bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2024–05–26
25 papers selected by
Dylan Ryan, University of Cambridge
  1. Metabolic coordination between skin epithelium and type 17 immunity sustains chronic skin inflammation.
  2. A metabolic dependency of EBV can be targeted to hinder B cell transformation.
  3. Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance.
  4. SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production.
  5. TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA.
  6. Decoding macrophage immunometabolism in human viral infection.
  7. The Glucose Transporter 5 Enhances CAR-T Cell Metabolic Function and Anti-tumour Durability.
  8. Glycolysis inhibition affects proliferation and cytotoxicity of Vγ9Vδ2 T cells expanded for adoptive cell therapy.
  9. Lactococcus lactis subsp. cremoris C60 Upregulates Macrophage Function by Modifying Metabolic Preference in Enhanced Anti-Tumor Immunity.
  10. Metabolomic analysis reveals macrophage metabolic reprogramming and polarization under different nutritional cues.
  11. The integration of metabolic and proteomic data uncovers an augmentation of the sphingolipid biosynthesis pathway during T-cell differentiation.
  12. Distinct metabolic responses to heme in inflammatory human and mouse macrophages - Role of nitric oxide.
  13. The immune response to RNA suppresses nucleic acid synthesis by limiting ribose 5-phosphate.
  14. Fasting and Glucose Metabolism Differentially Impact Peripheral Inflammation in Human Type 2 Diabetes.
  15. 4-Octyl Itaconate Attenuates Neuroinflammation in Experimental Autoimmune Encephalomyelitis Via Regulating Microglia.
  16. Glutamate from the microbiome controls host metabolism.
  17. Deleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies.
  18. mTOR signaling is required for phagocyte free radical production, GLUT1 expression, and control of Staphylococcus aureus infection.
  19. IRG1/itaconate alleviates acute liver injury in septic mice by suppressing NLRP3 expression and its mediated macrophage pyroptosis via regulation of the Nrf2 pathway.
  20. Itaconate reduces proliferation and migration of fibroblast-like synoviocytes and ameliorates arthritis models.
  21. Mitochondrial DNA release and sensing in innate immune responses.
  22. Distinct immunometabolic signatures in circulating immune cells define disease outcome in acute-on-chronic liver failure.
  23. Different lactate metabolism subtypes reveal heterogeneity in clinical outcomes and immunotherapy in lung adenocarcinoma patients.
  24. LC-MS-based rheumatoid arthritis serum metabolomics reveals the role of deoxyinosine in attenuating collagen-induced arthritis in mice.
  25. Nucleolin myocardial-specific knockout exacerbates glucose metabolism disorder in endotoxemia-induced myocardial injury.
  1. Immunity. 2024 May 14. pii: S1074-7613(24)00227-9. [Epub ahead of print]
    Metabolic coordination between skin epithelium and type 17 immunity sustains chronic skin inflammation.
    Ipsita Subudhi, Piotr Konieczny, Aleksandr Prystupa, Rochelle L Castillo, Erica Sze-Tu, Yue Xing, Daniel Rosenblum, Ilana Reznikov, Ikjot Sidhu, Cynthia Loomis, Catherine P Lu, Niroshana Anandasabapathy, Mayte Suárez-Fariñas, Johann E Gudjonsson, Aristotelis Tsirigos, Jose U Scher, Shruti Naik.
      Inflammatory epithelial diseases are spurred by the concomitant dysregulation of immune and epithelial cells. How these two dysregulated cellular compartments simultaneously sustain their heightened metabolic demands is unclear. Single-cell and spatial transcriptomics (ST), along with immunofluorescence, revealed that hypoxia-inducible factor 1α (HIF1α), downstream of IL-17 signaling, drove psoriatic epithelial remodeling. Blocking HIF1α in human psoriatic lesions ex vivo impaired glycolysis and phenocopied anti-IL-17 therapy. In a murine model of skin inflammation, epidermal-specific loss of HIF1α or its target gene, glucose transporter 1, ameliorated epidermal, immune, vascular, and neuronal pathology. Mechanistically, glycolysis autonomously fueled epithelial pathology and enhanced lactate production, which augmented the γδ T17 cell response. RORγt-driven genetic deletion or pharmacological inhibition of either lactate-producing enzymes or lactate transporters attenuated epithelial pathology and IL-17A expression in vivo. Our findings identify a metabolic hierarchy between epithelial and immune compartments and the consequent coordination of metabolic processes that sustain inflammatory disease.
    Keywords:  HIF1α; epithelium; glycolysis; inflammation; lactate; metabolism; skin; type 17 cells
    DOI:  https://doi.org/10.1016/j.immuni.2024.04.022
  2. Science. 2024 May 23. eadk4898
    A metabolic dependency of EBV can be targeted to hinder B cell transformation.
    Swiss Transplant Cohort Study#
      Following infection of B cells, Epstein Barr virus (EBV) engages host pathways that mediate cell proliferation and transformation, contributing to the propensity of the virus to drive immune dysregulation and lymphomagenesis. We found that the EBV protein EBNA2 initiates NAD de novo biosynthesis by driving expression of the metabolic enzyme IDO1 in infected B cells. Virus-enforced NAD production sustained mitochondrial complex I activity, to match ATP-production with bioenergetic requirements of proliferation and transformation. In transplant patients, IDO1 expression in EBV-infected B cells, and a serum signature of increased IDO1 activity, preceded development of lymphoma. In humanized mice infected with EBV, IDO1 inhibition reduced both viremia and lymphomagenesis. Virus-orchestrated NAD biosynthesis is, thus, a druggable metabolic vulnerability of EBV-driven B cell transformation-opening therapeutic possibilities for EBV-related diseases.
    DOI:  https://doi.org/10.1126/science.adk4898
  3. Immunity. 2024 May 14. pii: S1074-7613(24)00229-2. [Epub ahead of print]
    Metabolic regulator LKB1 controls adipose tissue ILC2 PD-1 expression and mitochondrial homeostasis to prevent insulin resistance.
    Jiping Sun, Youqin Zhang, Qingbing Zhang, Lin Hu, Linfeng Zhao, Hongdong Wang, Yue Yuan, Hongshen Niu, Dongdi Wang, Huasheng Zhang, Jianyue Liu, Xujiao Feng, Xiaohui Su, Ju Qiu, Jing Sun, Heping Xu, Catherine Zhang, Kathleen Wang, Yan Bi, Edgar G Engleman, Lei Shen.
      Adipose tissue group 2 innate lymphoid cells (ILC2s) help maintain metabolic homeostasis by sustaining type 2 immunity and promoting adipose beiging. Although impairment of the ILC2 compartment contributes to obesity-associated insulin resistance, the underlying mechanisms have not been elucidated. Here, we found that ILC2s in obese mice and humans exhibited impaired liver kinase B1 (LKB1) activation. Genetic ablation of LKB1 disrupted ILC2 mitochondrial metabolism and suppressed ILC2 responses, resulting in exacerbated insulin resistance. Mechanistically, LKB1 deficiency induced aberrant PD-1 expression through activation of NFAT, which in turn enhanced mitophagy by suppressing Bcl-xL expression. Blockade of PD-1 restored the normal functions of ILC2s and reversed obesity-induced insulin resistance in mice. Collectively, these data present the LKB1-PD-1 axis as a promising therapeutic target for the treatment of metabolic disease.
    Keywords:  PD-1; group 2 innate lymphoid cells; insulin resistance; liver kinase B1; mitophagy
    DOI:  https://doi.org/10.1016/j.immuni.2024.04.024
  4. Cell Stem Cell. 2024 May 14. pii: S1934-5909(24)00176-0. [Epub ahead of print]
    SDHAF1 confers metabolic resilience to aging hematopoietic stem cells by promoting mitochondrial ATP production.
    Shintaro Watanuki, Hiroshi Kobayashi, Yuki Sugiura, Masamichi Yamamoto, Daiki Karigane, Kohei Shiroshita, Yuriko Sorimachi, Takayuki Morikawa, Shinya Fujita, Kotaro Shide, Miho Haraguchi, Shinpei Tamaki, Takumi Mikawa, Hiroshi Kondoh, Hiroyasu Nakano, Kenta Sumiyama, Go Nagamatsu, Nobuhito Goda, Shinichiro Okamoto, Ayako Nakamura-Ishizu, Kazuya Shimoda, Makoto Suematsu, Toshio Suda, Keiyo Takubo.
      Aging generally predisposes stem cells to functional decline, impairing tissue homeostasis. Here, we report that hematopoietic stem cells (HSCs) acquire metabolic resilience that promotes cell survival. High-resolution real-time ATP analysis with glucose tracing and metabolic flux analysis revealed that old HSCs reprogram their metabolism to activate the pentose phosphate pathway (PPP), becoming more resistant to oxidative stress and less dependent on glycolytic ATP production at steady state. As a result, old HSCs can survive without glycolysis, adapting to the physiological cytokine environment in bone marrow. Mechanistically, old HSCs enhance mitochondrial complex II metabolism during stress to promote ATP production. Furthermore, increased succinate dehydrogenase assembly factor 1 (SDHAF1) in old HSCs, induced by physiological low-concentration thrombopoietin (TPO) exposure, enables rapid mitochondrial ATP production upon metabolic stress, thereby improving survival. This study provides insight into the acquisition of resilience through metabolic reprogramming in old HSCs and its molecular basis to ameliorate age-related hematopoietic abnormalities.
    Keywords:  SDHAF1; adenosine triphosphate; hematopoietic stem cell; mitochondria; stem cell aging; stem cell metabolism; thrombopoietin
    DOI:  https://doi.org/10.1016/j.stem.2024.04.023
  5. Nat Cell Biol. 2024 May 23.
    TFAM is an autophagy receptor that limits inflammation by binding to cytoplasmic mitochondrial DNA.
    Hao Liu, Cien Zhen, Jianming Xie, Zhenhuan Luo, Lin Zeng, Guojun Zhao, Shaohua Lu, Haixia Zhuang, Hualin Fan, Xia Li, Zhaojie Liu, Shiyin Lin, Huilin Jiang, Yuqian Chen, Jiahao Cheng, Zhiyu Cao, Keyu Dai, Jinhua Shi, Zhaohua Wang, Yongquan Hu, Tian Meng, Chuchu Zhou, Zhiyuan Han, Huansen Huang, Qinghua Zhou, Pengcheng He, Du Feng.
      When cells are stressed, DNA from energy-producing mitochondria can leak out and drive inflammatory immune responses if not cleared. Cells employ a quality control system called autophagy to specifically degrade damaged components. We discovered that mitochondrial transcription factor A (TFAM)-a protein that binds mitochondrial DNA (mtDNA)-helps to eliminate leaked mtDNA by interacting with the autophagy protein LC3 through an autolysosomal pathway (we term this nucleoid-phagy). TFAM contains a molecular zip code called the LC3 interacting region (LIR) motif that enables this binding. Although mutating TFAM's LIR motif did not affect its normal mitochondrial functions, more mtDNA accumulated in the cell cytoplasm, activating inflammatory signalling pathways. Thus, TFAM mediates autophagic removal of leaked mtDNA to restrict inflammation. Identifying this mechanism advances understanding of how cells exploit autophagy machinery to selectively target and degrade inflammatory mtDNA. These findings could inform research on diseases involving mitochondrial damage and inflammation.
    DOI:  https://doi.org/10.1038/s41556-024-01419-6
  6. Adv Protein Chem Struct Biol. 2024 ;pii: S1876-1623(23)00107-4. [Epub ahead of print]140 493-523
    Decoding macrophage immunometabolism in human viral infection.
    Takhellambam Malemnganba, Aditi Rattan, Vijay Kumar Prajapati.
      Immune-metabolic interactions play a pivotal role in both host defense and susceptibility to various diseases. Immunometabolism, an interdisciplinary field, seeks to elucidate how metabolic processes impact the immune system. In the context of viral infections, macrophages are often exploited by viruses for their replication and propagation. These infections trigger significant metabolic reprogramming within macrophages and polarization of distinct M1 and M2 phenotypes. This metabolic reprogramming involves alterations in standard- pathways such as the Krebs cycle, glycolysis, lipid metabolism, the pentose phosphate pathway, and amino acid metabolism. Disruptions in the balance of key intermediates like spermidine, itaconate, and citrate within these pathways contribute to the severity of viral diseases. In this chapter, we describe the manipulation of metabolic pathways by viruses and how they crosstalk between signaling pathways to evade the immune system. This intricate interplay often involves the upregulation or downregulation of specific metabolites, making these molecules potential biomarkers for diseases like HIV, HCV, and SARS-CoV. Techniques such as Nuclear Magnetic Resonance (NMR) and Mass Spectrometry, are the evaluative ways to analyze these metabolites. Considering the importance of macrophages in the inflammatory response, addressing their metabolome holds great promise for the creating future therapeutic targets aimed at combating a wide spectrum of viral infections.
    Keywords:  Cellular cross-talk; Immunometabolism; Macrophages; Metabolic reprogramming; Viral infection
    DOI:  https://doi.org/10.1016/bs.apcsb.2023.12.003
  7. Res Sq. 2024 May 07. pii: rs.3.rs-4342820. [Epub ahead of print]
    The Glucose Transporter 5 Enhances CAR-T Cell Metabolic Function and Anti-tumour Durability.
    Roddy O'Connor, Bakir Valentić, Andre Kelly, Alexander Shestov, Zhiyang Gan, Feng Shen, Adam Chatoff, Alison Jaccard, Claudia Crispim, John Scholler, Simon Heeke, Nathaniel Snyder, Saba Ghassemi, Nicholas Jones, Saar Gill.
      Activated T cells undergo a metabolic shift to aerobic glycolysis to support the energetic demands of proliferation, differentiation, and cytolytic function. Transmembrane glucose flux is facilitated by glucose transporters (GLUT) that play a vital role in T cell metabolic reprogramming and anti-tumour function. GLUT isoforms are regulated at the level of expression and subcellular distribution. GLUTs also display preferential selectivity for carbohydrate macronutrients including glucose, galactose, and fructose. GLUT5, which selectively transports fructose over glucose, has never been explored as a genetic engineering strategy to enhance CAR-T cells in fructose-rich tumour environments. Fructose levels are significantly elevated in the bone marrow and the plasma of acute myeloid leukaemia (AML) patients. Here, we demonstrate that the expression of wild-type GLUT5 restores T cell metabolic fitness in glucose-free, high fructose conditions. We find that fructose supports maximal glycolytic capacity and ATP replenishment rates in GLUT5-expressing T cells. Using steady state tracer technology, we show that 13C6 fructose supports glycolytic reprogramming and TCA anaplerosis in CAR-T cells undergoing log phase expansion. In cytotoxicity assays, GLUT5 rescues T cell cytolytic function in glucose-free medium. The fructose/GLUT5 metabolic axis also supports maximal migratory velocity, which provides mechanistic insight into why GLUT5-expressing CAR-Ts have superior effector function as they undergo "hit-and-run" serial killing. These findings translate to superior anti-tumour function in a xenograft model of AML. In fact, we found that GLUT5 enhances CAR-T cell anti-tumour function in vivo without any need for fructose intervention. Accordingly, we hypothesize that GLUT5 is sufficient to enhance CAR-T resilience by increasing the cells' competitiveness for glucose at physiologic metabolite levels. Our findings have immediate translational relevance by providing the first evidence that GLUT5 confers a competitive edge in a fructose-enriched milieu, and is a novel approach to overcome glucose depletion in hostile tumour microenvironments (TMEs).
    DOI:  https://doi.org/10.21203/rs.3.rs-4342820/v1
  8. Cytotherapy. 2024 May 01. pii: S1465-3249(24)00684-4. [Epub ahead of print]
    Glycolysis inhibition affects proliferation and cytotoxicity of Vγ9Vδ2 T cells expanded for adoptive cell therapy.
    Pia Aehnlich, Marta Velasco Santiago, Søren Helweg Dam, Sara Fresnillo Saló, Anne Rahbech, Lars Rønn Olsen, Per Thor Straten, Claus Desler, Gitte Holmen Olofsson.
       BACKGROUND AIMS: Vγ9Vδ2 T cells are under investigation as alternative effector cells for adoptive cell therapy (ACT) in cancer. Despite promising in vitro results, anti-tumor efficacies in early clinical studies have been lower than expected, which could be ascribed to the complex interplay of tumor and immune cell metabolism competing for the same nutrients in the tumor microenvironment.
    METHODS: To contribute to the scarce knowledge regarding gamma delta T-cell metabolism, we investigated the metabolic phenotype of 25-day-expanded Vγ9Vδ2 T cells and how it is intertwined with functionality.
    RESULTS: We found that Vγ9Vδ2 T cells displayed a quiescent metabolism, utilizing both glycolysis and oxidative phosphorylation (OXPHOS) for energy production, as measured in Seahorse assays. Upon T-cell receptor activation, both pathways were upregulated, and inhibition with metabolic inhibitors showed that Vγ9Vδ2 T cells were dependent on glycolysis and the pentose phosphate pathway for proliferation. The dependency on glucose for proliferation was confirmed in glucose-free conditions. Cytotoxicity against malignant melanoma was reduced by glycolysis inhibition but not OXPHOS inhibition.
    CONCLUSIONS: These findings lay the groundwork for further studies on manipulation of Vγ9Vδ2 T-cell metabolism for improved ACT outcome.
    Keywords:  Vγ9Vδ2 T cells; adoptive cell therapy; cytotoxicity; glycolysis; metabolism; γδ T cells
    DOI:  https://doi.org/10.1016/j.jcyt.2024.04.072
  9. Cancers (Basel). 2024 May 18. pii: 1928. [Epub ahead of print]16(10):
    Lactococcus lactis subsp. cremoris C60 Upregulates Macrophage Function by Modifying Metabolic Preference in Enhanced Anti-Tumor Immunity.
    Suguru Saito, Duo-Yao Cao, Toshio Maekawa, Noriko M Tsuji, Alato Okuno.
      Lactococcus lactis subsp. cremoris C60 is a probiotic strain of lactic acid bacteria (LAB) which induces various immune modifications in myeloid lineage cells. These modifications subsequently regulate T cell function, resulting in enhanced immunity both locally and systemically. Here, we report that C60 suppresses tumor growth by enhancing macrophage function via metabolic alterations, thereby increasing adenosine triphosphate (ATP) production in a murine melanoma model. Intragastric (i.g.) administration of C60 significantly reduced tumor volume compared to saline administration in mice. The anti-tumor function of intratumor (IT) macrophage was upregulated in mice administered with C60, as evidenced by an increased inflammatory phenotype (M1) rather than an anti-inflammatory/reparative (M2) phenotype, along with enhanced antigen-presenting ability, resulting in increased tumor antigen-specific CD8+ T cells. Through this functional modification, we identified that C60 establishes a glycolysis-dominant metabolism, rather than fatty acid oxidation (FAO), in IT macrophages, leading to increased intracellular ATP levels. To address the question of why orally supplemented C60 exhibits functions in distal places, we found a possibility that bacterial cell wall components, which could be distributed throughout the body from the gut, may induce stimulatory signals in peripheral macrophages via Toll-like receptors (TLRs) signaling activation. Thus, C60 strengthens macrophage anti-tumor immunity by promoting a predominant metabolic shift towards glycolysis upon TLR-mediated stimulation, thereby increasing substantial energy production.
    Keywords:  ATP; anti-tumor immunity; glycolysis; macrophage; probiotics
    DOI:  https://doi.org/10.3390/cancers16101928
  10. Clin Chim Acta. 2024 May 19. pii: S0009-8981(24)01987-9. [Epub ahead of print]560 119735
    Metabolomic analysis reveals macrophage metabolic reprogramming and polarization under different nutritional cues.
    Zhongxiao Zhang, Zhou Peng, Rui Wang, Xirong Guo, Jianfang Gao.
       BACKGROUND AND AIMS: Obesity-induced chronic inflammation and metabolic abnormalities are highly relevant to the functional dysregulation of macrophages, especially under obese conditions. Hyperglycemia and hyperlipidemia, central to obesity, directly alter macrophage activity. However, the impacts of different nutritional cues on the intricate metabolic networks in macrophages remain unclear.
    MATERIALS AND METHODS: In this study, we employed metabolomic approaches to examine the metabolic responses of macrophages to high glucose, high fat and their coexistence, aiming to delineate the molecular mechanisms of nutritional factors on macrophage activation and obesity-related diseases from a metabolic perspective.
    RESULTS: Our findings revealed that different nutritional conditions could reprogram key metabolism in macrophages. Additionally, we identified a metabolite derived from macrophages, Long-Chain Phosphatidylcholine (LPC), which exerts beneficial effects on obese mice. It ameliorates the obesity phenotype and improves glucose metabolism profiles. This discovery suggests that LPC has a significant therapeutic potential in the context of obesity-induced metabolic dysfunctions. Our study unveils the metabolic phenotype of macrophages in high-fat and high-sugar environments and uncovers a macrophage-derived metabolite that significantly ameliorates the obesity phenotype.
    CONCLUSION: This finding reveals a potential dialogue mechanism between macrophages and adipocytes, shedding light on the complex interplay of immune and metabolic systems in obesity. This discovery not only enhances our understanding of obesity's underlying mechanisms but also opens up new avenues for therapeutic interventions targeting macrophage-adipocyte interactions.
    Keywords:  Macrophage; Metabolic reprogramming; Metabolomic; Obesity
    DOI:  https://doi.org/10.1016/j.cca.2024.119735
  11. Commun Biol. 2024 May 23. 7(1): 622
    The integration of metabolic and proteomic data uncovers an augmentation of the sphingolipid biosynthesis pathway during T-cell differentiation.
    Toshio Kanno, Ryo Konno, Masaru Sato, Atsushi Kurabayashi, Keisuke Miyako, Takahiro Nakajima, Satoru Yokoyama, Shigemi Sasamoto, Hikari K Asou, Junichiro Ohzeki, Yoshinori Hasegawa, Kazutaka Ikeda, Yusuke Kawashima, Osamu Ohara, Yusuke Endo.
      Recent studies have highlighted the significance of cellular metabolism in the initiation of clonal expansion and effector differentiation of T cells. Upon exposure to antigens, naïve CD4+ T cells undergo metabolic reprogramming to meet their metabolic requirements. However, only few studies have simultaneously evaluated the changes in protein and metabolite levels during T cell differentiation. Our research seeks to fill the gap by conducting a comprehensive analysis of changes in levels of metabolites, including sugars, amino acids, intermediates of the TCA cycle, fatty acids, and lipids. By integrating metabolomics and proteomics data, we discovered that the quantity and composition of cellular lipids underwent significant changes in different effector Th cell subsets. Especially, we found that the sphingolipid biosynthesis pathway was commonly activated in Th1, Th2, Th17, and iTreg cells and that inhibition of this pathway led to the suppression of Th17 and iTreg cells differentiation. Additionally, we discovered that Th17 and iTreg cells enhance glycosphingolipid metabolism, and inhibition of this pathway also results in the suppression of Th17 and iTreg cell generation. These findings demonstrate that the utility of our combined metabolomics and proteomics analysis in furthering the understanding of metabolic transition during Th cell differentiation.
    DOI:  https://doi.org/10.1038/s42003-024-06339-7
  12. Redox Biol. 2024 May 13. pii: S2213-2317(24)00169-1. [Epub ahead of print]73 103191
    Distinct metabolic responses to heme in inflammatory human and mouse macrophages - Role of nitric oxide.
    Pooja Pradhan, Vijith Vijayan, Bin Liu, Beatriz Martinez-Delgado, Nerea Matamala, Christoph Nikolin, Robert Greite, David S DeLuca, Sabina Janciauskiene, Roberto Motterlini, Roberta Foresti, Stephan Immenschuh.
      Activation of inflammation is tightly associated with metabolic reprogramming in macrophages. The iron-containing tetrapyrrole heme can induce pro-oxidant and pro-inflammatory effects in murine macrophages, but has been associated with polarization towards an anti-inflammatory phenotype in human macrophages. In the current study, we compared the regulatory responses to heme and the prototypical Toll-like receptor (TLR)4 ligand lipopolysaccharide (LPS) in human and mouse macrophages with a particular focus on alterations of cellular bioenergetics. In human macrophages, bulk RNA-sequencing analysis indicated that heme led to an anti-inflammatory transcriptional profile, whereas LPS induced a classical pro-inflammatory gene response. Co-stimulation of heme with LPS caused opposing regulatory patterns of inflammatory activation and cellular bioenergetics in human and mouse macrophages. Specifically, in LPS-stimulated murine, but not human macrophages, heme led to a marked suppression of oxidative phosphorylation and an up-regulation of glycolysis. The species-specific alterations in cellular bioenergetics and inflammatory responses to heme were critically dependent on the availability of nitric oxide (NO) that is generated in inflammatory mouse, but not human macrophages. Accordingly, studies with an inducible nitric oxide synthase (iNOS) inhibitor in mouse, and a pharmacological NO donor in human macrophages, reveal that NO is responsible for the opposing effects of heme in these cells. Taken together, the current findings indicate that NO is critical for the immunomodulatory role of heme in macrophages.
    Keywords:  Heme; Inflammation; Lipopolysaccharide; Macrophages; Mitochondrial metabolism; Nitric oxide
    DOI:  https://doi.org/10.1016/j.redox.2024.103191
  13. EMBO J. 2024 May 22.
    The immune response to RNA suppresses nucleic acid synthesis by limiting ribose 5-phosphate.
    Pushpak Bhattacharjee, Die Wang, Dovile Anderson, Joshua N Buckler, Eveline de Geus, Feng Alex Yan, Galina Polekhina, Ralf Schittenhelm, Darren J Creek, Lawrence D Harris, Anthony J Sadler.
      During infection viruses hijack host cell metabolism to promote their replication. Here, analysis of metabolite alterations in macrophages exposed to poly I:C recognises that the antiviral effector Protein Kinase RNA-activated (PKR) suppresses glucose breakdown within the pentose phosphate pathway (PPP). This pathway runs parallel to central glycolysis and is critical to producing NADPH and pentose precursors for nucleotides. Changes in metabolite levels between wild-type and PKR-ablated macrophages show that PKR controls the generation of ribose 5-phosphate, in a manner distinct from its established function in gene expression but dependent on its kinase activity. PKR phosphorylates and inhibits the Ribose 5-Phosphate Isomerase A (RPIA), thereby preventing interconversion of ribulose- to ribose 5-phosphate. This activity preserves redox control but decreases production of ribose 5-phosphate for nucleotide biosynthesis. Accordingly, the PKR-mediated immune response to RNA suppresses nucleic acid production. In line, pharmacological targeting of the PPP during infection decreases the replication of the Herpes simplex virus. These results identify an immune response-mediated control of host cell metabolism and suggest targeting the RPIA as a potential innovative antiviral treatment.
    Keywords:  Antiviral; Immunity; Metabolism; Nucleotide Biosynthesis; PKR (Protein Kinase RNA-Activated); PPP (Pentose Phosphate Pathway); RPIA (Ribose 5-Phosphate Isomerase A)
    DOI:  https://doi.org/10.1038/s44318-024-00100-w
  14. Nutrients. 2024 May 07. pii: 1404. [Epub ahead of print]16(10):
    Fasting and Glucose Metabolism Differentially Impact Peripheral Inflammation in Human Type 2 Diabetes.
    Gabriella H Kalantar, Shubh Saraswat, Sara SantaCruz-Calvo, Fatemeh Gholamrezaeinejad, Aida Javidan, Madhur Agrawal, Rui Liu, Philip A Kern, Xiaohua Douglas Zhang, Barbara S Nikolajczyk.
      Cytokines produced by peripheral T-helper 1/17 cells disproportionately contribute to the inflammation (i.e., metaflammation) that fuels type 2 diabetes (T2D) pathogenesis. Shifts in the nutrient milieu could influence inflammation through changes in T-cell metabolism. We aimed to determine whether changes in glucose utilization alter cytokine profiles in T2D. Peripheral blood mononuclear cells (PBMCs), CD4+ T-cells, and CD4+CD25- T-effector (Teff) cells were isolated from age-matched humans classified by glycemic control and BMI. Cytokines secreted by CD3/CD28-stimulated PBMCs and Teff were measured in supernatants with multiplex cytokine assays and a FLEXMAP-3D. Metabolic activity of stimulated CD4+ T-cells was measured by a Seahorse XFe96 analyzer. In this study, we demonstrated that T-cell stimulated PBMCs from non-fasted people with T2D produced higher amounts of cytokines compared to fasting. Although dysglycemia characterizes T2D, cytokine production by PBMCs or CD4+ T-cells in T2D was unaltered by hyperglycemic media. Moreover, pharmacological suppression of mitochondrial glucose oxidation did not change T-cell metabolism in T2D, yet enhanced cytokine competency. In conclusion, fasting and glucose metabolism differentially impact peripheral inflammation in human T2D, suggesting that glucose, along with fatty acid metabolites per our previous work, partner to regulate metaflammation. These data expose a major disconnect in the use of glycemic control drugs to target T2D-associated metaflammation.
    Keywords:  Hba1C; cytokines; extracellular flux; glycemic control; obesity; partial least squares discriminant analysis; systemic inflammation
    DOI:  https://doi.org/10.3390/nu16101404
  15. Inflammation. 2024 May 18.
    4-Octyl Itaconate Attenuates Neuroinflammation in Experimental Autoimmune Encephalomyelitis Via Regulating Microglia.
    Ning Zhao, Ming Yi, Lin-Jie Zhang, Qiu-Xia Zhang, Li Yang.
      Abnormal activation of microglia, the resident macrophages in the central nervous system, plays an important role in the pathogenesis of multiple sclerosis (MS). The immune responsive gene 1(IRG1)/itaconate axis is involved in regulating microglia-mediated neuroinflammation. 4-Octyl itaconate (4-OI), a derivative of itaconate, plays a crucial immunomodulatory role in macrophages. This study investigated the effects and mechanisms of action of 4-OI on experimental autoimmune encephalomyelitis (EAE) and inflammatory BV2 microglia. In an EAE mouse model, clinical evaluation was conducted during the disease course. Hematoxylin and eosin staining was performed to assess inflammatory infiltration and Luxol Fast Blue was used to visualize pathological damage. Quantitative real-time polymerase chain reaction, western blotting and immunofluorescence were used to evaluate inflammatory response and microglial function status in EAE mice. BV2 microglia were used to further investigate the effects and mechanisms of action of 4-OI in vitro. 4-OI significantly alleviated the clinical symptoms of EAE, the inflammatory infiltration, and demyelination; reduced the levels of inflammatory factors; and inhibited the classical activation of microglia in the spinal cord. 4-OI successfully suppressed the classical activation of BV2 microglia and decreased the levels of inflammatory factors by activating the Nrf2/HO-1 signaling pathway. Furthermore, 4-OI downregulated IRG1 expression in both EAE mice and inflammatory BV2 microglia. 4-OI attenuates the microglia-mediated neuroinflammation and has promising therapeutic effects in MS.
    Keywords:  4-Octyl itaconate; experimental autoimmune encephalomyelitis; immune responsive gene 1; microglia; multiple sclerosis; nuclear factor erythroid 2-related factor 2
    DOI:  https://doi.org/10.1007/s10753-024-02050-1
  16. Nat Metab. 2024 May 22.
    Glutamate from the microbiome controls host metabolism.
    Gwenola Le Dréan, Hervé M Blottière.
      
    DOI:  https://doi.org/10.1038/s42255-024-01050-7
  17. Nat Commun. 2024 May 24. 15(1): 4444
    Deleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8+ T cell adoptive therapies in pre-clinical studies.
    Meng-Han Wu, Felipe Valenca-Pereira, Francesca Cendali, Emily L Giddings, Catherine Pham-Danis, Michael C Yarnell, Amanda J Novak, Tonya M Brunetti, Scott B Thompson, Jorge Henao-Mejia, Richard A Flavell, Angelo D'Alessandro, M Eric Kohler, Mercedes Rincon.
      Mitochondrial respiration is essential for the survival and function of T cells used in adoptive cellular therapies. However, strategies that specifically enhance mitochondrial respiration to promote T cell function remain limited. Here, we investigate methylation-controlled J protein (MCJ), an endogenous negative regulator of mitochondrial complex I expressed in CD8 cells, as a target for improving the efficacy of adoptive T cell therapies. We demonstrate that MCJ inhibits mitochondrial respiration in murine CD8+ CAR-T cells and that deletion of MCJ increases their in vitro and in vivo efficacy against murine B cell leukaemia. Similarly, MCJ deletion in ovalbumin (OVA)-specific CD8+ T cells also increases their efficacy against established OVA-expressing melanoma tumors in vivo. Furthermore, we show for the first time that MCJ is expressed in human CD8 cells and that the level of MCJ expression correlates with the functional activity of CD8+ CAR-T cells. Silencing MCJ expression in human CD8 CAR-T cells increases their mitochondrial metabolism and enhances their anti-tumor activity. Thus, targeting MCJ may represent a potential therapeutic strategy to increase mitochondrial metabolism and improve the efficacy of adoptive T cell therapies.
    DOI:  https://doi.org/10.1038/s41467-024-48653-y
  18. mBio. 2024 May 20. e0086224
    mTOR signaling is required for phagocyte free radical production, GLUT1 expression, and control of Staphylococcus aureus infection.
    Christopher J Genito, Benjamin P Darwitz, Callista P Reber, Nathaniel J Moorman, Christina L Graves, Andrew J Monteith, Lance R Thurlow.
      Mammalian target of rapamycin (mTOR) is a key regulator of metabolism in the mammalian cell. Here, we show the essential role for mTOR signaling in the immune response to bacterial infection. Inhibition of mTOR during infection with Staphylococcus aureus revealed that mTOR signaling is required for bactericidal free radical production by phagocytes. Mechanistically, mTOR supported glucose transporter GLUT1 expression, potentially through hypoxia-inducible factor 1α, upon phagocyte activation. Cytokine and chemokine signaling, inducible nitric oxide synthase, and p65 nuclear translocation were present at similar levels during mTOR suppression, suggesting an NF-κB-independent role for mTOR signaling in the immune response during bacterial infection. We propose that mTOR signaling primarily mediates the metabolic requirements necessary for phagocyte bactericidal free radical production. This study has important implications for the metabolic requirements of innate immune cells during bacterial infection as well as the clinical use of mTOR inhibitors.IMPORTANCESirolimus, everolimus, temsirolimus, and similar are a class of pharmaceutics commonly used in the clinical treatment of cancer and the anti-rejection of transplanted organs. Each of these agents suppresses the activity of the mammalian target of rapamycin (mTOR), a master regulator of metabolism in human cells. Activation of mTOR is also involved in the immune response to bacterial infection, and treatments that inhibit mTOR are associated with increased susceptibility to bacterial infections in the skin and soft tissue. Infections caused by Staphylococcus aureus are among the most common and severe. Our study shows that this susceptibility to S. aureus infection during mTOR suppression is due to an impaired function of phagocytic immune cells responsible for controlling bacterial infections. Specifically, we observed that mTOR activity is required for phagocytes to produce antimicrobial free radicals. These results have important implications for immune responses during clinical treatments and in disease states where mTOR is suppressed.
    Keywords:  Staphylococcus aureus; immune dysfunction; mTOR
    DOI:  https://doi.org/10.1128/mbio.00862-24
  19. Int Immunopharmacol. 2024 May 22. pii: S1567-5769(24)00797-5. [Epub ahead of print]135 112277
    IRG1/itaconate alleviates acute liver injury in septic mice by suppressing NLRP3 expression and its mediated macrophage pyroptosis via regulation of the Nrf2 pathway.
    Pei Zhou, Lei Yang, Ruidong Li, Yuping Yin, Gengchen Xie, Xinghua Liu, Liang Shi, Kaixiong Tao, Peng Zhang.
      Sepsis, a systemic inflammatory response triggered by infection, has a considerably high mortality rate. However, effective prevention and intervention measures against sepsis remain insufficient. Therefore, this study aimed to investigate the mechanisms underlying the protective properties of immune response gene-1 (IRG1) and 4-Octyl itaconate (OI) during acute liver damage in mice with sepsis. A sepsis mouse model was established to compare wild-type and IRG1-/- groups. The impact of IRG1/Itaconate on pro- and anti-inflammatory cytokines was evaluated using J774A.1 cells. IRG1/Itaconate substantially reduced pro-inflammatory cytokines and increased the release of anti-inflammatory cytokines. It reduced pathological damage to liver tissues, preserved normal liver function, decreased the release of reactive oxygen species (ROS) and LDH, and enhanced the GSH/GSSG ratio. Moreover, IRG1 and itaconic acid activated the Nrf2 signaling pathway, regulating the expression of its downstream antioxidative stress-related proteins. Additionally, they inhibited the activity of NLRP3 inflammatory vesicles to suppress the expression of macrophage-associated pyroptosis signaling molecules. Our findings demonstrate that IRG1/OI inhibits NLRP3 inflammatory vesicle activation and macrophage pyroptosis by modulating the Nrf2 signaling pathway, thereby attenuating acute liver injury in mice with sepsis. These findings could facilitate the clinical application of IRG1/Itaconate to prevent sepsis-induced acute liver injury.
    Keywords:  Acute liver injury; IRG1; NLRP3; Nrf2; Pyroptosis; Sepsis
    DOI:  https://doi.org/10.1016/j.intimp.2024.112277
  20. Clin Immunol. 2024 May 18. pii: S1521-6616(24)00364-4. [Epub ahead of print]264 110255
    Itaconate reduces proliferation and migration of fibroblast-like synoviocytes and ameliorates arthritis models.
    Maria Tada, Yuki Kudo, Michihito Kono, Masatoshi Kanda, Shuhei Takeyama, Kodai Sakiyama, Hotaka Ishizu, Tomohiro Shimizu, Tsutomu Endo, Ryo Hisada, Yuichiro Fujieda, Masaru Kato, Olga Amengual, Norimasa Iwasaki, Tatsuya Atsumi.
      Fibroblast-like synoviocytes (FLS) play critical roles in rheumatoid arthritis (RA). Itaconate (ITA), an endogenous metabolite derived from the tricarboxylic acid (TCA) cycle, has attracted attention because of its anti-inflammatory, antiviral, and antimicrobial effects. This study evaluated the effect of ITA on FLS and its potential to treat RA. ITA significantly decreased FLS proliferation and migration in vitro, as well as mitochondrial oxidative phosphorylation and glycolysis measured by an extracellular flux analyzer. ITA accumulates metabolites including succinate and citrate in the TCA cycle. In rats with type II collagen-induced arthritis (CIA), intra-articular injection of ITA reduced arthritis and bone erosion. Irg1-deficient mice lacking the ability to produce ITA had more severe arthritis than control mice in the collagen antibody-induced arthritis. ITA ameliorated CIA by inhibiting FLS proliferation and migration. Thus, ITA may be a novel therapeutic agent for RA.
    Keywords:  Fibroblast-like synoviocytes; Intracellular metabolism; Itaconate; Rheumatoid arthritis
    DOI:  https://doi.org/10.1016/j.clim.2024.110255
  21. Hum Mol Genet. 2024 May 22. 33(R1): R80-R91
    Mitochondrial DNA release and sensing in innate immune responses.
    Jordyn J VanPortfliet, Cole Chute, Yuanjiu Lei, Timothy E Shutt, A Phillip West.
      Mitochondria are pleiotropic organelles central to an array of cellular pathways including metabolism, signal transduction, and programmed cell death. Mitochondria are also key drivers of mammalian immune responses, functioning as scaffolds for innate immune signaling, governing metabolic switches required for immune cell activation, and releasing agonists that promote inflammation. Mitochondrial DNA (mtDNA) is a potent immunostimulatory agonist, triggering pro-inflammatory and type I interferon responses in a host of mammalian cell types. Here we review recent advances in how mtDNA is detected by nucleic acid sensors of the innate immune system upon release into the cytoplasm and extracellular space. We also discuss how the interplay between mtDNA release and sensing impacts cellular innate immune endpoints relevant to health and disease.
    Keywords:  NLRP3; TLR9; cGAS-STING; inflammation; innate immunity; mitochondria; mitochondrial DNA
    DOI:  https://doi.org/10.1093/hmg/ddae031
  22. Hepatology. 2024 May 16.
    Distinct immunometabolic signatures in circulating immune cells define disease outcome in acute-on-chronic liver failure.
    Rita Feio-Azevedo, Markus Boesch, Silvia Radenkovic, Lukas van Melkebeke, Lena Smets, Marie Wallays, Bram Boeckx, Gino Philips, Janaíne Prata de Oliveira, Mohammad Ghorbani, Wim Laleman, Philippe Meersseman, Alexander Wilmer, David Cassiman, Hannah van Malenstein, Evangelos Triantafyllou, Cristina Sánchez, Ferran Aguilar, Frederik Nevens, Jef Verbeek, Richard Moreau, Vicente Arroyo, Alexandre Denadai Souza, Joan Clària, Diether Lambrechts, Bart Ghesquière, Hannelie Korf, Schalk van der Merwe.
       BACKGROUND AIMS: Acute-on-chronic liver failure (ACLF) is a complication of cirrhosis characterized by multiple organ failure and high short-term mortality. The pathophysiology of ACLF involves elevated systemic inflammation leading to organ failure, along with immune dysfunction that heightens susceptibility to bacterial infections. However, it is unclear how these aspects are associated with recovery and non-recovery in ACLF.
    APPROACH RESULTS: Here we mapped the single-cell transcriptome of circulating immune cells from ACLF-, acute decompensated (AD) cirrhosis patients and healthy individuals. We further interrogate how these findings as well as immunometabolic- and functional profiles associate with ACLF recovery (ACLF-R) or non-recovery (ACLF-NR). Our analysis unveiled two distinct states of classical monocytes (cMon). Hereto, ACLF-R cMons were characterized by transcripts associated with immune- and stress tolerance, including anti-inflammatory genes such as RETN and LGALS1 . Additional metabolomic- and functional validation experiments implicated an elevated oxidative phosphorylation metabolic program as well as an impaired ACLF-R cMon functionality. Interestingly, we observed a common stress-induced tolerant state, oxidative phosphorylation program and blunted activation among lymphoid populations in ACLF-R patients. Conversely, ACLF-NR cMon featured elevated expression of inflammatory- and stress response genes such as VIM , LGALS2 , and TREM1 along with blunted metabolic activity and increased functionality.
    CONCLUSIONS: This study identifies distinct immuno-metabolic cellular states that contribute to disease outcome in ACLF patients. Our findings provide valuable insights into the pathogenesis of ACLF, shedding light on factors driving either recovery or non-recovery phenotypes which may be harnessed as potential therapeutic targets in the future.
    DOI:  https://doi.org/10.1097/HEP.0000000000000907
  23. Heliyon. 2024 May 30. 10(10): e30781
    Different lactate metabolism subtypes reveal heterogeneity in clinical outcomes and immunotherapy in lung adenocarcinoma patients.
    Jing Zhang, Yun Bao, Yang Li, Xin Shi, Xiangyu Su, Xuejun He.
       Background: The excessive accumulation of lactate within the tumor microenvironment (TME) has been demonstrated to facilitate tumor advancement and evade the immune system. Nonetheless, the metabolic status of lactate in lung adenocarcinoma (LUAD) remains uncertain.
    Method: By analyzing the transcriptome profile of patients with LUAD, we created a lactate metabolism score (LMS) to predict survival. We then conducted a comprehensive examination of the biological functions and immune infiltration among different LMS patient groups. Moreover, we assessed the LMS predictive efficacy in chemotherapy and immunotherapy. Finally, we validated the detrimental phenotypic effects of SLC16A3 on LUAD cell lines (PC9 and A549) through in vitro experiments. We collected clinical samples to assess the prognostic impact of SLC16A3.
    Results: We constructed an LMS model with 6 lactate metabolism regulatory factors using LASSO regression. The high LMS model indicates worse clinical outcomes for LUAD patients. High LMS patients are associated with metabolic dysregulation and increased infiltration of M0 and M1 macrophages. Low LMS patients are related to upregulated citric acid metabolism pathways and memory immune cells. High LMS patients are suitable for traditional chemotherapy, while patients with low LMS are more likely to benefit from immunotherapy. Lastly, downregulating SLC16A3 significantly reduces the proliferative and invasive capabilities of LUAD cell lines. Clinical cohort shows that patients with high expression of SLC16A3 have a worse prognosis.
    Conclusions: The LMS model constructed based on the lactate metabolism pathway displays high effectiveness in predicting the outcome of patients with LUAD. LMS can offer direction regarding chemotherapy as well as immunotherapy in LUAD.
    Keywords:  Drug resistance; Immune microenvironment; Lactate metabolism; Lung adenocarcinoma (LUAD); SLC16A3
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e30781
  24. Heliyon. 2024 May 30. 10(10): e30903
    LC-MS-based rheumatoid arthritis serum metabolomics reveals the role of deoxyinosine in attenuating collagen-induced arthritis in mice.
    Delai Xu, Liuxing Tang, Yueyuan Wang, Jie Pan, Cunjin Su.
      Rheumatoid arthritis (RA) is a persistent autoimmune condition with no identified cure currently. Recently, scientists have applied metabolomics to investigate altered metabolic profiles and unique diseases-associated metabolic signatures. Herein, we applied metabolomics approach to analyze serum samples of 41 RA patients and 42 healthy controls (HC) with the aim to characterize RA patients' metabolic profile, investigate related underlying pathological processes, and identify target metabolites. By utilizing ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry, we found 168 proposed metabolites and 45 vital metabolic pathways. Our analysis revealed that deoxyinosine (DI), a metabolite of the purine metabolic pathway, was the most significant reduced metabolite in RA patients. Furthermore, through targeted detection, we confirmed lower concentration of DI in RA patients' peripheral blood. Moreover, DI inhibited lipopolysaccharide-induced inflammation both in vitro and in vivo. We further assessed DI's therapeutic potential in a collagen-induced arthritis (CIA) murine model. The results revealed that DI attenuated CIA, as evidenced by significantly lowered clinical scores of arthritis, alleviated joint swelling, and mitigated bone destruction. Moreover, we elucidated the underlying mechanism by which DI increased the population of myeloid-derived suppressor cells (MDSCs) and suppressed the proliferation of induced T cells. Collectively, these findings suggested that DI potentially ameliorated RA by inducing immunosuppressive MDSCs. The study provides key observations on RA pathogenesis and may contribute to developing novel therapeutic strategies for this debilitating condition.
    Keywords:  CIA; Collagen-induced arthritis; Deoxyinosine; Metabolomics; Myeloid-derived suppressor cells; Rheumatoid arthritis; Untargeted metabolomics
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e30903
  25. PeerJ. 2024 ;12 e17414
    Nucleolin myocardial-specific knockout exacerbates glucose metabolism disorder in endotoxemia-induced myocardial injury.
    Yuting Tang, Leijing Yin, Ludong Yuan, Xiaofang Lin, Bimei Jiang.
       Background: Sepsis-induced myocardial injury, as one of the important complications of sepsis, can significantly increase the mortality of septic patients. Our previous study found that nucleolin affected mitochondrial function in energy synthesis and had a protective effect on septic cardiomyopathy in mice. During sepsis, glucose metabolism disorders aggravated myocardial injury and had a negative effect on septic patients.
    Objectives: We investigated whether nucleolin could regulate glucose metabolism during endotoxemia-induced myocardial injury.
    Methods: The study tested whether the nucleolin cardiac-specific knockout in the mice could affect glucose metabolism through untargeted metabolomics, and the results of metabolomics were verified experimentally in H9C2 cells. The ATP content, lactate production, and oxygen consumption rate (OCR) were evaluated.
    Results: The metabolomics results suggested that glycolytic products were increased in endotoxemia-induced myocardial injury, and that nucleolin myocardial-specific knockout altered oxidative phosphorylation-related pathways. The experiment data showed that TNF-α combined with LPS stimulation could increase the lactate content and the OCR values by about 25%, and decrease the ATP content by about 25%. However, interference with nucleolin expression could further decrease ATP content and OCR values by about 10-20% and partially increase the lactate level in the presence of TNF-α and LPS. However, nucleolin overexpression had the opposite protective effect, which partially reversed the decrease in ATP content and the increase in lactate level.
    Conclusion: Down-regulation of nucleolin can exacerbate glucose metabolism disorders in endotoxemia-induced myocardial injury. Improving glucose metabolism by regulating nucleolin was expected to provide new therapeutic ideas for patients with septic cardiomyopathy.
    Keywords:  Endotoxemia; Glycolysis; Metabolomics; Myocardial injury; Nucleolin; Sepsis
    DOI:  https://doi.org/10.7717/peerj.17414
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