
    Keywords:  adaptive immunity; adiponectin; inflammation; innate immunity; metabolic diseases
    DOI:  https://doi.org/10.1111/dom.15151
  16. Cell Rep. 2023 Jun 06. pii: S2211-1247(23)00650-2. [Epub ahead of print]42(6): 112639
    Retraction Notice to: mTORC1-Induced HK1-Dependent Glycolysis Regulates NLRP3 Inflammasome Activation.
    Jong-Seok Moon, Shu Hisata, Mi-Ae Park, Gina M DeNicola, Stefan W Ryter, Kiichi Nakahira, Augustine M K Choi.
      
    DOI:  https://doi.org/10.1016/j.celrep.2023.112639
  17. Mol Immunol. 2023 Jun 02. pii: S0161-5890(23)00111-6. [Epub ahead of print]159 58-68
    Immunometabolic changes of β-glucan-trained immunity induction and inhibition on neonatal calf immune innate cells.
    Miriam Angulo, Carlos Angulo.
      The growing antibiotic resistance and low-efficient vaccines make searching for alternatives a need to fight infectious diseases in newborn calves. Thus, trained immunity could be used as a tool to optimize immune response against a wide range of pathogens. Although β-glucans have shown to induce trained immunity, it has not been demonstrated in bovines yet. Uncontrolled trained immunity activation can generate chronic inflammation in mice and humans, and inhibiting it might reduce excessive immune activation. The aim of this study is to demonstrate that in vitro β-glucan training induces metabolic changes in calf monocytes, characterized by an increase in lactate production and glucose consumption upon restimulation with lipopolysaccharide. These metabolic shifts can be abolished by co-incubation with MCC950, a trained immunity inhibitor. Moreover, the dose-response relationship of β-glucan on the viability of calf monocytes was demonstrated. In newborn calves, in vivo β-glucan oral administration also induced a trained phenotype in innate immune cells, leading to immunometabolic changes, upon ex vivo challenge with E.coli. β-glucan-induced trained immunity improved phagocytosis, nitric oxide production, myeloperoxidase activity, and TNF-α gene expression through up-regulation genes of the TLR2/NF-κB pathway. Furthermore, β-glucan oral doses enhanced consumption and production of glycolysis metabolites (glucose and lactate, respectively), as well as up-regulated expression of mTOR and HIF1-α mRNA. Therefore, the results suggest that β-glucan immune training may confer calf protection from a secondary bacterial challenge, and trained phenotype induced by β-glucan can be inhibited.
    Keywords:  Calves; Innate immune memory; Metabolic reprogramming
    DOI:  https://doi.org/10.1016/j.molimm.2023.05.008
  18. Biotechnol Adv. 2023 Jun 06. pii: S0734-9750(23)00091-5. [Epub ahead of print] 108184
    Understanding glycosylation: Regulation through the metabolic flux of precursor pathways.
    Aert F Scheper, Jack Schofield, Raghvendra Bohara, Thomas Ritter, Abhay Pandit.
      Glycosylation is how proteins and lipids are modified with complex carbohydrates known as glycans. The post-translational modification of proteins with glycans is not a template-driven process in the same way as genetic transcription or protein translation. Glycosylation is instead dynamically regulated by metabolic flux. This metabolic flux is determined by the concentrations and activities of the glycotransferase enzymes, which synthesise glycans, the metabolites that act as their precursors and transporter proteins. This review provides an overview of the metabolic pathways underlying glycan synthesis. Pathological dysregulation of glycosylation, particularly increased glycosylation occurring during inflammation, is also elucidated. The resulting inflammatory hyperglycosylation acts as a glycosignature of disease, and we report on the changes in the metabolic pathways which feed into glycan synthesis, revealing alterations to key enzymes. Finally, we examine studies in developing metabolic inhibitors targeting these critical enzymes. These results provide the tools for researchers investigating the role of glycan metabolism in inflammation and have helped to identify promising glycotherapeutic approaches to inflammation.
    Keywords:  Glycan synthesis; Glycosylation; Inflammation; Metabolic flux
    DOI:  https://doi.org/10.1016/j.biotechadv.2023.108184
  19. Redox Biol. 2023 May 31. pii: S2213-2317(23)00170-2. [Epub ahead of print]64 102769
    The CH24H metabolite, 24HC, blocks viral entry by disrupting intracellular cholesterol homeostasis.
    Yueming Yuan, An Fang, Zongmei Wang, Zhihui Wang, Baokun Sui, Yunkai Zhu, Yuan Zhang, Caiqian Wang, Rong Zhang, Ming Zhou, Huanchun Chen, Zhen F Fu, Ling Zhao.
      Cholesterol-24-hydroxylase (CH24H or Cyp46a1) is a reticulum-associated membrane protein that plays an irreplaceable role in cholesterol metabolism in the brain and has been well-studied in several neuro-associated diseases in recent years. In the present study, we found that CH24H expression can be induced by several neuroinvasive viruses, including vesicular stomatitis virus (VSV), rabies virus (RABV), Semliki Forest virus (SFV) and murine hepatitis virus (MHV). The CH24H metabolite, 24-hydroxycholesterol (24HC), also shows competence in inhibiting the replication of multiple viruses, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 24HC can increase the cholesterol concentration in multivesicular body (MVB)/late endosome (LE) by disrupting the interaction between OSBP and VAPA, resulting in viral particles being trapped in MVB/LE, ultimately compromising VSV and RABV entry into host cells. These findings provide the first evidence that brain cholesterol oxidation products may play a critical role in viral infection.
    Keywords:  24HC; CH24H; Cholesterol metabolism; Multivesicular body/late endosome; Neuroinvasive virus
    DOI:  https://doi.org/10.1016/j.redox.2023.102769
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