bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2023–05–21
forty-six papers selected by
Dylan Ryan, University of Cambridge
  1. Complex Interplay Between Metabolism and CD4+ T-Cell Activation, Differentiation, and Function: a Novel Perspective for Atherosclerosis Immunotherapy.
  2. PKM2 Promotes Pro-Inflammatory Macrophage Activation in Ankylosing Spondylitis.
  3. Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages.
  4. Metformin reprograms tryptophan metabolism to stimulate CD8+ T cell function in colorectal cancer.
  5. Candida auris uses metabolic strategies to escape and kill macrophages while avoiding robust activation of the NLRP3 inflammasome response.
  6. A new frontier for fat: dietary palmitic acid induces innate immune memory.
  7. Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment.
  8. Butyrate regulates neutrophil homeostasis and impairs early antimicrobial activity in the lung.
  9. Butyrate limits inflammatory macrophage niche in NASH.
  10. Inflamed macrophages sans mitochondrial pyruvate carrier?
  11. Succinate based polymers drive immunometabolism in dendritic cells to generate cancer immunotherapy.
  12. The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy.
  13. Mitochondrial immune regulation and anti-tumor immunotherapy strategies targeting mitochondria.
  14. Aspirin loaded extracellular vesicles inhibit inflammation of macrophages via switching metabolic phenotype in periodontitis.
  15. LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation.
  16. Bacterial Lipoproteins Shift Cellular Metabolism to Glycolysis in Macrophages Causing Bone Erosion.
  17. Role of PFKFB3-driven glycolysis in sepsis.
  18. Real-time assessment of neutrophil metabolism and oxidative burst using extracellular flux analysis.
  19. The eIF4EBP-eIF4E axis regulates CD4+ T cell differentiation through modulation of T cell activation and metabolism.
  20. Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.
  21. Hippo Kinase MST1-Mediated Cell Metabolism Reprograms the Homeostasis and Differentiation of Granulocyte Progenitor Cells.
  22. Rewiring of the Host Cell Metabolome and Lipidome during Lytic Gammaherpesvirus Infection Is Essential for Infectious-Virus Production.
  23. Microbiota-assisted iron uptake promotes immune tolerance in the intestine.
  24. Glycolytic stress deteriorates 229E virulence to improve host defense response.
  25. Navigating the immunometabolic heterogeneity of B cells in murine hepatocellular carcinoma at single cell resolution.
  26. CD38: an ecto-enzyme with functional diversity in T cells.
  27. An immunometabolic patch facilitates mesenchymal stromal/stem cell therapy for myocardial infarction through a macrophage-dependent mechanism.
  28. Natural γδT17 cell development and functional acquisition is governed by the mTORC2-c-Maf-controlled mitochondrial fission pathway.
  29. Monomethyl fumarate prevents alloimmune rejection in mouse heart transplantation by inducing tolerogenic dendritic cells.
  30. Immunomodulatory Effects of Microbiota-Derived Short-Chain Fatty Acids in Autoimmune Liver Diseases.
  31. Integrative single-cell RNA sequencing and metabolomics decipher the imbalanced lipid-metabolism in maladaptive immune responses during sepsis.
  32. Oral ω-3 PUFA supplementation modulates inflammation in adipose tissue depots in morbidly obese women: A randomized trial.
  33. Impaired alveolar macrophage 11β-hydroxysteroid dehydrogenase type 1 reductase activity contributes to increased pulmonary inflammation and mortality in sepsis-related ARDS.
  34. Systems biology elucidates the distinctive metabolic niche filled by the human gut microbe Eggerthella lenta.
  35. 1,5-AG suppresses pro-inflammatory polarization of macrophages and promotes the survival of B-ALL in vitro by upregulating CXCL14.
  36. Fucose ameliorates the proinflammatory property of Fusobacterium nucleatum in colitis via altering its metabolism.
  37. Targeting mitochondrial function in macrophages: A novel treatment strategy for atherosclerotic cardiovascular disease?
  38. Galanin ameliorates liver inflammation and fibrosis in mice by activating AMPK/ACC signaling and modifying macrophage inflammatory phenotype.
  39. Targeting NAD+ metabolism of hepatocellular carcinoma cells by lenvatinib promotes M2 macrophages reverse polarization, suppressing the HCC progression.
  40. A novel methionine metabolism-related signature predicts prognosis and immunotherapy response in lung adenocarcinoma.
  41. Metabolic reprogramming of myeloid-derived suppressor cells in the context of organ transplantation.
  42. Targeting lactate metabolism and immune interaction in breast tumor via protease-triggered delivery.
  43. Copper boosts pro-inflammatory state of macrophages.
  44. Salvage of ribose from uridine or RNA supports glycolysis in nutrient-limited conditions.
  45. Poly(ADP)ribose polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production.
  46. Adoptive Treg therapy with metabolic intervention via perforated microneedles ameliorates psoriasis syndrome.
  1. Cardiovasc Drugs Ther. 2023 May 18.
    Complex Interplay Between Metabolism and CD4+ T-Cell Activation, Differentiation, and Function: a Novel Perspective for Atherosclerosis Immunotherapy.
    Jingmin Yang, Yanying Chen, Xiao Li, Huali Qin, Jinghui Bao, Chunfang Wang, Xiaochen Dong, Danyan Xu.
      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.
    Keywords:  AMPK; Atherosclerosis; CD4+ T cell; Immunometabolism; mTOR
    DOI:  https://doi.org/10.1007/s10557-023-07466-9
  2. J Leukoc Biol. 2023 May 16. pii: qiad054. [Epub ahead of print]
    PKM2 Promotes Pro-Inflammatory Macrophage Activation in Ankylosing Spondylitis.
    Weizhen Weng, Lian Gui, Yanli Zhang, Jingrong Chen, Weihang Zhu, Zhenguo Liang, Zhongming Wu, Yao Liang, Jiewen Xie, Qiujing Wei, Zetao Liao, Jieruo Gu, Yunfeng Pan, Yutong Jiang.
      Macrophages play a critical role in ankylosing spondylitis (AS) by promoting autoimmune tissue inflammation through various effector functions. The inflammatory potential of macrophages is highly influenced by their metabolic environment. Here, we demonstrate that glycolysis is linked to the pro-inflammatory activation of human blood monocyte-derived macrophages (MDMs) in AS. Specifically, AS macrophages produced excessive inflammation, including TNFα, IL1β, and IL23, and displayed an overactive status by exhibiting stronger co-stimulatory signals, such as CD80, CD86, and HLA-DR. Moreover, we found that patient-derived monocyte-derived M1 type macrophages (M1 macrophages) exhibited intensified glycolysis, as evidenced by higher extracellular acidification rate (ECAR). Upregulation of PKM2 and GLUT1 was observed in AS-derived monocytes and MDMs, especially in M1 macrophages, indicating glucose metabolic alteration in AS macrophages. To investigate the impact of glycolysis on macrophage inflammatory ability, we treated AS M1 macrophages with two inhibitors: 2-Deoxy-D-glucose (2-DG), a glycolysis inhibitor, and Shikonin, a PKM2 inhibitor. Both inhibitors reduced pro-inflammatory function and reversed the overactive status of AS macrophages, suggesting their potential utility in treating the disease. These data place PKM2 at the cross-talk between glucose metabolic changes and the activation of inflammatory macrophages in AS patients.
    Keywords:  Ankylosing spondylitis; PKM2; glycolysis; macrophage
    DOI:  https://doi.org/10.1093/jleuko/qiad054
  3. Nat Metab. 2023 May 15.
    Mitochondrial pyruvate carrier-mediated metabolism is dispensable for the classical activation of macrophages.
    Linyu Ran, Song Zhang, Guosheng Wang, Pei Zhao, Jiaxing Sun, Jiaqi Zhou, Haiyun Gan, Ryounghoon Jeon, Qiang Li, Joerg Herrmann, Feilong Wang.
      Glycolysis is essential for the classical activation of macrophages (M1), but how glycolytic pathway metabolites engage in this process remains to be elucidated. Glycolysis leads to production of pyruvate, which can be transported into the mitochondria by the mitochondrial pyruvate carrier (MPC) followed by utilization in the tricarboxylic acid cycle. Based on studies that used the MPC inhibitor UK5099, the mitochondrial route has been considered to be of significance for M1 activation. Using genetic approaches, here we show that the MPC is dispensable for metabolic reprogramming and activation of M1 macrophages. In addition, MPC depletion in myeloid cells has no impact on inflammatory responses and macrophage polarization toward the M1 phenotype in a mouse model of endotoxemia. While UK5099 reaches maximal MPC inhibitory capacity at approximately 2-5 μM, higher concentrations are required to inhibit inflammatory cytokine production in M1 and this is independent of MPC expression. Taken together, MPC-mediated metabolism is dispensable for the classical activation of macrophages and UK5099 inhibits inflammatory responses in M1 macrophages due to effects other than MPC inhibition.
    DOI:  https://doi.org/10.1038/s42255-023-00800-3
  4. Cancer Res. 2023 May 17. pii: CAN-22-3042. [Epub ahead of print]
    Metformin reprograms tryptophan metabolism to stimulate CD8+ T cell function in colorectal cancer.
    Xiaowen Huang, Tiantian Sun, Jilin Wang, Xialu Hong, Huimin Chen, Tingting Yan, Chengbei Zhou, Danfeng Sun, Chen Yang, TaChung Yu, Wenyu Su, Wan Du, Hua Xiong.
      Colorectal carcinogenesis coincides with immune cell dysfunction. Metformin has been reported to play a role in stimulating anti-tumor immunity, suggesting it could be used to overcome immunosuppression in colorectal cancer (CRC). Herein, using single-cell RNA sequencing, we showed that metformin remodels the immune landscape of CRC. In particular, metformin treatment expanded the proportion of CD8+ T cells and potentiated their function. Analysis of the metabolic activities of cells in the CRC tumor microenvironment (TME) at a single-cell resolution demonstrated that metformin reprogrammed tryptophan metabolism, which was reduced in CRC cells and increased in CD8+ T cells. Untreated CRC cells outcompeted CD8+ T cells for tryptophan, leading to impaired CD8+ T cell function. Metformin in turn reduced tryptophan uptake by CRC cells, thereby restoring tryptophan availability for CD8+ T cells and increasing their cytotoxicity. Metformin inhibited tryptophan uptake in CRC cells by downregulating MYC, which led to a reduction in the tryptophan transporter SLC7A5. This work highlights metformin as an essential regulator of T-cell antitumor immunity by reprogramming tryptophan metabolism, suggesting it could be a potential immunotherapeutic strategy for treating CRC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-3042
  5. Cell Rep. 2023 May 18. pii: S2211-1247(23)00533-8. [Epub ahead of print]42(5): 112522
    Candida auris uses metabolic strategies to escape and kill macrophages while avoiding robust activation of the NLRP3 inflammasome response.
    Harshini Weerasinghe, Claudia Simm, Tirta Mario Djajawi, Irma Tedja, Tricia L Lo, Daniel S Simpson, David Shasha, Naama Mizrahi, Françios A B Olivier, Mary Speir, Kate E Lawlor, Ronen Ben-Ami, Ana Traven.
      Metabolic adaptations regulate the response of macrophages to infection. The contributions of metabolism to macrophage interactions with the emerging fungal pathogen Candida auris are poorly understood. Here, we show that C. auris-infected macrophages undergo immunometabolic reprogramming and increase glycolysis but fail to activate a strong interleukin (IL)-1β cytokine response or curb C. auris growth. Further analysis shows that C. auris relies on its own metabolic capacity to escape from macrophages and proliferate in vivo. Furthermore, C. auris kills macrophages by triggering host metabolic stress through glucose starvation. However, despite causing macrophage cell death, C. auris does not trigger robust activation of the NLRP3 inflammasome. Consequently, inflammasome-dependent responses remain low throughout infection. Collectively, our findings show that C. auris uses metabolic regulation to eliminate macrophages while remaining immunologically silent to ensure its own survival. Thus, our data suggest that host and pathogen metabolism could represent therapeutic targets for C. auris infections.
    Keywords:  CP: Immunology; Candida auris; NLRP3 inflammasome; immunometabolism; innate immunity; macrophage
    DOI:  https://doi.org/10.1016/j.celrep.2023.112522
  6. Immunometabolism (Cobham). 2023 Apr;5(2): e00021
    A new frontier for fat: dietary palmitic acid induces innate immune memory.
    Amy L Seufert, Brooke A Napier.
      Dietary saturated fats have recently been appreciated for their ability to modify innate immune cell function, including monocytes, macrophages, and neutrophils. Many dietary saturated fatty acids (SFAs) embark on a unique pathway through the lymphatics following digestion, and this makes them intriguing candidates for inflammatory regulation during homeostasis and disease. Specifically, palmitic acid (PA) and diets enriched in PA have recently been implicated in driving innate immune memory in mice. PA has been shown to induce long-lasting hyper-inflammatory capacity against secondary microbial stimuli in vitro and in vivo, and PA-enriched diets alter the developmental trajectory of stem cell progenitors in the bone marrow. Perhaps the most relevant finding is the ability of exogenous PA to enhance clearance of fungal and bacterial burdens in mice; however, the same PA treatment enhances endotoxemia severity and mortality. Westernized countries are becoming increasingly dependent on SFA-enriched diets, and a deeper understanding of SFA regulation of innate immune memory is imperative in this pandemic era.
    Keywords:  CD36; ceramide; chylomicron; epigenetics; hematopoietic stem cell; inflammation; innate immune memory; ketogenic diet; macrophages; metabolism; monocytes; oleic acid; palmitic acid; priming; saturated fatty acid; toll-like receptor; trained immunity; western diet
    DOI:  https://doi.org/10.1097/IN9.0000000000000021
  7. Cell Metab. 2023 May 05. pii: S1550-4131(23)00171-7. [Epub ahead of print]
    Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment.
    Jie Cheng, Jinxin Yan, Ying Liu, Jiangzhou Shi, Haoyu Wang, Hanyang Zhou, Yinglin Zhou, Tongcun Zhang, Lina Zhao, Xianbin Meng, Haipeng Gong, Xinxiang Zhang, Haichuan Zhu, Peng Jiang.
      Metabolic alterations in the microenvironment significantly modulate tumor immunosensitivity, but the underlying mechanisms remain obscure. Here, we report that tumors depleted of fumarate hydratase (FH) exhibit inhibition of functional CD8+ T cell activation, expansion, and efficacy, with enhanced malignant proliferative capacity. Mechanistically, FH depletion in tumor cells accumulates fumarate in the tumor interstitial fluid, and increased fumarate can directly succinate ZAP70 at C96 and C102 and abrogate its activity in infiltrating CD8+ T cells, resulting in suppressed CD8+ T cell activation and anti-tumor immune responses in vitro and in vivo. Additionally, fumarate depletion by increasing FH expression strongly enhances the anti-tumor efficacy of anti-CD19 CAR T cells. Thus, these findings demonstrate a role for fumarate in controlling TCR signaling and suggest that fumarate accumulation in the tumor microenvironment (TME) is a metabolic barrier to CD8+ T cell anti-tumor function. And potentially, fumarate depletion could be an important strategy for tumor immunotherapy.
    Keywords:  CD8(+) T cell activation; FH; ZAP70; anti-tumor immune response; fumarate; fumarate hydrolase; succination; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cmet.2023.04.017
  8. Mucosal Immunol. 2023 May 11. pii: S1933-0219(23)00036-3. [Epub ahead of print]
    Butyrate regulates neutrophil homeostasis and impairs early antimicrobial activity in the lung.
    Anh Thu Dang, Christina Begka, Céline Pattaroni, Laura R Caley, R Andres Floto, Daniel G Peckham, Benjamin J Marsland.
      Short-chain fatty acids (SCFAs) are metabolites that are produced following microbial fermentation of dietary fibre and impact cell metabolism and anti-inflammatory pathways both locally in the gut and systemically. In preclinical models, administration of SCFAs, such as butyrate, ameliorates a range of inflammatory disease models including allergic airway inflammation, atopic dermatitis and influenza infection. Here we report the effect of butyrate on a bacteria-induced acute neutrophil-driven immune response in the airways. Butyrate impacted discrete aspects of haematopoiesis in the bone marrow resulting in the accumulation of immature neutrophils. During Pseudomonas aeruginosa infection, butyrate treatment led to enhanced mobilization of neutrophils to the lungs as a result of increased CXCR2 expression by lung macrophages. Despite this increase in granulocyte numbers and their enhanced phagocytic capacity, neutrophils failed to control early bacterial growth. Butyrate reduced expression of nicotinamide adenine dinucleotide phosphate (NADPH), oxidase complex components required for reactive oxygen species (ROS) production, and reduced secondary granule enzymes, culminating in impaired bactericidal activity. These data reveal that SCFAs tune neutrophil maturation and effector function in the bone marrow under homeostatic conditions, potentially to mitigate against excessive granulocyte-driven immunopathology, but their consequently restricted bactericidal capacity impairs early control of Pseudomonas infection.
    Keywords:  butyrate; hematopoiesis; lung; metabolite; neutrophil
    DOI:  https://doi.org/10.1016/j.mucimm.2023.05.005
  9. Cell Death Dis. 2023 May 18. 14(5): 332
    Butyrate limits inflammatory macrophage niche in NASH.
    Ankita Sarkar, Priya Mitra, Abhishake Lahiri, Tanusree Das, Jit Sarkar, Sandip Paul, Partha Chakrabarti.
      Immune cell infiltrations with lobular inflammation in the background of steatosis and deregulated gut-liver axis are the cardinal features of non-alcoholic steatohepatitis (NASH). An array of gut microbiota-derived metabolites including short-chain fatty acids (SCFA) multifariously modulates NASH pathogenesis. However, the molecular basis for the favorable impact of sodium butyrate (NaBu), a gut microbiota-derived SCFA, on the immunometabolic homeostasis in NASH remains elusive. We show that NaBu imparts a robust anti-inflammatory effect in lipopolysaccharide (LPS) stimulated or classically activated M1 polarized macrophages and in the diet-induced murine NASH model. Moreover, it impedes monocyte-derived inflammatory macrophage recruitment in liver parenchyma and induces apoptosis of proinflammatory liver macrophages (LM) in NASH livers. Mechanistically, by histone deactylase (HDAC) inhibition NaBu enhanced acetylation of canonical NF-κB subunit p65 along with its differential recruitment to the proinflammatory gene promoters independent of its nuclear translocation. NaBu-treated macrophages thus exhibit transcriptomic signatures that corroborate with a M2-like prohealing phenotype. NaBu quelled LPS-mediated catabolism and phagocytosis of macrophages, exhibited a differential secretome which consequently resulted in skewing toward prohealing phenotype and induced death of proinflammatory macrophages to abrogate metaflammation in vitro and in vivo. Thus NaBu could be a potential therapeutic as well as preventive agent in mitigating NASH.
    DOI:  https://doi.org/10.1038/s41419-023-05853-6
  10. Nat Metab. 2023 May 15.
    Inflamed macrophages sans mitochondrial pyruvate carrier?
    Laurent Yvan-Charvet, Edward Benjamin Thorp.
      
    DOI:  https://doi.org/10.1038/s42255-023-00789-9
  11. J Control Release. 2023 May 15. pii: S0168-3659(23)00327-9. [Epub ahead of print]358 541-554
    Succinate based polymers drive immunometabolism in dendritic cells to generate cancer immunotherapy.
    Sahil Inamdar, Abhirami P Suresh, Joslyn L Mangal, Nathan D Ng, Alison Sundem, Hoda Shokrollahzadeh Behbahani, Thomas E Rubino, Xiaojian Shi, Sharon T Loa, Jordan R Yaron, Taro Hitosugi, Matthew Green, Haiwei Gu, Marion Curtis, Abhinav P Acharya.
      Boosting the metabolism of immune cells while restricting cancer cell metabolism is challenging. Herein, we report that using biomaterials for the controlled delivery of succinate metabolite to phagocytic immune cells activates them and modulates their metabolism in the presence of metabolic inhibitors. In young immunocompetent mice, polymeric microparticles, with succinate incorporated in the backbone, induced strong pro-inflammatory anti-melanoma responses. Administration of poly(ethylene succinate) (PES MP)-based vaccines and glutaminase inhibitor to young immunocompetent mice with aggressive and large, established B16F10 melanoma tumors increased their survival three-fold, a result of increased cytotoxic T cells expressing RORγT (Tc17). Mechanistically, PES MPs directly modulate glutamine and glutamate metabolism, upregulate succinate receptor SUCNR1, activate antigen presenting cells through and HIF-1alpha, TNFa and TSLP-signaling pathways, and are dependent on alpha-ketoglutarate dehydrogenase for their activity, which demonstrates correlation of succinate delivery and these pathways. Overall, our findings suggest that immunometabolism-modifying PES MP strategies provide an approach for developing robust cancer immunotherapies.
    Keywords:  Cancer; Dendritic cells; Immune system; Metabolism; Succinate; Vaccine
    DOI:  https://doi.org/10.1016/j.jconrel.2023.05.014
  12. Front Immunol. 2023 ;14 1172931
    The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy.
    Shonik Ganjoo, Priti Gupta, Halil Ibrahim Corbali, Selene Nanez, Thomas S Riad, Lisa K Duong, Hampartsoum B Barsoumian, Fatemeh Masrorpour, Hong Jiang, James W Welsh, Maria Angelica Cortez.
      Immunotherapy has revolutionized cancer treatment and revitalized efforts to harness the power of the immune system to combat a variety of cancer types more effectively. However, low clinical response rates and differences in outcomes due to variations in the immune landscape among patients with cancer continue to be major limitations to immunotherapy. Recent efforts to improve responses to immunotherapy have focused on targeting cellular metabolism, as the metabolic characteristics of cancer cells can directly influence the activity and metabolism of immune cells, particularly T cells. Although the metabolic pathways of various cancer cells and T cells have been extensively reviewed, the intersections among these pathways, and their potential use as targets for improving responses to immune-checkpoint blockade therapies, are not completely understood. This review focuses on the interplay between tumor metabolites and T-cell dysfunction as well as the relationship between several T-cell metabolic patterns and T-cell activity/function in tumor immunology. Understanding these relationships could offer new avenues for improving responses to immunotherapy on a metabolic basis.
    Keywords:  T cell; cancer; immunotherapy; metabolism; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2023.1172931
  13. Cancer Lett. 2023 May 10. pii: S0304-3835(23)00174-X. [Epub ahead of print]564 216223
    Mitochondrial immune regulation and anti-tumor immunotherapy strategies targeting mitochondria.
    Rilan Bai, Jiuwei Cui.
      Cancer cells adapt to increasing energy and biosynthetic demands by reprogramming their metabolic pathways. Mitochondria are important organelles for the metabolic reprogramming of tumor cells. In addition to supplying energy, they play crucial roles in the survival, immune evasion, tumor progression, and treatment resistance of the hypoxic tumor microenvironment (TME) in cancer cells. With the development of the life sciences, scientists have gained an in-depth understanding of immunity, metabolism, and cancer, and numerous studies have emphasized that mitochondria are essential for tumor immune escape and the regulation of immune cell metabolism and activation. Moreover, recent evidence suggests that targeting the mitochondria-related pathway with anticancer drugs can initiate the killing of cancer cells by increasing the ability of cancer cells to be recognized by immune cells, tumor antigen presentation ability, and the anti-tumor function of immune cells. This review discusses the effects of mitochondrial morphology and function on the phenotype and function of immune cells under normal and TME conditions, the effects of mitochondrial changes in tumors and microenvironments on tumor immune escape and immune cell function, and finally focuses on the recent research progress and future challenges of novel anti-tumor immunotherapy strategies targeting mitochondria.
    Keywords:  Immune regulation; Immunotherapy; Mitochondria; Neoplasm; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2023.216223
  14. Biochem Biophys Res Commun. 2023 May 12. pii: S0006-291X(23)00579-X. [Epub ahead of print]667 25-33
    Aspirin loaded extracellular vesicles inhibit inflammation of macrophages via switching metabolic phenotype in periodontitis.
    Yuanyuan Shi, Ruijie Zhang, Ningning Da, Yiming Wang, Jianhua Yang, Bei Li, Xiaoning He.
       OBJECTIVES: Changes of macrophage in the local immune microenvironment of periodontitis cause alveolar bone resorption. This study aims to investigate the effect of a new drug delivery method of aspirin on the immune microenvironment of periodontitis to promote alveolar bone repair, and to explore mechanism of aspirin's effect on macrophage.
    METHODS: We isolated extracellular vesicles (EVs) from periodontal stem cells (PDLSCs) and loaded with aspirin by sonication, and then evaluated the treatment efficacy of aspirin-loaded vesicles (EVs-ASP) in periodontitis model in mice. In vitro, we explored the role of EVs-ASP in the regulation of LPS-induced macrophages. The underlying mechanism by which EVs-ASP regulates phenotypic remodeling of macrophages in periodontitis was further investigated.
    RESULTS: EVs-ASP inhibited the inflammatory environment of LPS-induced macrophage, and promoted anti-inflammatory macrophages formation both in vivo and in vitro, and reduced bone loss in periodontitis models. Moreover, EVs-ASP enhanced oxidative phosphorylation and suppressed glycolysis in macrophages.
    CONCLUSIONS: Consequently, EVs-ASP improves the periodontal immune microenvironment by enhancing oxidative phosphorylation (OXPHOS) in macrophages, resulting in a certain degree of regeneration of alveolar bone height. Our study provides a new potential strategy for bone repair in periodontitis therapy.
    Keywords:  Aspirin; Drug loading; Extracellular vesicles; Macrophages; Metabolic reprograming; Periodontitis
    DOI:  https://doi.org/10.1016/j.bbrc.2023.05.024
  15. Mol Cell. 2023 May 02. pii: S1097-2765(23)00288-5. [Epub ahead of print]
    LKB1 controls inflammatory potential through CRTC2-dependent histone acetylation.
    Shelby E Compton, Susan M Kitchen-Goosen, Lisa M DeCamp, Kin H Lau, Batsirai Mabvakure, Matthew Vos, Kelsey S Williams, Kwok-Kin Wong, Xiaobing Shi, Scott B Rothbart, Connie M Krawczyk, Russell G Jones.
      Deregulated inflammation is a critical feature driving the progression of tumors harboring mutations in the liver kinase B1 (LKB1), yet the mechanisms linking LKB1 mutations to deregulated inflammation remain undefined. Here, we identify deregulated signaling by CREB-regulated transcription coactivator 2 (CRTC2) as an epigenetic driver of inflammatory potential downstream of LKB1 loss. We demonstrate that LKB1 mutations sensitize both transformed and non-transformed cells to diverse inflammatory stimuli, promoting heightened cytokine and chemokine production. LKB1 loss triggers elevated CRTC2-CREB signaling downstream of the salt-inducible kinases (SIKs), increasing inflammatory gene expression in LKB1-deficient cells. Mechanistically, CRTC2 cooperates with the histone acetyltransferases CBP/p300 to deposit histone acetylation marks associated with active transcription (i.e., H3K27ac) at inflammatory gene loci, promoting cytokine expression. Together, our data reveal a previously undefined anti-inflammatory program, regulated by LKB1 and reinforced through CRTC2-dependent histone modification signaling, that links metabolic and epigenetic states to cell-intrinsic inflammatory potential.
    Keywords:  CREB; CREB-regulated transcription coactivator 2; CRTC2; H3K27; IL-1β; IL-6; LIF; LKB1; SIKs; cAMP response element binding protein; histone acetylation; inflammation; interleukin-6; leukemia inhibitory factor; liver kinase B1; salt-inducible kinases
    DOI:  https://doi.org/10.1016/j.molcel.2023.04.017
  16. Microbiol Spectr. 2023 May 16. e0429322
    Bacterial Lipoproteins Shift Cellular Metabolism to Glycolysis in Macrophages Causing Bone Erosion.
    Minh-Thu Nguyen, Zhicheng Hu, Majd Mohammad, Hannah Schöttler, Silke Niemann, Michelle Schultz, Katarzyna Barczyk-Kahlert, Tao Jin, Heiko Hayen, Mathias Herrmann.
      Belonging to a group of membrane proteins, bacterial lipoproteins (LPPs) are defined by a unique lipid structure at their N-terminus providing the anchor in the bacterial cell membrane. In Gram-positive bacteria, LPPs play a key role in host immune activation triggered through a Toll-like receptor 2 (TLR2)-mediated action resulting in macrophage stimulation and subsequent tissue damage demonstrated in in vivo experimental models. Yet the physiologic links between LPP activation, cytokine release, and any underlying switches in cellular metabolism remain unclear. In this study, we demonstrate that Staphylococcus aureus Lpl1 not only triggers cytokine production but also confers a shift toward fermentative metabolism in bone marrow-derived macrophages (BMDMs). Lpl1 consists of di- and tri-acylated LPP variants; hence, the synthetic P2C and P3C, mimicking di-and tri-acylated LPPs, were employed to reveal their effect on BMDMs. Compared to P3C, P2C was found to shift the metabolism of BMDMs and the human mature monocytic MonoMac 6 (MM6) cells more profoundly toward the fermentative pathway, as indicated by lactate accumulation, glucose consumption, pH reduction, and oxygen consumption. In vivo, P2C caused more severe joint inflammation, bone erosion, and lactate and malate accumulation than P3C. These observed P2C effects were completely abrogated in monocyte/macrophage-depleted mice. Taken together, these findings now solidly confirm the hypothesized link between LPP exposure, a macrophage metabolic shift toward fermentation, and ensuing bone destruction. IMPORTANCE Osteomyelitis caused by S. aureus is a severe infection of the bone, typically associated with severe bone function impairment, therapeutic failure, high morbidity, invalidity, and occasionally even death. The hallmark of staphylococcal osteomyelitis is the destruction of the cortical bone structures, yet the mechanisms contributing to this pathology are hitherto poorly understood. One bacterial membrane constituent found in all bacteria is bacterial lipoproteins (LPPs). Previously, we have shown that injection of purified S. aureus LPPs into wild-type mouse knee joints caused a TLR2-dependent chronic destructive arthritis but failed to elicit such effect in monocyte/macrophage-depleted mice. This observation stirred our interest in investigating the interaction of LPPs and macrophages and analyzing the underlying physiological mechanisms. This ascertainment of LPP-induced changes in the physiology of macrophages provides an important clue in the understanding of the mechanisms of bone disintegration, opening novel avenues to manage the course of S. aureus disease.
    Keywords:  Pam2Cys; Pam3Cys; bacterial lipoprotein; bone erosion; bone marrow-derived macrophages; cellular metabolism; lactate
    DOI:  https://doi.org/10.1128/spectrum.04293-22
  17. Ann Med. 2023 Dec;55(1): 1278-1289
    Role of PFKFB3-driven glycolysis in sepsis.
    Min Xiao, Dadong Liu, Yao Xu, Wenjian Mao, Weiqin Li.
      Sepsis is still the leading cause of death as a result of infection. Metabolic disorder plays a vital role in sepsis progression. Glycolysis intensification is the most characteristic feature of sepsis-related metabolic disorders. The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) is a critical engine that controls the rate of glycolysis. Recent studies have revealed that sepsis accelerates the rate of PFKFB3-driven glycolysis in different cells, including macrophages, neutrophils, endothelial cells and lung fibroblasts. Furthermore, increased PFKFB3 is closely related to the excessive inflammatory response and high mortality in sepsis. Interestingly, inhibition of PFKFB3 alone or in combination has also shown great potential in the treatment of sepsis. Therefore, an improved understanding of the canonical and noncanonical functions of PFKFB3 may provide a novel combinatorial therapeutic target for sepsis. This review summarizes the role of PFKFB3-driven glycolysis in the regulation of immunocyte activation and nonimmune cell damage in sepsis. In addition, we present recent achievements in the development of PFKFB3 drugs and discuss their potential therapeutic roles in sepsis.KEY MESSAGESepsis induces high expression of PFKFB3 in immunocytes and nonimmune cells, thereby enhancing cellular glycolytic flux.PFKFB3-driven glycolysis reprogramming is closely related to an excessive inflammatory response and high mortality in sepsis.Inhibition of PFKFB3 alone or in combination provides a novel combinatorial therapeutic target for sepsis.
    Keywords:  PFKFB3; glycolysis; sepsis
    DOI:  https://doi.org/10.1080/07853890.2023.2191217
  18. Front Immunol. 2023 ;14 1083072
    Real-time assessment of neutrophil metabolism and oxidative burst using extracellular flux analysis.
    Frances S Grudzinska, Alice Jasper, Elizabeth Sapey, David R Thickett, Claudio Mauro, Aaron Scott, Jonathan Barlow.
      Neutrophil responses are critical during inflammatory and infective events, and neutrophil dysregulation has been associated with poor patient outcomes. Immunometabolism is a rapidly growing field that has provided insights into cellular functions in health and disease. Neutrophils are highly glycolytic when activated, with inhibition of glycolysis associated with functional deficits. There is currently very limited data available assessing metabolism in neutrophils. Extracellular flux (XF) analysis assesses real time oxygen consumption and the rate of proton efflux in cells. This technology allows for the automated addition of inhibitors and stimulants to visualise the effect on metabolism. We describe optimised protocols for an XFe96 XF Analyser to (i) probe glycolysis in neutrophils under basal and stimulated conditions, (ii) probe phorbol 12-myristate 13-acetate induced oxidative burst, and (iii) highlight challenges of using XF technology to examine mitochondrial function in neutrophils. We provide an overview of how to analyze XF data and identify pitfalls of probing neutrophil metabolism with XF analysis. In summary we describe robust methods for assessing glycolysis and oxidative burst in human neutrophils and discuss the challenges around using this technique to assess mitochondrial respiration. XF technology is a powerful platform with a user-friendly interface and data analysis templates, however we suggest caution when assessing neutrophil mitochondrial respiration.
    Keywords:  extracellular flux analysis; glycolysis; immunometabolism; neutrophils; oxidative burst
    DOI:  https://doi.org/10.3389/fimmu.2023.1083072
  19. iScience. 2023 May 19. 26(5): 106683
    The eIF4EBP-eIF4E axis regulates CD4+ T cell differentiation through modulation of T cell activation and metabolism.
    Roman Istomine, Tho-Alfakar Al-Aubodah, Fernando Alvarez, Jacob A Smith, Carston Wagner, Ciriaco A Piccirillo.
      CD4+ T cells are critical for adaptive immunity, differentiating into distinct effector and regulatory subsets. Although the transcriptional programs underlying their differentiation are known, recent research has highlighted the importance of mRNA translation in determining protein abundance. We previously conducted genome-wide analysis of translation in CD4+ T cells revealing distinct translational signatures distinguishing these subsets, identifying eIF4E as a central differentially translated transcript. As eIF4E is vital for eukaryotic translation, we examined how altered eIF4E activity affected T cell function using mice lacking eIF4E-binding proteins (BP-/-). BP-/- effector T cells showed elevated Th1 responses ex vivo and upon viral challenge with enhanced Th1 differentiation observed in vitro. This was accompanied by increased TCR activation and elevated glycolytic activity. This study highlights how regulating T cell-intrinsic eIF4E activity can influence T cell activation and differentiation, suggesting the eIF4EBP-eIF4E axis as a potential therapeutic target for controlling aberrant T cell responses.
    Keywords:  Biological sciences; Immunology; Molecular biology; Proteomics
    DOI:  https://doi.org/10.1016/j.isci.2023.106683
  20. J Transl Med. 2023 May 19. 21(1): 331
    Inflammatory and interferon gene expression signatures in patients with mitochondrial disease.
    Emily B Warren, Eliza M Gordon-Lipkin, Foo Cheung, Jinguo Chen, Amrita Mukherjee, Richard Apps, John S Tsang, Jillian Jetmore, Melissa L Schlein, Shannon Kruk, Yuanjiu Lei, A Phillip West, Peter J McGuire.
       BACKGROUND: People with mitochondrial disease (MtD) are susceptible to metabolic decompensation and neurological symptom progression in response to an infection. Increasing evidence suggests that mitochondrial dysfunction may cause chronic inflammation, which may promote hyper-responsiveness to pathogens and neurodegeneration. We sought to examine transcriptional changes between MtD patients and healthy controls to identify common gene signatures of immune dysregulation in MtD.
    METHODS: We collected whole blood from a cohort of MtD patients and healthy controls and performed RNAseq to examine transcriptomic differences. We performed GSEA analyses to compare our findings against existing studies to identify commonly dysregulated pathways.
    RESULTS: Gene sets involved in inflammatory signaling, including type I interferons, interleukin-1β and antiviral responses, are enriched in MtD patients compared to controls. Monocyte and dendritic cell gene clusters are also enriched in MtD patients, while T cell and B cell gene sets are negatively enriched. The enrichment of antiviral response corresponds with an independent set of MELAS patients, and two mouse models of mtDNA dysfunction.
    CONCLUSIONS: Through the convergence of our results, we demonstrate translational evidence of systemic peripheral inflammation arising from MtD, predominantly through antiviral response gene sets. This provides key evidence linking mitochondrial dysfunction to inflammation, which may contribute to the pathogenesis of primary MtD and other chronic inflammatory disorders associated with mitochondrial dysfunction.
    Keywords:  Anti-viral signaling; Inflammation; Interferon; Mitochondrial disease; PBMCs
    DOI:  https://doi.org/10.1186/s12967-023-04180-w
  21. J Immunol. 2023 May 15. pii: ji2200615. [Epub ahead of print]
    Hippo Kinase MST1-Mediated Cell Metabolism Reprograms the Homeostasis and Differentiation of Granulocyte Progenitor Cells.
    Anna Jia, Yufei Wang, Qiuli Yang, Yuexin Wang, Yijin Huang, Yujing Bi, Guangwei Liu.
      The mechanism of the development of granulocyte progenitor cells into neutrophils under steady-state and pathological conditions remains unclear. In this study, our results showed that with the development of neutrophils from hematopoietic stem cells to mature neutrophils, the expression level of the Hippo kinase MST1 gradually increased. Mst1-specific deficiency in myeloid cells caused neutrophilia, with an expanded granulocytic compartment resulting from a cell-autonomous increase in the number of granulocyte-macrophage progenitors under steady-state conditions and during Listeria monocytogenes infection. Mechanistically, mTOR and HIF1α signaling are required for regulating the balance between glycolysis and succinate dehydrogenase-mediated oxidative phosphorylation, which is crucial for Mst1-/--induced proliferation of granulocyte-monocyte progenitors, lineage-decision factor C/EBPα expression, and granulopoiesis. HIF1α directly regulated C/EBPα promoter activities. Blocking mTOR and HIF1α or adjusting the balance between glycolysis and succinate dehydrogenase-mediated oxidative phosphorylation reversed the granulopoiesis induced by Mst1-/- under steady-state conditions or infection in mice. Thus, our findings identify a previously unrecognized interplay between Hippo kinase MST1 signaling and mTOR-HIF1α metabolic reprogramming in granulocyte progenitor cells that underlies granulopoiesis.
    DOI:  https://doi.org/10.4049/jimmunol.2200615
  22. J Virol. 2023 May 16. e0050623
    Rewiring of the Host Cell Metabolome and Lipidome during Lytic Gammaherpesvirus Infection Is Essential for Infectious-Virus Production.
    Sarah A Clark, Angie Vazquez, Kelsey Furiya, Madeleine K Splattstoesser, Abdullah K Bashmail, Haleigh Schwartz, Makaiya Russell, Shun-Je Bhark, Osvaldo K Moreno, Morgan McGovern, Eric R Owsley, Timothy A Nelson, Erica L Sanchez, Tracie Delgado.
      Oncogenic virus infections are estimated to cause ~15% of all cancers. Two prevalent human oncogenic viruses are members of the gammaherpesvirus family: Epstein-Barr virus (EBV) and Kaposi's sarcoma herpesvirus (KSHV). We use murine herpesvirus 68 (MHV-68), which shares significant homology with KSHV and EBV, as a model system to study gammaherpesvirus lytic replication. Viruses implement distinct metabolic programs to support their life cycle, such as increasing the supply of lipids, amino acids, and nucleotide materials necessary to replicate. Our data define the global changes in the host cell metabolome and lipidome during gammaherpesvirus lytic replication. Our metabolomics analysis found that MHV-68 lytic infection induces glycolysis, glutaminolysis, lipid metabolism, and nucleotide metabolism. We additionally observed an increase in glutamine consumption and glutamine dehydrogenase protein expression. While both glucose and glutamine starvation of host cells decreased viral titers, glutamine starvation led to a greater loss in virion production. Our lipidomics analysis revealed a peak in triacylglycerides early during infection and an increase in free fatty acids and diacylglyceride later in the viral life cycle. Furthermore, we observed an increase in the protein expression of multiple lipogenic enzymes during infection. Interestingly, pharmacological inhibitors of glycolysis or lipogenesis resulted in decreased infectious virus production. Taken together, these results illustrate the global alterations in host cell metabolism during lytic gammaherpesvirus infection, establish essential pathways for viral production, and recommend targeted mechanisms to block viral spread and treat viral induced tumors. IMPORTANCE Viruses are intracellular parasites which lack their own metabolism, so they must hijack host cell metabolic machinery in order to increase the production of energy, proteins, fats, and genetic material necessary to replicate. Using murine herpesvirus 68 (MHV-68) as a model system to understand how similar human gammaherpesviruses cause cancer, we profiled the metabolic changes that occur during lytic MHV-68 infection and replication. We found that MHV-68 infection of host cells increases glucose, glutamine, lipid, and nucleotide metabolic pathways. We also showed inhibition or starvation of glucose, glutamine, or lipid metabolic pathways results in an inhibition of virus production. Ultimately, targeting changes in host cell metabolism due to viral infection can be used to treat gammaherpesvirus-induced cancers and infections in humans.
    Keywords:  EBV; Epstein-Barr virus; KSHV; Kaposi’s sarcoma herpesvirus; MHV-68; gammaherpesvirus; herpesvirus; lipidomics; metabolism; metabolomics; murine herpesvirus 68
    DOI:  https://doi.org/10.1128/jvi.00506-23
  23. Nat Commun. 2023 May 15. 14(1): 2790
    Microbiota-assisted iron uptake promotes immune tolerance in the intestine.
    Lizhen Zhu, Geng Li, Zhixin Liang, Tuan Qi, Kui Deng, Jiancheng Yu, Yue Peng, Jusheng Zheng, Yan Song, Xing Chang.
      Iron deficiencies are the most common nonenteric syndromes observed in patients with inflammatory bowel disease, but little is known about their impacts on immune tolerance. Here we show that homeostasis of regulatory T cells in the intestine was dependent on high cellular iron levels, which were fostered by pentanoate, a short-chain fatty acid produced by intestinal microbiota. Iron deficiencies in Treg caused by the depletion of Transferrin receptor 1, a major iron transporter, result in the abrogation of Treg in the intestine and lethal autoimmune disease. Transferrin receptor 1 is required for differentiation of c-Maf+ Treg, major constituents of intestinal Treg. Mechanistically, iron enhances the translation of HIF-2α mRNA, and HIF-2α in turn induces c-Maf expression. Importantly, microbiota-produced pentanoate promotes iron uptake and Treg differentiation in the intestine. This subsequently restores immune tolerance and ameliorated iron deficiencies in mice with colitis. Our results thus reveal an association between nutrient uptake and immune tolerance in the intestine.
    DOI:  https://doi.org/10.1038/s41467-023-38444-2
  24. Microbes Infect. 2023 May 11. pii: S1286-4579(23)00053-9. [Epub ahead of print] 105150
    Glycolytic stress deteriorates 229E virulence to improve host defense response.
    Neha Kaushik, Paritosh Patel, Pradeep Bhartiya, Yungoh Shin, June Hyun Kim, Eun Ha Choi, Nagendra Kumar Kaushik.
      Viral infection treatment is a difficult task due to its complex structure and metabolism. Additionally, viruses can alter the metabolism of host cells, mutate, and readily adjust to harsh environments. Coronavirus stimulates glycolysis, weakens mitochondrial activity, and impairs infected cells. In this study, we investigated the efficacy of 2-DG in inhibiting coronavirus-induced metabolic processes and antiviral host defense systems, which have not been explored so far. 2-Deoxy-d-glucose (2-DG), a molecule restricting substrate availability, has recently gained attention as a potential antiviral drug. The results revealed that 229E human coronavirus promoted glycolysis, producing a significant increase in the concentration of fluorescent 2-NBDG, a glucose analog, particularly in the infected host cells. The addition of 2-DG decreased its viral replication and suppressed infection-induced cell death and cytopathic effects, thereby improving the antiviral host defense response. It was also observed that administration of low doses of 2-DG inhibited glucose uptake, indicating that 2-DG consumption in virus-infected host cells was mediated by high-affinity glucose transporters, whose levels were amplified upon coronavirus infection. Our findings indicated that 2-DG could be a potential drug to improve the host defense system in coronavirus-infected cells.
    Keywords:  antimetabolite; host antiviral response; metabolic reprogramming; spike protein reduction; viral inactivation
    DOI:  https://doi.org/10.1016/j.micinf.2023.105150
  25. Int Immunopharmacol. 2023 May 12. pii: S1567-5769(23)00578-7. [Epub ahead of print]120 110257
    Navigating the immunometabolic heterogeneity of B cells in murine hepatocellular carcinoma at single cell resolution.
    Xindong Zhao, Huanran Zhang, Yiru Han, Chengyu Fang, Jingqi Liu.
      Induction of antitumor immunity is critical for the therapeutic efficacy of hepatocellular carcinoma (HCC) immunotherapy. The cellular metabolic state underpins the effector function of immune cells, yet our understanding of the phenotypic and metabolic heterogeneity of B cells within HCC microenvironment is poorly developed. Herein, we investigated the composition, distribution, phenotype, function and metabolic profiles of B-cell subsets in HCC and adjacent liver tissues from an orthotopic HCC mouse model using single-cell RNA sequencing (scRNA-seq). Our results identified six B-cell clusters, which can be classified into plasma cells and activated and exhausted B cells according to marker expression, functional and temporal distribution. Exhausted B cells exhibited low metabolic activities and impaired effector functions. Activated B and plasma cells showed higher metabolic activity than exhausted B cells, but there were clear differences in their metabolic profiles. In addition, we found that the effector function of exhausted B cells was further diminished in HCC tissues compared with adjacent liver tissues, but their metabolic activity was significantly enhanced. Collectively, we comprehensively characterized the metabolic profile and alterations in B-cell subsets in HCC, which contributes to the understanding of B-cell immunology in HCC and lays the foundation for exploring novel targets in HCC immunotherapy.
    Keywords:  B cells; Hepatocellular carcinoma; Immunometabolism; single-cell RNA-sequencing
    DOI:  https://doi.org/10.1016/j.intimp.2023.110257
  26. Front Immunol. 2023 ;14 1146791
    CD38: an ecto-enzyme with functional diversity in T cells.
    Alip Ghosh, Arshi Khanam, Krishanu Ray, Poonam Mathur, Ananya Subramanian, Bhawna Poonia, Shyam Kottilil.
      CD38, a nicotinamide adenine dinucleotide (NAD)+ glycohydrolase, is considered an activation marker of T lymphocytes in humans that is highly expressed during certain chronic viral infections. T cells constitute a heterogeneous population; however, the expression and function of CD38 has been poorly defined in distinct T cell compartments. We investigated the expression and function of CD38 in naïve and effector T cell subsets in the peripheral blood mononuclear cells (PBMCs) from healthy donors and people with HIV (PWH) using flow cytometry. Further, we examined the impact of CD38 expression on intracellular NAD+ levels, mitochondrial function, and intracellular cytokine production in response to virus-specific peptide stimulation (HIV Group specific antigen; Gag). Naïve T cells from healthy donors showed remarkably higher levels of CD38 expression than those of effector cells with concomitant reduced intracellular NAD+ levels, decreased mitochondrial membrane potential and lower metabolic activity. Blockade of CD38 by a small molecule inhibitor, 78c, increased metabolic function, mitochondrial mass and mitochondrial membrane potential in the naïve T lymphocytes. PWH exhibited similar frequencies of CD38+ cells in the T cell subsets. However, CD38 expression increased on Gag-specific IFN-γ and TNF-α producing cell compartments among effector T cells. 78c treatment resulted in reduced cytokine production, indicating its distinct expression and functional profile in different T cell subsets. In summary, in naïve cells high CD38 expression reflects lower metabolic activity, while in effector cells it preferentially contributes to immunopathogenesis by increasing inflammatory cytokine production. Thus, CD38 may be considered as a therapeutic target in chronic viral infections to reduce ongoing immune activation.
    Keywords:  CD38; HIV; NAD+; T cells metabolism; mitochondrial function
    DOI:  https://doi.org/10.3389/fimmu.2023.1146791
  27. Bioeng Transl Med. 2023 May;8(3): e10471
    An immunometabolic patch facilitates mesenchymal stromal/stem cell therapy for myocardial infarction through a macrophage-dependent mechanism.
    Weizhang Xiao, Ming Chen, Wenjing Zhou, Liang Ding, Ziying Yang, Lianbo Shao, Jingjing Li, Weiqian Chen, Zhenya Shen.
      Mesenchymal stromal/stem cells (MSCs) have emerged as a promising approach against myocardial infarction. Due to hostile hyperinflammation, however, poor retention of transplanted cells seriously impedes their clinical applications. Proinflammatory M1 macrophages, which rely on glycolysis as their main energy source, aggravate hyperinflammatory response and cardiac injury in ischemic region. Here, we showed that the administration of an inhibitor of glycolysis, 2-deoxy-d-glucose (2-DG), blocked the hyperinflammatory response within the ischemic myocardium and subsequently extended effective retention of transplanted MSCs. Mechanistically, 2-DG blocked the proinflammatory polarization of macrophages and suppressed the production of inflammatory cytokines. Selective macrophage depletion abrogated this curative effect. Finally, to avoid potential organ toxicity caused by systemic inhibition of glycolysis, we developed a novel chitosan/gelatin-based 2-DG patch that directly adhered to the infarcted region and facilitated MSC-mediated cardiac healing with undetectable side effects. This study pioneered the application of an immunometabolic patch in MSC-based therapy and provided insights into the therapeutic mechanism and advantages of this innovative biomaterial.
    Keywords:  glycolysis; immunometabolism; macrophage; mesenchymal stromal/stem cells; myocardial infarction; patch
    DOI:  https://doi.org/10.1002/btm2.10471
  28. iScience. 2023 May 19. 26(5): 106630
    Natural γδT17 cell development and functional acquisition is governed by the mTORC2-c-Maf-controlled mitochondrial fission pathway.
    Yunke Wang, Hui Qin, Yihua Cai, Xu Chen, Hong Li, Diego Elias Montoya-Durango, Chuanlin Ding, Xiaoling Hu, Julia H Chariker, Harshini Sarojini, Sufan Chien, Eric C Rouchka, Huang-Ge Zhang, Jie Zheng, Fuming Qiu, Jun Yan.
      Natural IL-17-producing γδ T cells (γδT17 cells) are unconventional innate-like T cells that undergo functional programming in the fetal thymus. However, the intrinsic metabolic mechanisms of γδT17 cell development remain undefined. Here, we demonstrate that mTORC2, not mTORC1, selectively controls the functional fate commitment of γδT17 cells through regulating transcription factor c-Maf expression. scRNA-seq data suggest that fetal and adult γδT17 cells predominately utilize mitochondrial metabolism. mTORC2 deficiency results in impaired Drp1-mediated mitochondrial fission and mitochondrial dysfunction characterized by mitochondrial membrane potential (ΔΨm) loss, reduced oxidative phosphorylation (OXPHOS), and subsequent ATP depletion. Treatment with the Drp1 inhibitor Mdivi-1 alleviates imiquimod-induced skin inflammation. Reconstitution of intracellular ATP levels by ATP-encapsulated liposome completely rescues γδT17 defect caused by mTORC2 deficiency, revealing the fundamental role of metabolite ATP in γδT17 development. These results provide an in-depth insight into the intrinsic link between the mitochondrial OXPHOS pathway and γδT17 thymic programming and functional acquisition.
    Keywords:  Cell biology; Immunology; Molecular biology; Molecular mechanism of gene regulation
    DOI:  https://doi.org/10.1016/j.isci.2023.106630
  29. Acta Biochim Biophys Sin (Shanghai). 2023 May 15.
    Monomethyl fumarate prevents alloimmune rejection in mouse heart transplantation by inducing tolerogenic dendritic cells.
    Juntao Chen, Yirui Cao, Ouyang Jia, Xuanchuan Wang, Yongsheng Luo, Yin Celeste Cheuk, Tongyu Zhu, Dong Zhu, Yi Zhang, Jina Wang.
      Dendritic cells (DCs) are important targets for eliciting allograft rejection after transplantation. Previous studies have demonstrated that metabolic reprogramming of DCs can transform their immune functions and induce their differentiation into tolerogenic DCs. In this study, we aim to investigate the protective effects and mechanisms of monomethyl fumarate (MMF), a bioactive metabolite of fumaric acid esters, in a mouse model of allogeneic heart transplantation. Bone marrow-derived DCs are harvested and treated with MMF to determine the impact of MMF on the phenotype and immunosuppressive function of DCs by flow cytometry and T-cell proliferation assays. RNA sequencing and Seahorse analyses are performed for mature DCs and MMF-treated DCs (MMF-DCs) to investigate the underlying mechanism. Our results show that MMF prolongs the survival time of heart grafts and inhibits the activation of DCs in vivo. MMF-DCs exhibit a tolerogenic phenotype and function in vitro. RNA sequencing and Seahorse analyses reveal that MMF activates the Nrf2 pathway and mediates metabolic reprogramming. Additionally, MMF-DC infusion prolongs cardiac allograft survival, induces regulatory T cells, and inhibits T-cell activation. MMF prevents allograft rejection in mouse heart transplantation by inducing tolerogenic DCs.
    Keywords:  Nrf2; dendritic cell; heart transplantation; immune tolerance; metabolic reprogramming; monomethyl fumarate
    DOI:  https://doi.org/10.3724/abbs.2023088
  30. J Immunol. 2023 Jun 01. 210(11): 1629-1639
    Immunomodulatory Effects of Microbiota-Derived Short-Chain Fatty Acids in Autoimmune Liver Diseases.
    Weici Zhang, Charles R Mackay, M Eric Gershwin.
      Nonpathogenic commensal microbiota and their metabolites and components are essential to maintain a tolerogenic environment and promote beneficial health effects. The metabolic environment critically impacts the outcome of immune responses and likely impacts autoimmune and allergic responses. Short-chain fatty acids (SCFAs) are the main metabolites produced by microbial fermentation in the gut. Given the high concentration of SCFAs in the gut and portal vein and their broad immune regulatory functions, SCFAs significantly influence immune tolerance and gut-liver immunity. Alterations of SCFA-producing bacteria and SCFAs have been identified in a multitude of inflammatory diseases. These data have particular significance in primary biliary cholangitis, primary sclerosing cholangitis, and autoimmune hepatitis because of the close proximity of the liver to the gut. In this focused review, we provide an update on the immunologic consequences of SCFA-producing microbiota and in particular on three dominant SCFAs in autoimmune liver diseases.
    DOI:  https://doi.org/10.4049/jimmunol.2300016
  31. Front Immunol. 2023 ;14 1181697
    Integrative single-cell RNA sequencing and metabolomics decipher the imbalanced lipid-metabolism in maladaptive immune responses during sepsis.
    Han She, Lei Tan, Yi Wang, Yuanlin Du, Yuanqun Zhou, Jun Zhang, Yunxia Du, Ningke Guo, Zhengbin Wu, Qinghui Li, Daiqin Bao, Qingxiang Mao, Yi Hu, Liangming Liu, Tao Li.
       Background: To identify differentially expressed lipid metabolism-related genes (DE-LMRGs) responsible for immune dysfunction in sepsis.
    Methods: The lipid metabolism-related hub genes were screened using machine learning algorithms, and the immune cell infiltration of these hub genes were assessed by CIBERSORT and Single-sample GSEA. Next, the immune function of these hub genes at the single-cell level were validated by comparing multiregional immune landscapes between septic patients (SP) and healthy control (HC). Then, the support vector machine-recursive feature elimination (SVM-RFE) algorithm was conducted to compare the significantly altered metabolites critical to hub genes between SP and HC. Furthermore, the role of the key hub gene was verified in sepsis rats and LPS-induced cardiomyocytes, respectively.
    Results: A total of 508 DE-LMRGs were identified between SP and HC, and 5 hub genes relevant to lipid metabolism (MAPK14, EPHX2, BMX, FCER1A, and PAFAH2) were screened. Then, we found an immunosuppressive microenvironment in sepsis. The role of hub genes in immune cells was further confirmed by the single-cell RNA landscape. Moreover, significantly altered metabolites were mainly enriched in lipid metabolism-related signaling pathways and were associated with MAPK14. Finally, inhibiting MAPK14 decreased the levels of inflammatory cytokines and improved the survival and myocardial injury of sepsis.
    Conclusion: The lipid metabolism-related hub genes may have great potential in prognosis prediction and precise treatment for sepsis patients.
    Keywords:  lipid-metabolism; machine learning algorithm; metabolomics; sepsis; single-cell RNA sequencing
    DOI:  https://doi.org/10.3389/fimmu.2023.1181697
  32. Nutrition. 2023 Apr 09. pii: S0899-9007(23)00085-0. [Epub ahead of print]111 112055
    Oral ω-3 PUFA supplementation modulates inflammation in adipose tissue depots in morbidly obese women: A randomized trial.
    Nathalie Bakker, Meave Hickey, Rebecca Shams, Cristobal F Rivera, John Vlahos, Huib A Cense, Ahmet Demirkiran, Bhama Ramkhelawon, Alexander Pj Houdijk.
       OBJECTIVES: Obesity is characterized by local and systemic low-grade inflammatory responses. Adipose tissue macrophages (ATM) play decisive roles in inflammation, insulin signaling, and various metabolic dysfunctions. Diets enriched with ω-3 polyunsaturated fatty acids (PUFAs) have been shown to improve health and mitigate pathologic conditions. However, the effects of ω-3 PUFA on adipose tissue inflammation, ATM number, and phenotype are poorly defined in human obesity. The aim of this study was to examine differences in expression of metabolic-inflammatory markers in omental, mesenteric, and subcutaneous fat depots of obese women supplemented with ω-3 PUFAs for 4 wk compared with a low-calorie diet before bariatric surgery.
    METHODS: In a randomized controlled trial, inflammatory markers in the abdominal adipose tissue and the systemic response in obese women were studied. Patients were treated with a 2-wk low-calorie diet (LCD) or a 4-wk ω-3 PUFA-enriched diet (920 mg eicosapentaenoic acid, 760 mg docosahexaenoic acid daily) before laparoscopic bypass surgery. Omental, mesenteric, and subcutaneous adipose tissue biopsies were collected during surgery and analyzed for quantity and phenotype of ATMs, and profiled for adipokines, cytokines, and signal transduction molecules.
    RESULTS: The chronic inflammatory state characterized by ATM markers was mostly improved by ω-3 PUFAs in visceral adipose tissue. We observed a decreased expression of CD45, CCL2, and CD68, indicating a lower inflammatory state. In patients with type 2 diabetes, ω-3 PUFAs lowered the expression of Netrin-1.
    CONCLUSIONS: Compared with an LCD, a diet enriched with ω-3 PUFAs influences the inflammatory state in different adipose tissue depots, by affecting markers of adipose tissue inflammation, macrophage phenotype, and retention. However, this was not reflected in clinical parameters such as insulin resistance and inflammatory cytokines. Subcutaneous adipose tissue and visceral adipose tissue have different responses to an LCD or a ω-3 PUFA-enriched diet. The presence of diabetes modifies the expression of inflammatory markers.
    Keywords:  Adipose tissue; Inflammation; Morbid obesity; ω-3 fatty acids
    DOI:  https://doi.org/10.1016/j.nut.2023.112055
  33. Front Immunol. 2023 ;14 1159831
    Impaired alveolar macrophage 11β-hydroxysteroid dehydrogenase type 1 reductase activity contributes to increased pulmonary inflammation and mortality in sepsis-related ARDS.
    Rahul Y Mahida, Siân Lax, Christopher R Bassford, Aaron Scott, Dhruv Parekh, Rowan S Hardy, Babu Naidu, Michael A Matthay, Paul M Stewart, Mark C Cooper, Gavin D Perkins, David R Thickett.
       Background: Acute Respiratory Distress Syndrome (ARDS) is a devastating pulmonary inflammatory disorder, commonly precipitated by sepsis. Glucocorticoids are immunomodulatory steroids that can suppress inflammation. Their anti-inflammatory properties within tissues are influenced by their pre-receptor metabolism and amplification from inactive precursors by 11β-hydroxysteroid dehydrogenase type-1 (HSD-1). We hypothesised that in sepsis-related ARDS, alveolar macrophage (AM) HSD-1 activity and glucocorticoid activation are impaired, and associated with greater inflammatory injury and worse outcomes.
    Methods: We analysed broncho-alveolar lavage (BAL) and circulating glucocorticoid levels, AM HSD-1 reductase activity and Receptor for Advanced Glycation End-products (RAGE) levels in two cohorts of critically ill sepsis patients, with and without ARDS. AM HSD-1 reductase activity was also measured in lobectomy patients. We assessed inflammatory injury parameters in models of lung injury and sepsis in HSD-1 knockout (KO) and wild type (WT) mice.
    Results: No difference in serum and BAL cortisol: cortisone ratios are shown between sepsis patients with and without ARDS. Across all sepsis patients, there is no association between BAL cortisol: cortisone ratio and 30-day mortality. However, AM HSD-1 reductase activity is impaired in patients with sepsis-related ARDS, compared to sepsis patients without ARDS and lobectomy patients (0.075 v 0.882 v 0.967 pM/hr/106 AMs, p=0.004). Across all sepsis patients (with and without ARDS), impaired AM HSD-1 reductase activity is associated with defective efferocytosis (r=0.804, p=0.008) and increased 30-day mortality. AM HSD-1 reductase activity negatively correlates with BAL RAGE in sepsis patients with ARDS (r=-0.427, p=0.017). Following intra-tracheal lipopolysaccharide (IT-LPS) injury, HSD-1 KO mice demonstrate increased alveolar neutrophil infiltration, apoptotic neutrophil accumulation, alveolar protein permeability and BAL RAGE concentrations compared to WT mice. Caecal Ligation and Puncture (CLP) injury in HSD-1 KO mice results in greater peritoneal apoptotic neutrophil accumulation compared to WT mice.
    Conclusions: AM HSD-1 reductase activity does not shape total BAL and serum cortisol: cortisone ratios, however impaired HSD-1 autocrine signalling renders AMs insensitive to the anti-inflammatory effects of local glucocorticoids. This contributes to the decreased efferocytosis, increased BAL RAGE concentrations and mortality seen in sepsis-related ARDS. Upregulation of alveolar HSD-1 activity could restore AM function and improve clinical outcomes in these patients.
    Keywords:  11b-hydroxysteroid dehydrogenase type-1; ARDS (acute respiratory disease syndrome); alveolar macrophage (AM); autocrine action; sepsis
    DOI:  https://doi.org/10.3389/fimmu.2023.1159831
  34. PLoS Biol. 2023 May 19. 21(5): e3002125
    Systems biology elucidates the distinctive metabolic niche filled by the human gut microbe Eggerthella lenta.
    Cecilia Noecker, Juan Sanchez, Jordan E Bisanz, Veronica Escalante, Margaret Alexander, Kai Trepka, Almut Heinken, Yuanyuan Liu, Dylan Dodd, Ines Thiele, Brian C DeFelice, Peter J Turnbaugh.
      Human gut bacteria perform diverse metabolic functions with consequences for host health. The prevalent and disease-linked Actinobacterium Eggerthella lenta performs several unusual chemical transformations, but it does not metabolize sugars and its core growth strategy remains unclear. To obtain a comprehensive view of the metabolic network of E. lenta, we generated several complementary resources: defined culture media, metabolomics profiles of strain isolates, and a curated genome-scale metabolic reconstruction. Stable isotope-resolved metabolomics revealed that E. lenta uses acetate as a key carbon source while catabolizing arginine to generate ATP, traits which could be recapitulated in silico by our updated metabolic model. We compared these in vitro findings with metabolite shifts observed in E. lenta-colonized gnotobiotic mice, identifying shared signatures across environments and highlighting catabolism of the host signaling metabolite agmatine as an alternative energy pathway. Together, our results elucidate a distinctive metabolic niche filled by E. lenta in the gut ecosystem. Our culture media formulations, atlas of metabolomics data, and genome-scale metabolic reconstructions form a freely available collection of resources to support further study of the biology of this prevalent gut bacterium.
    DOI:  https://doi.org/10.1371/journal.pbio.3002125
  35. Mol Immunol. 2023 May 11. pii: S0161-5890(23)00098-6. [Epub ahead of print]158 91-102
    1,5-AG suppresses pro-inflammatory polarization of macrophages and promotes the survival of B-ALL in vitro by upregulating CXCL14.
    Min Wu, Shule Zhang, Cheng Chi, Huasu Zhu, Huixian Ma, Linghong Liu, Qing Shi, Dong Li, Xiuli Ju.
      B-lineage acute lymphoblastic leukemia (B-ALL) is one of the most common malignancies in children. Despite advances in treatment, the role of the tumor microenvironment in B-ALL remains poorly understood. Among the key components of the immune microenvironment, macrophages play a critical role in the progression of the disease. However, recent research has suggested that abnormal metabolites may influence the function of macrophages, altering the immune microenvironment and promoting tumor growth. Our previous non-targeted metabolomic detection revealed that the metabolite 1,5-anhydroglucitol (1,5-AG) level in the peripheral blood of children newly diagnosed with B-ALL was significantly elevated. Except for its direct influence on leukemia cells, the effect of 1,5-AG on macrophages is still unclear. Herein, we demonstrated new potential therapeutic targets by focusing on the effect of 1,5-AG on macrophages. We used polarization-induced macrophages to determine how 1,5-AG acted on M1-like polarization and screened out the target gene CXCL14 via transcriptome sequencing. Furthermore, we constructed CXCL14 knocked-down macrophages and a macrophage-leukemia cell coculture model to validate the interaction between macrophages and leukemia cells. We discovered that 1,5-AG upregulated the CXCL14 expression, thereby inhibiting M1-like polarization. CXCL14 knockdown restored the M1-like polarization of macrophages and induced leukemia cells apoptosis in the coculture model. Our findings offer new possibilities for the genetic engineering of human macrophages to rehabilitate their immune activity against B-ALL in cancer immunotherapy.
    Keywords:  B-ALL; CXCL14; Immunosuppression; Macrophages; Metabolism
    DOI:  https://doi.org/10.1016/j.molimm.2023.05.003
  36. Front Cell Infect Microbiol. 2023 ;13 1190602
    Fucose ameliorates the proinflammatory property of Fusobacterium nucleatum in colitis via altering its metabolism.
    Caihan Duan, Lingzhi Hou, Xiaohua Deng, Junhao Wu, Wei Qian, Chaoqun Han, Xiaohua Hou.
       Introduction: Previous studies reported that fucose plays a protective role in inhibiting pathogens. Fusobacterium nucleatum (Fn) was recently found to promote the progression of colitis. However, the effects of fucose on Fn are poorly understood. This study aimed to explore whether fucose could ameliorate the proinflammatory property of Fn in colitis and the underlying mechanisms.
    Methods: To validate our hypothesis, mice were administrated with Fn and fucose-treated Fn (Fnf) before dextran sulfate sodium (DSS) treatment to establish Fn related colitis model. The metabolism variation of Fn was detected by metabolomic analysis. To verify the effects of bacterial metabolites on intestinal epithelial cells (IECs), Caco-2 cells were treated with bacterial supernatant.
    Results: More severe inflammation, intestinal barrier damage, autophagy block, and apoptosis in the colon were noted in DSS mice that were administrated with Fn or Fnf. However, the severity degree in Fnf+DSS group was less compared to Fn+DSS group. Metabolic pathways of Fn were altered after fucose treatment and proinflammatory metabolites were decreased. The supernatant of Fnf induced a lower level of inflammation than Fn in Caco-2 cells. One of the decreased metabolites, homocysteine thiolactone (HT), was proven to induce inflammatory effects in Caco-2 cells.
    Discussion: In conclusion, fucose ameliorates the proinflammatory property of Fn via altering its metabolism and these findings provide evidence for the application of fucose as functional food or prebiotic in the treatment of Fn related colitis.
    Keywords:  Fusobacterium nucleatum; fucose; inflammatory bowel disease; intestinal epithelial cell; metabolism
    DOI:  https://doi.org/10.3389/fcimb.2023.1190602
  37. Pharmacol Ther. 2023 May 16. pii: S0163-7258(23)00105-5. [Epub ahead of print] 108441
    Targeting mitochondrial function in macrophages: A novel treatment strategy for atherosclerotic cardiovascular disease?
    Pierre-Hadrien Becker, Patrice Thérond, Pauline Gaignard.
      Atherosclerotic cardiovascular disease is a major cause of morbidity and mortality due to chronic arterial injury caused by hyperlipidemia, hypertension, inflammation and oxidative stress. Recent studies have shown that the progression of this disease is associated with mitochondrial dysfunction and with the accumulation of mitochondrial alterations within macrophages of atherosclerotic plaques. These alterations contribute to processes of inflammation and oxidative stress. Among the many players involved, macrophages play a pivotal role in atherogenesis as they can exert both beneficial and deleterious effects due to their anti- and pro-inflammatory properties. Their atheroprotective functions, such as cholesterol efflux and efferocytosis, as well as the maintenance of their polarization towards an anti-inflammatory state, are particularly dependent on mitochondrial metabolism. Moreover, in vitro studies have demonstrated deleterious effects of oxidized LDL on macrophage mitochondrial function, resulting in a switch to a pro-inflammatory state and to a potential loss of atheroprotective capacity. Therefore, preservation of mitochondrial function is now considered a legitimate therapeutic strategy. This review focuses on the potential therapeutic strategies that could improve the mitochondrial function of macrophages, enabling them to maintain their atheroprotective capacity. These emerging therapies could play a valuable role in counteracting the progression of atherosclerotic lesions and possibly inducing their regression.
    Keywords:  Atherosclerotic cardiovascular disease; Macrophages; Mitochondria; Mitophagy; Oxidative stress; Oxidized LDL
    DOI:  https://doi.org/10.1016/j.pharmthera.2023.108441
  38. Front Immunol. 2023 ;14 1161676
    Galanin ameliorates liver inflammation and fibrosis in mice by activating AMPK/ACC signaling and modifying macrophage inflammatory phenotype.
    Lingnan He, Chao Huang, Hui Wang, Naibin Yang, Jianbin Zhang, Leiming Xu, Ting Gu, Zhenghong Li, Yuanwen Chen.
       Background and aims: Galanin is a naturally occurring peptide that plays a critical role in regulating inflammation and energy metabolism, with expression in the liver. The exact involvement of galanin in non-alcoholic fatty liver disease and related fibrosis remains controversial.
    Methods: The effects of subcutaneously administered galanin were studied in mice with non-alcoholic steatohepatitis (NASH) induced by a high-fat and high-cholesterol diet for 8 weeks, and in mice with liver fibrosis induced by CCl4 for 7 weeks. The underlying mechanism was also studied in vitro on murine macrophage cells (J774A.1 and RAW264.7).
    Results: Galanin reduced inflammation, CD68-positive cell count, MCP-1 level, and mRNA levels of inflammation-related genes in the liver of NASH mice. It also mitigated liver injury and fibrosis caused by CCl4. In vitro, galanin had anti-inflammatory effects on murine macrophages, including reduced phagocytosis and intracellular reactive oxygen species (ROS). Galanin also activated AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling.
    Conclusion: Galanin ameliorates liver inflammation and fibrosis in mice, potentially by modifying macrophage inflammatory phenotype and activating AMPK/ACC signaling.
    Keywords:  AMPK; galanin; liver fibrosis; macrophage; non-alcoholic steatohepatitis
    DOI:  https://doi.org/10.3389/fimmu.2023.1161676
  39. Hepatol Int. 2023 May 19.
    Targeting NAD+ metabolism of hepatocellular carcinoma cells by lenvatinib promotes M2 macrophages reverse polarization, suppressing the HCC progression.
    Qingcan Sun, Mengying Shen, Subin Zhu, Yanxia Liao, Dongyan Zhang, Jingyuan Sun, Zeqin Guo, Leyuan Wu, Lushan Xiao, Li Liu.
       BACKGROUND: Lowered nicotinamide adenine dinucleotide (NAD+) levels in tumor cells drive tumor hyperprogression during immunotherapy, and its restoration activates immune cells. However, the effect of lenvatinib, a first-line treatment for unresectable hepatocellular carcinoma (HCC), on NAD+ metabolism in HCC cells, and the metabolite crosstalk between HCC and immune cells after targeting NAD+ metabolism of HCC cells remain unelucidated.
    METHODS: Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and ultra-high-performance liquid chromatography multiple reaction monitoring-mass spectrometry (UHPLC-MRM-MS) were used to detect and validate differential metabolites. RNA sequencing was used to explore mRNA expression in macrophages and HCC cells. HCC mouse models were used to validate the effects of lenvatinib on immune cells and NAD+ metabolism. The macrophage properties were elucidated using cell proliferation, apoptosis, and co-culture assays. In silico structural analysis and interaction assays were used to determine whether lenvatinib targets tet methylcytosine dioxygenase 2 (TET2). Flow cytometry was performed to assess changes in immune cells.
    RESULTS: Lenvatinib targeted TET2 to synthesize and increase NAD+ levels, thereby inhibiting decomposition in HCC cells. NAD+ salvage increased lenvatinib-induced apoptosis of HCC cells. Lenvatinib also induced CD8+ T cells and M1 macrophages infiltration in vivo. And lenvatinib suppressed niacinamide, 5-Hydroxy-L-tryptophan and quinoline secretion of HCC cells, and increased hypoxanthine secretion, which contributed to proliferation, migration and polarization function of macrophages. Consequently, lenvatinib targeted NAD+ metabolism and elevated HCC-derived hypoxanthine to enhance the macrophages polarization from M2 to M1. Glycosaminoglycan binding disorder and positive regulation of cytosolic calcium ion concentration were characteristic features of the reverse polarization.
    CONCLUSIONS: Targeting HCC cells NAD+ metabolism by lenvatinib-TET2 pathway drives metabolite crosstalk, leading to M2 macrophages reverse polarization, thereby suppressing HCC progression. Collectively, these novel insights highlight the role of lenvatinib or its combination therapies as promising therapeutic alternatives for HCC patients with low NAD+ levels or high TET2 levels.
    Keywords:  Hepatocellular carcinoma; Lenvatinib; Macrophage polarization; NAD+ metabolism; TET2
    DOI:  https://doi.org/10.1007/s12072-023-10544-7
  40. Aging (Albany NY). 2023 May 02. 15
    A novel methionine metabolism-related signature predicts prognosis and immunotherapy response in lung adenocarcinoma.
    Qing-Hua Chang, Yuan-Cui Zhang, Dong-Ying Zhang, Ting Mao, Ran Chang, Nan Wang, Yun Ye, Zi-Jun Xu.
      Recent research revealed methionine metabolism as a key mediator of tumor initiation and immune evasion. However, the relationship between methionine metabolism and tumor microenvironment (TME) in lung adenocarcinoma (LUAD) remains unknown. Here, we comprehensively analyzed the genomic alterations, expression patterns, and prognostic values of 68 methionine-related regulators (MRGs) in LUAD. We found that most MRGs were highly prognostic based on 30 datasets including 5024 LUAD patients. Three distinct MRG modification patterns were identified, which showed significant differences in clinical outcomes and TME characteristics: The C2 subtype was characterized by higher immune score, while the C3 subtype had more malignant cells and worse survival. We developed a MethScore to measure the level of methionine metabolism in LUAD. MethScore was positively correlated with T-cell dysfunction and tumor-associated macrophages (TAMs), indicating a dysfunctional TME phenotype in the high MethScore group. In addition, two immunotherapy cohorts confirmed that patients with a lower MethScore exhibited significant clinical benefits. Our study highlights the important role of methionine metabolism in modeling the TME. Evaluating methionine modification patterns will enhance our understanding of TME characteristics and can guide more effective immunotherapy strategies.
    Keywords:  immunotherapy; lung adenocarcinoma; methionine metabolism; molecular subtype; tumor microenvironment
    DOI:  https://doi.org/10.18632/aging.204687
  41. Cytotherapy. 2023 May 18. pii: S1465-3249(23)00104-4. [Epub ahead of print]
    Metabolic reprogramming of myeloid-derived suppressor cells in the context of organ transplantation.
    Jasper Iske, Yu Cao, Maximilian J Roesel, Zhongyang Shen, Yeqi Nian.
      Myeloid-derived suppressor cells (MDSCs) are naturally occurring leukocytes that develop from immature myeloid cells under inflammatory conditions that were discovered initially in the context of tumor immunity. Because of their robust immune inhibitory activities, there has been growing interest in MDSC-based cellular therapies for transplant tolerance induction. Indeed, various pre-clinical studies have introduced in vivo expansion or adoptive transfer of MDSC as a promising therapeutic strategy leading to a profound extension of allograft survival due to suppression of alloreactive T cells. However, several limitations of cellular therapies using MDSCs remain to be addressed, including their heterogeneous nature and limited expansion capacity. Metabolic reprogramming plays a crucial role for differentiation, proliferation and effector function of immune cells. Notably, recent reports have focused on a distinct metabolic phenotype underlying the differentiation of MDSCs in an inflammatory microenvironment representing a regulatory target. A better understanding of the metabolic reprogramming of MDSCs may thus provide novel insights for MDSC-based treatment approaches in transplantation. In this review, we will summarize recent, interdisciplinary findings on MDSCs metabolic reprogramming, dissect the underlying molecular mechanisms and discuss the relevance for potential treatment approaches in solid-organ transplantation.
    DOI:  https://doi.org/10.1016/j.jcyt.2023.04.010
  42. J Control Release. 2023 May 17. pii: S0168-3659(23)00337-1. [Epub ahead of print]
    Targeting lactate metabolism and immune interaction in breast tumor via protease-triggered delivery.
    Pengfei Zhao, Shuang Wang, Jizong Jiang, Yanyong Gao, Yuewei Wang, Yuge Zhao, Jiaxin Zhang, Meng Zhang, Yongzhuo Huang.
      Lactate is abundant in cancer tissues due to active glycolysis (aka Warburg effect) and mediates crosstalk between tumor cells and the immune microenvironment (TIME) to promote the progression of breast cancer. Quercetin (QU) is a potent monocarboxylate transporters (MCT) inhibitor, which can reduce lactate production and secretion of tumor cells. Doxorubicin (DOX) can induce immunogenic cell death (ICD), which promotes tumor-specific immune activation. Thus, we propose a combination therapy of QU&DOX to inhibit lactate metabolism and stimulate anti-tumor immunity. To enhance tumor-targeting efficiency, we developed a legumain-activatable liposome system (KC26-Lipo) with modification of KC26 peptide for co-delivery of QU&DOX for modulation of tumor metabolism and TIME in breast cancer. The KC26 peptide is a legumain-responsive, hairpin-structured cell-penetrating peptide (polyarginine) derivative. Legumain is a protease overexpressed in breast tumors, allowing selective activation of the KC26-Lipo to subsequently facilitate intra-tumoral and intracellular penetration. The KC26-Lipo effectively inhibited 4 T1 breast cancer tumor growth through chemotherapy and anti-tumor immunity. Besides, inhibition of lactate metabolism suppressed the HIF-1α/VEGF pathway and angiogenesis and repolarized the tumor-associated macrophages (TAMs). This work provides a promising breast cancer therapy strategy by regulating lactate metabolism and TIME.
    Keywords:  Immunometabolism; Lactate; Legumain; Quercetin; Tumor immune microenvironment (TIME)
    DOI:  https://doi.org/10.1016/j.jconrel.2023.05.024
  43. Nat Rev Immunol. 2023 May 12.
    Copper boosts pro-inflammatory state of macrophages.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-023-00889-3
  44. Nat Metab. 2023 May 17.
    Salvage of ribose from uridine or RNA supports glycolysis in nutrient-limited conditions.
    Owen S Skinner, Joan Blanco-Fernández, Russell P Goodman, Akinori Kawakami, Hongying Shen, Lajos V Kemény, Lena Joesch-Cohen, Matthew G Rees, Jennifer A Roth, David E Fisher, Vamsi K Mootha, Alexis A Jourdain.
      Glucose is vital for life, serving as both a source of energy and carbon building block for growth. When glucose is limiting, alternative nutrients must be harnessed. To identify mechanisms by which cells can tolerate complete loss of glucose, we performed nutrient-sensitized genome-wide genetic screens and a PRISM growth assay across 482 cancer cell lines. We report that catabolism of uridine from the medium enables the growth of cells in the complete absence of glucose. While previous studies have shown that uridine can be salvaged to support pyrimidine synthesis in the setting of mitochondrial oxidative phosphorylation deficiency1, our work demonstrates that the ribose moiety of uridine or RNA can be salvaged to fulfil energy requirements via a pathway based on: (1) the phosphorylytic cleavage of uridine by uridine phosphorylase UPP1/UPP2 into uracil and ribose-1-phosphate (R1P), (2) the conversion of uridine-derived R1P into fructose-6-P and glyceraldehyde-3-P by the non-oxidative branch of the pentose phosphate pathway and (3) their glycolytic utilization to fuel ATP production, biosynthesis and gluconeogenesis. Capacity for glycolysis from uridine-derived ribose appears widespread, and we confirm its activity in cancer lineages, primary macrophages and mice in vivo. An interesting property of this pathway is that R1P enters downstream of the initial, highly regulated steps of glucose transport and upper glycolysis. We anticipate that 'uridine bypass' of upper glycolysis could be important in the context of disease and even exploited for therapeutic purposes.
    DOI:  https://doi.org/10.1038/s42255-023-00774-2
  45. J Clin Invest. 2023 May 18. pii: e158630. [Epub ahead of print]
    Poly(ADP)ribose polymerase 9 mediates early protection against Mycobacterium tuberculosis infection by regulating type I IFN production.
    Shyamala Thirunavukkarasu, Mushtaq Ahmed, Bruce A Rosa, Mark Boothby, Sung Hoon Cho, Javier Rangel-Moreno, Stanley K Mbandi, Valérie Schreiber, Ananya Gupta, Joaquin Zúñiga, Makedonka Mitreva, Deepak Kaushal, Thomas J Scriba, Shabaana A Khader.
      The ADP ribosyl transferases (PARPs 1-17) regulate diverse cellular processes, including DNA damage repair. PARPs are classified based on their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). While PARP9 mRNA expression is significantly increased in progressive human tuberculosis (TB), its participation in host immunity to TB is unknown. Here, we show that PARP9 mRNA encoding the MARylating PARP9 enzyme is upregulated during TB in humans and mice and provide evidence of a critical modulatory role for PARP9 in DNA damage, cGAS and type I IFN production during TB. Thus, Parp9-deficient mice are susceptible to Mtb infection and exhibit increased TB disease, cGAS expression, cGAMP and type I IFN production along with upregulation of complement and coagulation pathways. Enhanced Mtb susceptibility is type I IFN-dependent, as blockade of IFNAR signaling reversed the enhanced susceptibility of Parp9-/- mice. Thus, in sharp contrast with PARP9 enhancement of type I IFN production in viral infections, this member of the MAR family plays a protective role by limiting type I IFN responses during TB.
    Keywords:  Bacterial infections; Immunology; Infectious disease; Innate immunity; Tuberculosis
    DOI:  https://doi.org/10.1172/JCI158630
  46. Sci Adv. 2023 May 19. 9(20): eadg6007
    Adoptive Treg therapy with metabolic intervention via perforated microneedles ameliorates psoriasis syndrome.
    Wentao Zhang, Yingxin Chen, Zhengjie Zhao, Hanqi Zheng, Shenqiang Wang, Ziyan Liao, Tao Sheng, Sheng Zhao, Wenhui Hou, Xinmin Yu, Fang He, Jicheng Yu, Yuqi Zhang, Zhen Gu.
      Regulatory T (Treg) cells underlie multiple autoimmune disorders and potentialize an anti-inflammation treatment with adoptive cell therapy. However, systemic delivery of cellular therapeutics often lacks tissue targeting and accumulation for localized autoimmune diseases. Besides, the instability and plasticity of Treg cells also induce phenotype transition and functional loss, impeding clinical translation. Here, we developed a perforated microneedle (PMN) with favorable mechanical performance and a spacious encapsulation cavity to support cell survival, as well as tunable channels to facilitate cell migration for local Treg therapy of psoriasis. In addition, the enzyme-degradable microneedle matrix could release fatty acid in the hyperinflammatory area of psoriasis, enhancing the Treg suppressive functions via the fatty acid oxidation (FAO)-mediated metabolic intervention. Treg cells administered through PMN substantially ameliorated psoriasis syndrome with the assistance of fatty acid-mediated metabolic intervention in a psoriasis mouse model. This tailorable PMN could offer a transformative platform for local cell therapy to treat a variety of diseases.
    DOI:  https://doi.org/10.1126/sciadv.adg6007
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