bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2023–12–24
47 papers selected by
Dylan Ryan, University of Cambridge
  1. T Lymphocyte Metabolic Features and Techniques to Modulate Them.
  2. Metabolic interplay: tumor macrophages and regulatory T cells.
  3. Monocyte immunometabolic reprogramming in human pregnancy: contribution of trophoblast cells.
  4. Nutrient inputs and social metabolic control of T cell fate.
  5. CTRP6 promotes the macrophage inflammatory response, and its deficiency attenuates LPS-induced inflammation.
  6. A Metabolic Axis of Immune Intractability.
  7. Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose starvation.
  8. Staphylococcus aureus suppresses the pentose phosphate pathway in human neutrophils via the adenosine receptor A2aR to enhance intracellular survival.
  9. PRKAG2.2 is essential for FoxA1+ regulatory T cell differentiation and metabolic rewiring distinct from FoxP3+ regulatory T cells.
  10. Regulation of Mitochondrial Metabolism by Hepatitis B Virus.
  11. CHTOP Promotes Microglia-Mediated Inflammation by Regulating Cell Metabolism and Inflammatory Gene Expression.
  12. Translational profiling identifies sex-specific metabolic and epigenetic reprogramming of cortical microglia/macrophages in APPPS1-21 mice with an antibiotic-perturbed-microbiome.
  13. FAP expression in adipose tissue macrophages promotes obesity and metabolic inflammation.
  14. Metabolic Modulators in Cardiovascular Complications of Systemic Lupus Erythematosus.
  15. The Role of Tumor Metabolic Reprogramming in Tumor Immunity.
  16. Muscle immune cells protect mitochondrial organelles during exercise.
  17. The Influence of Metabolism on Immune Response: A Journey to Understand Immunometabolism in the Context of Viral Infection.
  18. Lactate helps in tissue repair by promoting efferocytosis-induced macrophage proliferation.
  19. Metabolic reprogramming by Syntenin-1 directs RA FLS and endothelial cell-mediated inflammation and angiogenesis.
  20. Leishmania mexicana promotes pain-reducing metabolomic reprogramming in cutaneous lesions.
  21. How to eliminate pathogen without killing oneself? Immunometabolism of encapsulation and melanization in Drosophila.
  22. Emerging mechanisms of obesity-associated immune dysfunction.
  23. Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis.
  24. The multi-faceted role of NADPH in regulating inflammation in activated myeloid cells.
  25. Reprogramming mitochondrial metabolism of macrophages by miRNA-released microporous coatings to prevent peri-implantitis.
  26. GeneMAP: A discovery platform for metabolic gene function.
  27. The Implication of Sphingolipids in Viral Infections.
  28. Plasma metabonomics of classical swine fever virus-infected pigs.
  29. 1,25-Dihydroxyvitamin D3 potentiates the innate immune response of peripheral blood mononuclear cells from Japanese Black cattle.
  30. 6'-sialyllactose ameliorates the ototoxic effects of the aminoglycoside antibiotic neomycin in susceptible mice.
  31. Microbiota-dependent indole production stimulates the development of collagen-induced arthritis in mice.
  32. Effect of metabolic reprogramming on the immune microenvironment in gastric cancer.
  33. Lipid accumulation-mediated histone hypoacetylation drives persistent NK cell dysfunction in anti-tumor immunity.
  34. Squaramides enhance NLRP3 inflammasome activation by lowering intracellular potassium.
  35. Central glucagon-like peptide 1 receptor activation inhibits Toll-like receptor agonist-induced inflammation.
  36. KCNN4 links PIEZO-dependent mechanotransduction to NLRP3 inflammasome activation.
  37. Cholesterol Metabolism in Antigen-Presenting Cells and HIV-1 Trans-Infection of CD4+ T Cells.
  38. Apoptosis releases hydrogen sulfide to inhibit Th17 cell differentiation.
  39. Single-Cell RNA Sequencing Reveals Metabolic Stress-Dependent Activation of Cardiac Macrophages in a Model of Dyslipidemia-Induced Diastolic Dysfunction.
  40. A ketogenic diet reduces age-induced chronic neuroinflammation in mice.
  41. Untargeted metabolomics of the intestinal tract of DEV-infected ducks.
  42. Bone marrow adipocytes support fatty acid metabolism during MI-mediated emergency haematopoiesis.
  43. Host autophagy is exploited by the intracellular parasite Toxoplasma gondii to enhance amino acids levels.
  44. Integrated analysis of transcriptome and metabolome reveals the regulatory mechanism of largemouth bass (Micropterus salmoides) in response to Nocardia seriolae infection.
  45. 7-Ketocholesterol plays a key role in cholesterol-induced hepatitis via macrophage and neutrophil infiltration.
  46. Metabolomics reveals the mechanism of action of meropenem and amikacin combined in the treatment of Pseudomonas aeruginosa.
  47. Fecal metabolite profiling identifies liver transplant recipients at risk for postoperative infection.
  1. Biochemistry (Mosc). 2023 Nov;88(11): 1857-1873
    T Lymphocyte Metabolic Features and Techniques to Modulate Them.
    Violetta V Vlasova, Konstantin V Shmagel.
      T cells demonstrate high degree of complexity and broad range of functions, which distinguish them from other immune cells. Throughout their lifetime, T lymphocytes experience several functional states: quiescence, activation, proliferation, differentiation, performance of effector and regulatory functions, memory formation, and apoptosis. Metabolism supports all functions of T cells, providing lymphocytes with energy, biosynthetic substrates, and signaling molecules. Therefore, T cells usually restructure their metabolism as they transition from one functional state to another. Strong association between the metabolism and T cell functions implies that the immune response can be controlled by manipulating metabolic processes within T lymphocytes. This review aims to highlight the main metabolic adaptations necessary for the T cell function, as well as the recent progress in techniques to modulate metabolic features of lymphocytes.
    Keywords:  OXPHOS; T lymphocytes; TCA cycle; differentiation; exhaustion; glycolysis; immunological memory; metabolism; mitochondria; proliferation
    DOI:  https://doi.org/10.1134/S0006297923110159
  2. Trends Cancer. 2023 Dec 22. pii: S2405-8033(23)00238-8. [Epub ahead of print]
    Metabolic interplay: tumor macrophages and regulatory T cells.
    Stefania Vilbois, Yingxi Xu, Ping-Chih Ho.
      The tumor microenvironment (TME) contains a complex cellular ecosystem where cancer, stromal, vascular, and immune cells interact. Macrophages and regulatory T cells (Tregs) are critical not only for maintaining immunological homeostasis and tumor growth but also for monitoring the functional states of other immune cells. Emerging evidence reveals that metabolic changes in macrophages and Tregs significantly influence their pro-/antitumor functions through the regulation of signaling cascades and epigenetic reprogramming. Hence, they are increasingly recognized as therapeutic targets in cancer immunotherapy. Specific metabolites in the TME may also affect their pro-/antitumor functions by intervening with the metabolic machinery. We discuss how metabolites influence the immunosuppressive phenotypes of tumor-associated macrophages (TAMs) and Tregs. We then describe how TAMs and Tregs, independently or collaboratively, utilize metabolic mechanisms to suppress the activity of CD8+ T cells. Finally, we highlight promising metabolic interventions that can improve the outcome of current cancer therapies.
    Keywords:  cancer immunotherapy; immunometabolism; immunosuppression; macrophage; regulatory T cell; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2023.11.007
  3. Am J Physiol Endocrinol Metab. 2023 Dec 20.
    Monocyte immunometabolic reprogramming in human pregnancy: contribution of trophoblast cells.
    Fátima Merech, Soledad Gori, Guillermina Calo, Vanesa Hauk, Daniel Paparini, Daiana Rios, Brenda Lara, Luciana Doga, Luciana D'Eramo, Aldo Squassi, Rossana Ramhorst, Rafael J Argüello, Claudia Pérez Leirós, Daiana Vota.
      Immunometabolism research is uncovering the relationship between metabolic features and immune cell functions in physiological and pathological conditions. Normal pregnancy entails a fine immune and metabolic regulation of the maternal-fetal interaction to assist the energetic demands of the fetus with immune homeostasis maintenance. Here, we determined the immunometabolic status of monocytes of pregnant women compared to non-pregnant controls and its impact on monocyte antiinflammatory functions such as efferocytosis. Monocytes from pregnant women (16-20 weeks) and non-pregnant age-matched controls were studied. Single cell-based metabolic assays using freshly isolated monocytes from both groups were carried out in parallel with functional assays ex vivo to evaluate monocyte efferocytic capacity. On the other hand, various in vitro metabolic assays with human monocytes or monocyte-derived macrophages were designed to explore the effect of trophoblast cells in the profiles observed. We found that pregnancy alters monocyte metabolism and function. An increased glucose dependency and enhanced efferocytosis were detected in monocytes from pregnant women at resting states, compared to non-pregnant controls. Furthermore, monocytes display a reduced glycolytic response when stimulated with LPS. The metabolic profiling of monocytes at this stage of pregnancy was comparable with the immunometabolic phenotypes of human monocytes treated in vitro with human first trimester trophoblast cell conditioned media. These findings suggest that immunometabolic mechanisms are involved in the functional shaping of monocytes during pregnancy with a contribution of trophoblast cells. Results provide new clues for future hypotheses regarding pregnancies complicated by metabolic disorders.
    Keywords:  Early pregnancy; Glucose metabolism; Immunometabolism; Monocytes; Trophoblast soluble factors
    DOI:  https://doi.org/10.1152/ajpendo.00357.2023
  4. Cell Metab. 2023 Dec 12. pii: S1550-4131(23)00460-6. [Epub ahead of print]
    Nutrient inputs and social metabolic control of T cell fate.
    Zachary A Bacigalupa, Madelyn D Landis, Jeffrey C Rathmell.
      Cells in multicellular organisms experience diverse neighbors, signals, and evolving physical environments that drive functional and metabolic demands. To maintain proper development and homeostasis while avoiding inappropriate cell proliferation or death, individual cells interact with their neighbors via "social" cues to share and partition available nutrients. Metabolic signals also contribute to cell fate by providing biochemical links between cell-extrinsic signals and available resources. In addition to metabolic checkpoints that sense nutrients and directly supply molecular intermediates for biosynthetic pathways, many metabolites directly signal or provide the basis for post-translational modifications of target proteins and chromatin. In this review, we survey the landscape of T cell nutrient sensing and metabolic signaling that supports proper immunity while avoiding immunodeficiency or autoimmunity. The integration of cell-extrinsic microenvironmental cues with cell-intrinsic metabolic signaling provides a social metabolic control model to integrate cell signaling, metabolism, and fate.
    Keywords:  T cells; epigenetics; immunometabolism; metabolic signaling; social control model
    DOI:  https://doi.org/10.1016/j.cmet.2023.12.009
  5. J Biol Chem. 2023 Dec 14. pii: S0021-9258(23)02594-2. [Epub ahead of print] 105566
    CTRP6 promotes the macrophage inflammatory response, and its deficiency attenuates LPS-induced inflammation.
    Cheng Xu, Dylan C Sarver, Xia Lei, Ageline Sahagun, Jun Zhong, Chan Hyun Na, Assaf Rudich, G William Wong.
      Macrophages play critical roles in inflammation and tissue homeostasis, and their functions are regulated by various autocrine, paracrine, and endocrine factors. We have previously shown that CTRP6, a secreted protein of the C1q family, targets both adipocytes and macrophages to promote obesity-linked inflammation. However, the gene programs and signaling pathways directly regulated by CTRP6 in macrophages remain unknown. Here, we combine transcriptomic and phosphoproteomic analyses to show that CTRP6 activates inflammatory gene programs and signaling pathways in mouse bone marrow-derived macrophages (BMDMs). Treatment of BMDMs with CTRP6 upregulated proinflammatory, and suppressed the anti-inflammatory, gene expression. We also showed that CTRP6 activates p44/42-MAPK, p38-MAPK, and NF-κB signaling pathways to promote inflammatory cytokine secretion from BMDMs, and that pharmacologic inhibition of these signaling pathways markedly attenuated the effects of CTRP6. Pretreatment of BMDMs with CTRP6 also sensitized and potentiated the BMDMs response to LPS-induced inflammatory signaling and cytokine secretion. Consistent with the metabolic phenotype of proinflammatory macrophages, CTRP6 treatment induced a shift toward aerobic glycolysis and lactate production, reduced oxidative metabolism, and elevated mitochondrial ROS production in BMDMs. Importantly, in accordance with our in vitro findings, BMDMs from CTRP6-deficient mice were less inflammatory at baseline and showed a marked suppression of LPS-induced inflammatory gene expression and cytokine secretion. Finally, loss of CTRP6 in mice also dampened LPS-induced inflammation and hypothermia. Collectively, our findings suggest that CTRP6 regulates and primes the macrophage response to inflammatory stimuli and thus may have a role in modulating tissue inflammatory tone in different physiological and disease contexts.
    Keywords:  CTRP; LPS; inflammation; macrophage; phosphoproteomics; signaling; transcriptomics
    DOI:  https://doi.org/10.1016/j.jbc.2023.105566
  6. Cancer Immunol Res. 2023 Dec 21. OF1-OF5
    A Metabolic Axis of Immune Intractability.
    Dominique C Hinshaw, Meet Patel, Lalita A Shevde.
      Immune cells in the tumor niche robustly influence disease progression. Remarkably, in cancer, developmental pathways are reenacted. Many parallels between immune regulation of embryonic development and immune regulation of tumor progression can be drawn, with evidence clearly supporting an immune-suppressive microenvironment in both situations. In these ecosystems, metabolic and bioenergetic circuits guide and regulate immune cell differentiation, plasticity, and functional properties of suppressive and inflammatory immune subsets. As such, there is an emerging pattern of intersection across the dynamic process of ontogeny and the ever-evolving tumor neighborhood. In this article, we focus on the convergence of immune programming during ontogeny and in the tumor microenvironment. Exemplifying dysregulation of Hedgehog (Hh) activity, a key player during ontogeny, we highlight a critical convergence of these fields and the metabolic axis of the nutrient sensing hexosamine biosynthetic pathway (HBP) that integrates glucose, glutamine, amino acids, acetyl CoA, and uridine-5'-triphosphate (UTP), culminating in the synthesis of UDP-GlcNAc, a metabolite that functions as a metabolic and bioenergetic sensor. We discuss an emerging pattern of immune regulation, orchestrated by O-GlcNAcylation of key transcriptional regulators, spurring suppressive activity of dysfunctional immune cells in the tumor microenvironment.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-23-0433
  7. mBio. 2023 Dec 20. e0303123
    Cytomegalovirus-induced inactivation of TSC2 disrupts the coupling of fatty acid biosynthesis to glucose availability resulting in a vulnerability to glucose starvation.
    Matthew H Raymonda, Irene Rodríguez-Sánchez, Xenia L Schafer, Leonid Smorodintsev-Schiller, Isaac S Harris, Joshua Munger.
       IMPORTANCE: Viruses modulate host cell metabolism to support the mass production of viral progeny. For human cytomegalovirus, we find that the viral UL38 protein is critical for driving these pro-viral metabolic changes. However, our results indicate that these changes come at a cost, as UL38 induces an anabolic rigidity that leads to a metabolic vulnerability. We find that UL38 decouples the link between glucose availability and fatty acid biosynthetic activity. Normal cells respond to glucose limitation by down-regulating fatty acid biosynthesis. Expression of UL38 results in the inability to modulate fatty acid biosynthesis in response to glucose limitation, which results in cell death. We find this vulnerability in the context of viral infection, but this linkage between fatty acid biosynthesis, glucose availability, and cell death could have broader implications in other contexts or pathologies that rely on glycolytic remodeling, for example, oncogenesis.
    Keywords:  TSC2; UL38; fatty acid biosynthesis; glycolysis; human cytomegalovirus; lipogenesis; metabolism
    DOI:  https://doi.org/10.1128/mbio.03031-23
  8. mBio. 2023 Dec 18. e0257123
    Staphylococcus aureus suppresses the pentose phosphate pathway in human neutrophils via the adenosine receptor A2aR to enhance intracellular survival.
    Emilio G Vozza, Clíodhna M Daly, Sinead A O'Rourke, Hannah K Fitzgerald, Aisling Dunne, Rachel M McLoughlin.
       IMPORTANCE: Staphylococcus aureus is one of the leading causes of antimicrobial-resistant infections whose success as a pathogen is facilitated by its massive array of immune evasion tactics, including intracellular survival within critical immune cells such as neutrophils, the immune system's first line of defense. In this study, we describe a novel pathway by which intracellular S. aureus can suppress the antimicrobial capabilities of human neutrophils by using the anti-inflammatory adenosine receptor, adora2a (A2aR). We show that signaling through A2aR suppresses the pentose phosphate pathway, a metabolic pathway used to fuel the antimicrobial NADPH oxidase complex that generates reactive oxygen species (ROS). As such, neutrophils show enhanced ROS production and reduced intracellular S. aureus when treated with an A2aR inhibitor. Taken together, we identify A2aR as a potential therapeutic target for combatting intracellular S. aureus infection.
    Keywords:  A2aR; Staphylococcus aureus; adora2a; host-pathogen interactions; intracellular pathogen; metabolism; neutrophil; pentose phosphate pathway
    DOI:  https://doi.org/10.1128/mbio.02571-23
  9. Sci Adv. 2023 Dec 22. 9(51): eadj8442
    PRKAG2.2 is essential for FoxA1+ regulatory T cell differentiation and metabolic rewiring distinct from FoxP3+ regulatory T cells.
    Sara Mandatori, Yawei Liu, Joana Marturia-Navarro, Mahdieh Hadi, Kristine Henriksen, Jin Zheng, Louise Munk Rasmussen, Salvatore Rizza, Klaus H Kaestner, Shohreh Issazadeh-Navikas.
      Forkhead box A1 (FoxA1)+ regulatory T cells (Tregs) exhibit distinct characteristics from FoxP3+ Tregs while equally effective in exerting anti-inflammatory properties. The role of FoxP3+ Tregs in vivo has been challenged, motivating a better understanding of other Tregs in modulating hyperactive immune responses. FoxA1+ Tregs are generated on activation of the transcription factor FoxA1 by interferon-β (IFNβ), an anti-inflammatory cytokine. T cell activation, expansion, and function hinge on metabolic adaptability. We demonstrated that IFNβ promotes a metabolic rearrangement of FoxA1+ Tregs by enhancing oxidative phosphorylation and mitochondria clearance by mitophagy. In response to IFNβ, FoxA1 induces a specific transcription variant of adenosine 5'-monophosphate-activated protein kinase (AMPK) γ2 subunit, PRKAG2.2. This leads to the activation of AMPK signaling, thereby enhancing mitochondrial respiration and mitophagy by ULK1-BNIP3. This IFNβ-FoxA1-PRKAG2.2-BNIP3 axis is pivotal for their suppressive function. The involvement of PRKAG2.2 in FoxA1+ Treg, not FoxP3+ Treg differentiation, underscores the metabolic differences between Treg populations and suggests potential therapeutic targets for autoimmune diseases.
    DOI:  https://doi.org/10.1126/sciadv.adj8442
  10. Viruses. 2023 Nov 30. pii: 2359. [Epub ahead of print]15(12):
    Regulation of Mitochondrial Metabolism by Hepatitis B Virus.
    Yumei Li, Jing-Hsiung James Ou.
      Mitochondria play important roles in the synthesis of ATP, the production of reactive oxygen species, and the regulation of innate immune response and apoptosis. Many viruses perturb mitochondrial activities to promote their replication and cause cell damage. Hepatitis B virus (HBV) is a hepatotropic virus that can cause severe liver diseases, including cirrhosis and hepatocellular carcinoma (HCC). This virus can also alter mitochondrial functions and metabolism to promote its replication and persistence. In this report, we summarize recent research progress on the interaction between HBV and mitochondrial metabolism, as well as the effect this interaction has on HBV replication and persistence.
    Keywords:  CD8+ T cells; hepatic macrophages; hepatitis B virus; innate immune response; mitochondrial metabolism; mitophagy; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/v15122359
  11. J Immunol. 2023 Dec 20. pii: ji2300572. [Epub ahead of print]
    CHTOP Promotes Microglia-Mediated Inflammation by Regulating Cell Metabolism and Inflammatory Gene Expression.
    Xin Zhou, Mengfei Lv, Zhongying Duan, Wenhao Liu, Feng Yan, Jiake Liu, Yu Cui.
      During the initiation of the inflammatory response of microglia, the expression of many inflammation- and cell metabolism-related genes alters. However, how the transcription of inflammation- and metabolism-related genes are coordinately regulated during inflammation initiation is poorly understood. In this study, we found that LPS stimulation induced the expression of the chromatin target of PRMT1 (protein arginine methyltransferase 1) (CHTOP) in microglia. Knocking down CHTOP in microglia decreased proinflammatory cytokine expression. In addition, CHTOP knockdown altered cell metabolism, as both the upregulated genes were enriched in cell metabolism-related pathways and the metabolites profile was greatly altered based on untargeted metabolomics analysis. Mechanistically, CHTOP could directly bind the regulatory elements of inflammation and cell metabolism-related genes to regulate their transcription. In addition, knocking down CHTOP increased neuronal viability in vitro and alleviated microglia-mediated neuroinflammation in a systemic LPS treatment mouse model. Collectively, these data revealed CHTOP as a novel regulator to promote microglia-mediated neuroinflammation by coordinately regulating the transcription of inflammation and cell metabolism-related genes.
    DOI:  https://doi.org/10.4049/jimmunol.2300572
  12. Mol Neurodegener. 2023 Dec 16. 18(1): 95
    Translational profiling identifies sex-specific metabolic and epigenetic reprogramming of cortical microglia/macrophages in APPPS1-21 mice with an antibiotic-perturbed-microbiome.
    Shabana M Shaik, Yajun Cao, Joseph V Gogola, Hemraj B Dodiya, Xulun Zhang, Hejer Boutej, Weinong Han, Jasna Kriz, Sangram S Sisodia.
       BACKGROUND: Microglia, the brain-resident macrophages perform immune surveillance and engage with pathological processes resulting in phenotype changes necessary for maintaining homeostasis. In preceding studies, we showed that antibiotic-induced perturbations of the gut microbiome of APPPS1-21 mice resulted in significant attenuation in Aβ amyloidosis and altered microglial phenotypes that are specific to male mice. The molecular events underlying microglial phenotypic transitions remain unclear. Here, by generating 'APPPS1-21-CD11br' reporter mice, we investigated the translational state of microglial/macrophage ribosomes during their phenotypic transition and in a sex-specific manner.
    METHODS: Six groups of mice that included WT-CD11br, antibiotic (ABX) or vehicle-treated APPPS1-21-CD11br males and females were sacrificed at 7-weeks of age (n = 15/group) and used for immunoprecipitation of microglial/macrophage polysomes from cortical homogenates using anti-FLAG antibody. Liquid chromatography coupled to tandem mass spectrometry and label-free quantification was used to identify newly synthesized peptides isolated from polysomes.
    RESULTS: We show that ABX-treatment leads to decreased Aβ levels in male APPPS1-21-CD11br mice with no significant changes in females. We identified microglial/macrophage polypeptides involved in mitochondrial dysfunction and altered calcium signaling that are associated with Aβ-induced oxidative stress. Notably, female mice also showed downregulation of newly-synthesized ribosomal proteins. Furthermore, male mice showed an increase in newly-synthesized polypeptides involved in FcγR-mediated phagocytosis, while females showed an increase in newly-synthesized polypeptides responsible for actin organization associated with microglial activation. Next, we show that ABX-treatment resulted in substantial remodeling of the epigenetic landscape, leading to a metabolic shift that accommodates the increased bioenergetic and biosynthetic demands associated with microglial polarization in a sex-specific manner. While microglia in ABX-treated male mice exhibited a metabolic shift towards a neuroprotective phenotype that promotes Aβ clearance, microglia in ABX-treated female mice exhibited loss of energy homeostasis due to persistent mitochondrial dysfunction and impaired lysosomal clearance that was associated with inflammatory phenotypes.
    CONCLUSIONS: Our studies provide the first snapshot of the translational state of microglial/macrophage cells in a mouse model of Aβ amyloidosis that was subject to ABX treatment. ABX-mediated changes resulted in metabolic reprogramming of microglial phenotypes to modulate immune responses and amyloid clearance in a sex-specific manner. This microglial plasticity to support neuro-energetic homeostasis for its function based on sex paves the path for therapeutic modulation of immunometabolism for neurodegeneration.
    Keywords:  Alzheimer’s disease; Epigenetics; Inflammation; Macrophage; Metabolism; Microbiome; Microglia; Proteomics; Sex; Translating ribosome affinity purification
    DOI:  https://doi.org/10.1186/s13024-023-00668-7
  13. Proc Natl Acad Sci U S A. 2023 Dec 19. 120(51): e2303075120
    FAP expression in adipose tissue macrophages promotes obesity and metabolic inflammation.
    Yunyun Wu, Chao Wu, Tiancong Shi, Qian Cai, Tianyao Wang, Yingluo Xiong, Yubin Zhang, Wei Jiang, Mingfang Lu, Zhengrong Chen, Jing Chen, Jiqiu Wang, Rui He.
      Adipose tissue macrophages (ATM) are key players in the development of obesity and associated metabolic inflammation which contributes to systemic metabolic dysfunction. We here found that fibroblast activation protein α (FAP), a well-known marker of cancer-associated fibroblast, is selectively expressed in murine and human ATM among adipose tissue-infiltrating leukocytes. Macrophage FAP deficiency protects mice against diet-induced obesity and proinflammatory macrophage infiltration in obese adipose tissues, thereby alleviating hepatic steatosis and insulin resistance. Mechanistically, FAP specifically mediates monocyte chemokine protein CCL8 expression by ATM, which is further upregulated upon high-fat-diet (HFD) feeding, contributing to the recruitment of monocyte-derived proinflammatory macrophages with no effect on their classical inflammatory activation. CCL8 overexpression restores HFD-induced metabolic phenotypes in the absence of FAP. Moreover, macrophage FAP deficiency enhances energy expenditure and oxygen consumption preceding differential body weight after HFD feeding. Such enhanced energy expenditure is associated with increased levels of norepinephrine (NE) and lipolysis in white adipose tissues, likely due to decreased expression of monoamine oxidase, a NE degradation enzyme, by Fap-/- ATM. Collectively, our study identifies FAP as a previously unrecognized regulator of ATM function contributing to diet-induced obesity and metabolic inflammation and suggests FAP as a potential immunotherapeutic target against metabolic disorders.
    Keywords:  CCL8; fibroblast activation protein (FAP); inflammation; macrophage; obesity
    DOI:  https://doi.org/10.1073/pnas.2303075120
  14. Biomedicines. 2023 Nov 25. pii: 3142. [Epub ahead of print]11(12):
    Metabolic Modulators in Cardiovascular Complications of Systemic Lupus Erythematosus.
    Sofía Miñano, Cristina González-Correa, Javier Moleón, Juan Duarte.
      Systemic lupus erythematosus (SLE) is a multifactorial disorder with contributions from hormones, genetics, and the environment, predominantly affecting young women. Cardiovascular disease is the primary cause of mortality in SLE, and hypertension is more prevalent among SLE patients. The dysregulation of both innate and adaptive immune cells in SLE, along with their infiltration into kidney and vascular tissues, is a pivotal factor contributing to the cardiovascular complications associated with SLE. The activation, proliferation, and differentiation of CD4+ T cells are intricately governed by cellular metabolism. Numerous metabolic inhibitors have been identified to target critical nodes in T cell metabolism. This review explores the existing evidence and knowledge gaps concerning whether the beneficial effects of metabolic modulators on autoimmunity, hypertension, endothelial dysfunction, and renal injury in lupus result from the restoration of a balanced immune system. The inhibition of glycolysis, mitochondrial metabolism, or mTORC1 has been found to improve endothelial dysfunction and prevent the development of hypertension in mouse models of SLE. Nevertheless, limited information is available regarding the potential vasculo-protective effects of drugs that act on immunometabolism in SLE patients.
    Keywords:  endothelial dysfunction; hypertension; immunometabolism; systemic lupus erythematosus
    DOI:  https://doi.org/10.3390/biomedicines11123142
  15. Int J Mol Sci. 2023 Dec 13. pii: 17422. [Epub ahead of print]24(24):
    The Role of Tumor Metabolic Reprogramming in Tumor Immunity.
    Xianhong Zhang, Weiguo Song, Yue Gao, Yu Zhang, Yuqi Zhao, Shuailin Hao, Ting Ni.
      The occurrence and development of tumors require the metabolic reprogramming of cancer cells, namely the alteration of flux in an autonomous manner via various metabolic pathways to meet increased bioenergetic and biosynthetic demands. Tumor cells consume large quantities of nutrients and produce related metabolites via their metabolism; this leads to the remodeling of the tumor microenvironment (TME) to better support tumor growth. During TME remodeling, the immune cell metabolism and antitumor immune activity are affected. This further leads to the escape of tumor cells from immune surveillance and therefore to abnormal proliferation. This review summarizes the regulatory functions associated with the abnormal biosynthesis and activity of metabolic signaling molecules during the process of tumor metabolic reprogramming. In addition, we provide a comprehensive description of the competition between immune cells and tumor cells for nutrients in the TME, as well as the metabolites required for tumor metabolism, the metabolic signaling pathways involved, and the functionality of the immune cells. Finally, we summarize current research targeted at the development of tumor immunotherapy. We aim to provide new concepts for future investigations of the mechanisms underlying the metabolic reprogramming of tumors and explore the association of these mechanisms with tumor immunity.
    Keywords:  immune cells; tumor immunity; tumor metabolism; tumor microenvironment; tumor therapy
    DOI:  https://doi.org/10.3390/ijms242417422
  16. Nature. 2024 Jan;625(7993): 35-36
    Muscle immune cells protect mitochondrial organelles during exercise.
    Gerald Coulis, S Armando Villalta.
      
    Keywords:  Cell biology; Immunology; Physiology
    DOI:  https://doi.org/10.1038/d41586-023-03972-w
  17. Viruses. 2023 Dec 09. pii: 2399. [Epub ahead of print]15(12):
    The Influence of Metabolism on Immune Response: A Journey to Understand Immunometabolism in the Context of Viral Infection.
    Daed El Safadi, Aurélie Paulo-Ramos, Mathilde Hoareau, Marjolaine Roche, Pascale Krejbich-Trotot, Wildriss Viranaicken, Grégorie Lebeau.
      In recent years, the emergence of the concept of immunometabolism has shed light on the pivotal role that cellular metabolism plays in both the activation of immune cells and the development of immune programs. The antiviral response, a widely distributed defense mechanism used by infected cells, serves to not only control infections but also to attenuate their deleterious effects. The exploration of the role of metabolism in orchestrating the antiviral response represents a burgeoning area of research, especially considering the escalating incidence of viral outbreaks coupled with the increasing prevalence of metabolic diseases. Here, we present a review of current knowledge regarding immunometabolism and the antiviral response during viral infections. Initially, we delve into the concept of immunometabolism by examining its application in the field of cancer-a domain that has long spearheaded inquiries into this fascinating intersection of disciplines. Subsequently, we explore examples of immune cells whose activation is intricately regulated by metabolic processes. Progressing with a systematic and cellular approach, our aim is to unravel the potential role of metabolism in antiviral defense, placing significant emphasis on the innate and canonical interferon response.
    Keywords:  antiviral response; immunometabolism; metabolic diseases; viral infections
    DOI:  https://doi.org/10.3390/v15122399
  18. Nat Metab. 2023 Dec;5(12): 2045-2046
    Lactate helps in tissue repair by promoting efferocytosis-induced macrophage proliferation.
      
    DOI:  https://doi.org/10.1038/s42255-023-00920-w
  19. Cell Mol Immunol. 2023 Dec 18.
    Metabolic reprogramming by Syntenin-1 directs RA FLS and endothelial cell-mediated inflammation and angiogenesis.
    Anja Meyer, Stephanie R Zack, Wes Nijim, Adel Burgos, Vishwa Patel, Brian Zanotti, Michael V Volin, M Asif Amin, Myles J Lewis, Costantino Pitzalis, Shiva Arami, Joseph A Karam, Nadera J Sweiss, Shiva Shahrara.
      A novel rheumatoid arthritis (RA) synovial fluid protein, Syntenin-1, and its receptor, Syndecan-1 (SDC-1), are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes (FLS). Syntenin-1 exacerbates the inflammatory landscape of endothelial cells and RA FLS by upregulating transcription of IRF1/5/7/9, IL-1β, IL-6, and CCL2 through SDC-1 ligation and HIF1α, or mTOR activation. Mechanistically, Syntenin-1 orchestrates RA FLS and endothelial cell invasion via SDC-1 and/or mTOR signaling. In Syntenin-1 reprogrammed endothelial cells, the dynamic expression of metabolic intermediates coincides with escalated glycolysis along with unchanged oxidative factors, AMPK, PGC-1α, citrate, and inactive oxidative phosphorylation. Conversely, RA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP capacity. The enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed RA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DRP1 expression. We found that VEGFR1/2 and Notch1 networks are responsible for the crosstalk between Syntenin-1 rewired endothelial cells and RA FLS, which are also represented in RA explants. Similar to RA explants, morphological and transcriptome studies authenticated the importance of VEGFR1/2, Notch1, RAPTOR, and HIF1α pathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient animals. Consistently, dysregulation of SDC-1, mTOR, and HIF1α negated Syntenin-1 inflammatory phenotype in RA explants, while inhibition of HIF1α impaired synovial angiogenic imprint amplified by Syntenin-1. In conclusion, since the current therapies are ineffective on Syntenin-1 and SDC-1 expression in RA synovial tissue and blood, targeting this pathway and its interconnected metabolic intermediates may provide a novel therapeutic strategy.
    Keywords:  RA FLS; RA explants; Syndecan-1; Syntenin-1; immunometabolism
    DOI:  https://doi.org/10.1038/s41423-023-01108-8
  20. iScience. 2023 Dec 15. 26(12): 108502
    Leishmania mexicana promotes pain-reducing metabolomic reprogramming in cutaneous lesions.
    Greta Volpedo, Timur Oljuskin, Blake Cox, Yulian Mercado, Candice Askwith, Nazli Azodi, Matthew Bernier, Hira L Nakhasi, Sreenivas Gannavaram, Abhay R Satoskar.
      Cutaneous leishmaniasis (CL) is characterized by extensive skin lesions, which are usually painless despite being associated with extensive inflammation. The molecular mechanisms responsible for this analgesia have not been identified. Through untargeted metabolomics, we found enriched anti-nociceptive metabolic pathways in L. mexicana-infected mice. Purines were elevated in infected macrophages and at the lesion site during chronic infection. These purines have anti-inflammatory and analgesic properties by acting through adenosine receptors, inhibiting TRPV1 channels, and promoting IL-10 production. We also found arachidonic acid (AA) metabolism enriched in the ear lesions compared to the non-infected controls. AA is a metabolite of anandamide (AEA) and 2-arachidonoylglycerol (2-AG). These endocannabinoids act on cannabinoid receptors 1 and 2 and TRPV1 channels to exert anti-inflammatory and analgesic effects. Our study provides evidence of metabolic pathways upregulated during L. mexicana infection that may mediate anti-nociceptive effects experienced by CL patients and identifies macrophages as a source of these metabolites.
    Keywords:  Immunology; Metabolomics; Parasitology
    DOI:  https://doi.org/10.1016/j.isci.2023.108502
  21. Front Immunol. 2023 ;14 1330312
    How to eliminate pathogen without killing oneself? Immunometabolism of encapsulation and melanization in Drosophila.
    Tomas Dolezal.
      Cellular encapsulation associated with melanization is a crucial component of the immune response in insects, particularly against larger pathogens. The infection of a Drosophila larva by parasitoid wasps, like Leptopilina boulardi, is the most extensively studied example. In this case, the encapsulation and melanization of the parasitoid embryo is linked to the activation of plasmatocytes that attach to the surface of the parasitoid. Additionally, the differentiation of lamellocytes that encapsulate the parasitoid, along with crystal cells, is accountable for the melanization process. Encapsulation and melanization lead to the production of toxic molecules that are concentrated in the capsule around the parasitoid and, at the same time, protect the host from this toxic immune response. Thus, cellular encapsulation and melanization represent primarily a metabolic process involving the metabolism of immune cell activation and differentiation, the production of toxic radicals, but also the production of melanin and antioxidants. As such, it has significant implications for host physiology and systemic metabolism. Proper regulation of metabolism within immune cells, as well as at the level of the entire organism, is therefore essential for an efficient immune response and also impacts the health and overall fitness of the organism that survives. The purpose of this "perspective" article is to map what we know about the metabolism of this type of immune response, place it in the context of possible implications for host physiology, and highlight open questions related to the metabolism of this important insect immune response.
    Keywords:  ROS; encapsulation; hemocyte; immunometabolism; lamellocyte; melanization; parasitoid wasp; phenoloxidase
    DOI:  https://doi.org/10.3389/fimmu.2023.1330312
  22. Nat Rev Endocrinol. 2023 Dec 21.
    Emerging mechanisms of obesity-associated immune dysfunction.
    Saame Raza Shaikh, Melinda A Beck, Yazan Alwarawrah, Nancie J MacIver.
      Obesity is associated with a wide range of complications, including type 2 diabetes mellitus, cardiovascular disease, hypertension and nonalcoholic fatty liver disease. Obesity also increases the incidence and progression of cancers, autoimmunity and infections, as well as lowering vaccine responsiveness. A unifying concept across these differing diseases is dysregulated immunity, particularly inflammation, in response to metabolic overload. Herein, we review emerging mechanisms by which obesity drives inflammation and autoimmunity, as well as impairing tumour immunosurveillance and the response to infections. Among these mechanisms are obesity-associated changes in the hormones that regulate immune cell metabolism and function and drive inflammation. The cargo of extracellular vesicles derived from adipose tissue, which controls cytokine secretion from immune cells, is also dysregulated in obesity, in addition to impairments in fatty acid metabolism related to inflammation. Furthermore, an imbalance exists in obesity in the biosynthesis and levels of polyunsaturated fatty acid-derived oxylipins, which control a range of outcomes related to inflammation, such as immune cell chemotaxis and cytokine production. Finally, there is a need to investigate how obesity influences immunity using innovative model systems that account for the heterogeneous nature of obesity in the human population.
    DOI:  https://doi.org/10.1038/s41574-023-00932-2
  23. Nat Commun. 2023 Dec 20. 14(1): 8474
    Mtfp1 ablation enhances mitochondrial respiration and protects against hepatic steatosis.
    Cecilia Patitucci, Juan Diego Hernández-Camacho, Elodie Vimont, Sonny Yde, Thomas Cokelaer, Thibault Chaze, Quentin Giai Gianetto, Mariette Matondo, Anastasia Gazi, Ivan Nemazanyy, David A Stroud, Daniella H Hock, Erminia Donnarumma, Timothy Wai.
      Hepatic steatosis is the result of imbalanced nutrient delivery and metabolism in the liver and is the first hallmark of Metabolic dysfunction-associated steatotic liver disease (MASLD). MASLD is the most common chronic liver disease and involves the accumulation of excess lipids in hepatocytes, inflammation, and cancer. Mitochondria play central roles in liver metabolism yet the specific mitochondrial functions causally linked to MASLD remain unclear. Here, we identify Mitochondrial Fission Process 1 protein (MTFP1) as a key regulator of mitochondrial and metabolic activity in the liver. Deletion of Mtfp1 in hepatocytes is physiologically benign in mice yet leads to the upregulation of oxidative phosphorylation (OXPHOS) activity and mitochondrial respiration, independently of mitochondrial biogenesis. Consequently, liver-specific knockout mice are protected against high fat diet-induced steatosis and metabolic dysregulation. Additionally, Mtfp1 deletion inhibits mitochondrial permeability transition pore opening in hepatocytes, conferring protection against apoptotic liver damage in vivo and ex vivo. Our work uncovers additional functions of MTFP1 in the liver, positioning this gene as an unexpected regulator of OXPHOS and a therapeutic candidate for MASLD.
    DOI:  https://doi.org/10.1038/s41467-023-44143-9
  24. Front Immunol. 2023 ;14 1328484
    The multi-faceted role of NADPH in regulating inflammation in activated myeloid cells.
    Kenneth K Y Ting, Jenny Jongstra-Bilen, Myron I Cybulsky.
      Recent advances in the immunometabolism field have demonstrated the importance of metabolites in fine-tuning the inflammatory responses in myeloid cells. Cofactors, which are metabolites comprised of inorganic ions and organic molecules, may tightly or loosely bind to distinct sites of enzymes to catalyze a specific reaction. Since many enzymes that mediate inflammatory and anti-inflammatory processes require the same cofactors to function, this raises the possibility that under conditions where the abundance of these cofactors is limited, inflammatory and anti-inflammatory enzymes must compete with each other for the consumption of cofactors. Thus, this competition may reflect a naturally evolved mechanism to efficiently co-regulate inflammatory versus anti-inflammatory pathways, fine-tuning the extent of an inflammatory response. The role of NADPH, the reduced form of nicotinamide adenine dinucleotide phosphate (NADP+), in mediating inflammatory and anti-inflammatory responses in activated myeloid cells has been well-established in the past decades. However, how the dynamic of NADPH consumption mediates the co-regulation between individual inflammatory and anti-inflammatory pathways is only beginning to be appreciated. In this review, we will summarize the established roles of NADPH in supporting inflammatory and anti-inflammatory pathways, as well as highlight how the competition for NADPH consumption by these opposing pathways fine-tunes the inflammatory response in activated myeloid cells.
    Keywords:  LPS (lipopolysaccharide); NADPH; cofactor coordination; cofactors; dendritic cells; immunometabolism; macrophages; myeloid cells
    DOI:  https://doi.org/10.3389/fimmu.2023.1328484
  25. J Nanobiotechnology. 2023 Dec 17. 21(1): 485
    Reprogramming mitochondrial metabolism of macrophages by miRNA-released microporous coatings to prevent peri-implantitis.
    Hongming Zhang, Yun Yuan, Hanxiao Xue, Runping Yu, Xiayue Jin, Xiaolin Wu, Hui Huang.
      Although various new biomaterials have enriched the methods for peri-implant inflammation treatment, their efficacy is still debated, and secondary operations on the implant area have also caused pain for patients. Recently, strategies that regulate macrophage polarization to prevent or even treat peri-implantitis have attracted increasing attention. Here, we prepared a laser-drilled and covered with metal organic framework-miR-27a agomir nanomembrane (L-MOF-agomir) implant, which could load and sustain the release of miR-27a agomir. In vitro, the L-MOF-agomir titanium plate promoted the repolarization of LPS-stimulated macrophages from M1 to M2, and the macrophage culture supernatant promoted BMSCs osteogenesis. In a ligation-induced rat peri-implantitis model, the L-MOF-agomir implants featured strong immunomodulatory activity of macrophage polarization and alleviated ligation-induced bone resorption. The mechanism of repolarization function may be that the L-MOF-agomir implants promote the macrophage mitochondrial function and metabolism reprogramming from glycolysis to oxidative phosphorylation. Our study demonstrates the feasibility of targeting cell metabolism to regulate macrophage immunity for peri-implantitis inhibition and provides a new perspective for the development of novel multifunctional implants.
    Keywords:  Dental implants; Macrophages; Mitochondrial metabolism; Peri-implantitis
    DOI:  https://doi.org/10.1186/s12951-023-02244-z
  26. bioRxiv. 2023 Dec 08. pii: 2023.12.07.570588. [Epub ahead of print]
    GeneMAP: A discovery platform for metabolic gene function.
    Artem Khan, Gokhan Unlu, Phillip Lin, Yuyang Liu, Ece Kilic, Timothy C Kenny, Kıvanç Birsoy, Eric R Gamazon.
      Organisms maintain metabolic homeostasis through the combined functions of small molecule transporters and enzymes. While many of the metabolic components have been well-established, a substantial number remains without identified physiological substrates. To bridge this gap, we have leveraged large-scale plasma metabolome genome-wide association studies (GWAS) to develop a multiomic Gene-Metabolite Associations Prediction (GeneMAP) discovery platform. GeneMAP can generate accurate predictions, even pinpointing genes that are distant from the variants implicated by GWAS. In particular, our work identified SLC25A48 as a genetic determinant of plasma choline levels. Mechanistically, SLC25A48 loss strongly impairs mitochondrial choline import and synthesis of its downstream metabolite, betaine. Rare variant testing and polygenic risk score analyses have elucidated choline-relevant phenomic consequences of SLC25A48 dysfunction. Altogether, our study proposes SLC25A48 as a mitochondrial choline transporter and provides a discovery platform for metabolic gene function.
    DOI:  https://doi.org/10.1101/2023.12.07.570588
  27. Int J Mol Sci. 2023 Dec 09. pii: 17303. [Epub ahead of print]24(24):
    The Implication of Sphingolipids in Viral Infections.
    Sanya Thomas, Stephen Varghese Samuel, Annmarie Hoch, Caitlin Syphurs, Joann Diray-Arce.
      Sphingolipids are involved in cell signaling and metabolic pathways, and their metabolites play a critical role in host defense against intracellular pathogens. Here, we review the known mechanisms of sphingolipids in viral infections and discuss the potential implication of the study of sphingolipid metabolism in vaccine and therapeutic development.
    Keywords:  lipid metabolism; sphingolipid metabolism; sphingolipids; sphingosine-1-phosphate; viral infections
    DOI:  https://doi.org/10.3390/ijms242417303
  28. Front Vet Sci. 2023 ;10 1171750
    Plasma metabonomics of classical swine fever virus-infected pigs.
    Jiedan Liao, Wenshuo Hu, Weijun Wang, Xinyan Wang, Shu Yu, Xinni Niu, Wenhui Zhu, Bolun Zhou, Yiwan Song, Weijun Zeng, Zhimin Lu, Jinding Chen.
      Classical swine fever (CSF) is an infectious disease caused by Classical swine fever virus (CSFV), which is characterized by depression, high fever, extensive skin bleeding, leukopenia, anorexia, alternating constipation, and diarrhea. Hemorrhagic infarction of the spleen is the main characteristic pathological change following CSFV infection. Large-scale outbreaks of CSF are rare in China and are mainly distributed regionally. The clinical symptoms of CSF are not obvious, and show variation from typical to atypical symptoms, which makes diagnosis based on clinical symptoms and pathology challenging. In recent years, the incidence of CSF-immunized pig farms in China has increased and new CSFV gene subtypes have appeared, posing new challenges to the prevention and control of CSF in China. Changes in metabolites caused by viral infection reflect the pathogenic process. Metabonomics can reveal the trace metabolites of organisms; however, plasma metabonomics of CSFV-infected pigs have rarely been investigated. Therefore, we used an established pig CSFV infection model to study changes in plasma metabolites. The results showed significant differences in forty-five plasma metabolites at different time periods after CSFV infection in pigs, with an increase in twenty-five metabolites and a decrease in twenty metabolites. These changed metabolites were mainly attributed to the tricarboxylic acid cycle, amino acid cycle, sugar metabolism, and fat metabolism. Thirteen metabolic pathways changed significantly in CSFV-infected pigs, including tricarboxylic acid cycle, inositol phosphate metabolism, glycine, serine and threonine metabolism,lysine degradation, alanine, aspartate and glutamic acid metabolism, pantothenate and CoA biosynthesis, β-alanine metabolism, lysine degradation, arginine and proline metabolism, glycerolipid metabolism, phenylalanine metabolism, arachidonic acid metabolism, linoleic acid metabolism. Among these, changes in fatty acid biosynthesis and metabolism occurred at all time periods post-infection. These results indicate that CSFV infection in pigs could seriously alter metabolic pathways.
    Keywords:  classical swine fever virus; heat map; metabolic pathway; metabonomics; tricarboxylic acid cycle
    DOI:  https://doi.org/10.3389/fvets.2023.1171750
  29. Anim Sci J. 2023 Jan-Dec;94(1):94(1): e13906
    1,25-Dihydroxyvitamin D3 potentiates the innate immune response of peripheral blood mononuclear cells from Japanese Black cattle.
    Youki Oyamada, Ei'ichi Iizasa, Amane Usa, Konosuke Otomaru.
      1,25-Dihydroxyvitamin D3 (1,25(OH)2 D3 ), a bioactive vitamin D, is known to regulate immune responses in mammals. However, its impact on the innate immune responses of Japanese Black cattle, which are beef cattle endemic to Japan, remains unknown. Thus, in this study, we investigated the effect of 1,25(OH)2 D3 on the immune responses of peripheral blood mononuclear cells from Japanese Black cattle. As a result, the treatment of 1,25(OH)2 D3 upregulated the expression of antibacterial peptides, bovine beta-defensin 10 (DEFB10), and lingual antimicrobial peptide (LAP), in the presence and absence of lipopolysaccharide (LPS) stimulation. Moreover, 1,25(OH)2 D3 enhanced the inflammatory responses, including C-X-C motif ligand 8 (CXCL8) and nitric oxide synthase (NOS2), while reducing the expression of anti-inflammatory cytokine IL10, leading to an inflammatory phenotype. However, in contrast to humans and mice, 1,25(OH)2 D3 did not alter the expression of tumor necrosis factor (TNF) and downregulated triggering receptor expressed on myeloid cell 1 (TREM1) with LPS treatment. These results suggest that 1,25(OH)2 D3 potentiates the innate immune responses of Japanese Black cattle, albeit with different effects and mechanisms as compared to humans and mice.
    Keywords:  Japanese Black cattle; innate immunity; peripheral blood mononuclear cells; vitamin D
    DOI:  https://doi.org/10.1111/asj.13906
  30. Front Immunol. 2023 ;14 1264060
    6'-sialyllactose ameliorates the ototoxic effects of the aminoglycoside antibiotic neomycin in susceptible mice.
    Tawfik Abou Assale, Thomas Kuenzel, Tamara Schink, Anahita Shahraz, Harald Neumann, Christine Klaus.
      Sialic acids are terminal sugars of the cellular glycocalyx and are highly abundant in the nervous tissue. Sialylation is sensed by the innate immune system and acts as an inhibitory immune checkpoint. Aminoglycoside antibiotics such as neomycin have been shown to activate tissue macrophages and induce ototoxicity. In this study, we investigated the systemic subcutaneous application of the human milk oligosaccharide 6'-sialyllactose (6SL) as a potential therapy for neomycin-induced ototoxicity in postnatal mice. Repeated systemic treatment of mice with 6SL ameliorated neomycin-induced hearing loss and attenuated neomycin-triggered macrophage activation in the cochlear spiral ganglion. In addition, 6SL reversed the neomycin-mediated increase in gene transcription of the pro-inflammatory cytokine interleukin-1β (Il-1b) and the apoptotic/inflammatory kinase Pik3cd in the inner ear. Interestingly, neomycin application also increased the transcription of desialylating enzyme neuraminidase 3 (Neu3) in the inner ear. In vitro, we confirmed that treatment with 6SL had anti-inflammatory, anti-phagocytic, and neuroprotective effects on cultured lipopolysaccharide-challenged human THP1-macrophages. Thus, our data demonstrated that treatment with 6SL has anti-inflammatory and protective effects against neomycin-mediated macrophage activation and ototoxicity.
    Keywords:  6’-sialyllactose; hearing loss; macrophages; neomycin; neuroinflammation; sialylation
    DOI:  https://doi.org/10.3389/fimmu.2023.1264060
  31. J Clin Invest. 2023 Dec 19. pii: e167671. [Epub ahead of print]
    Microbiota-dependent indole production stimulates the development of collagen-induced arthritis in mice.
    Brenda J Seymour, Brandon Trent, Brendan E Allen, Adam J Berlinberg, Jimmy Tangchittsumran, Widian K Jubair, Meagan E Chriswell, Sucai Liu, Alfredo Ornelas, Andrew Stahly, Erica E Alexeev, Alexander S Dowdell, Sunny L Sneed, Sabrina Fechtner, Jennifer M Kofonow, Charles E Robertson, Stephanie M Dillon, Cara C Wilson, Robert M Anthony, Daniel N Frank, Sean P Colgan, Kristine A Kuhn.
      Altered tryptophan catabolism has been identified in inflammatory diseases like rheumatoid arthritis (RA) and spondyloarthritis (SpA), but the causal mechanisms linking tryptophan metabolites to disease are unknown. Using the collagen-induced arthritis (CIA) model we identified alterations in tryptophan metabolism, and specifically indole, that correlated with disease. We demonstrated that both bacteria and dietary tryptophan were required for disease, and indole supplementation was sufficient to induce disease in their absence. When mice with CIA on a low-tryptophan diet were supplemented with indole, we observed significant increases in serum IL-6, TNF, and IL-1β; splenic RORγt+CD4+ T cells and ex vivo collagen-stimulated IL-17 production; and a pattern of anti-collagen antibody isotype switching and glycosylation that corresponded with increased complement fixation. IL-23 neutralization reduced disease severity in indole-induced CIA. Finally, exposure of human colon lymphocytes to indole increased expression of genes involved in IL-17 signaling and plasma cell activation. Altogether, we propose a mechanism by which intestinal dysbiosis during inflammatory arthritis results in altered tryptophan catabolism, leading to indole stimulation of arthritis development. Blockade of indole generation may present a unique therapeutic pathway for RA and SpA.
    Keywords:  Amino acid metabolism; Autoimmunity; Bacterial infections; Mouse models
    DOI:  https://doi.org/10.1172/JCI167671
  32. Biomed Pharmacother. 2023 Dec 20. pii: S0753-3322(23)01828-0. [Epub ahead of print]170 116030
    Effect of metabolic reprogramming on the immune microenvironment in gastric cancer.
    Zhengye Shang, Zhiyuan Ma, Enqin Wu, Xingzhao Chen, Biguang Tuo, Taolang Li, Xuemei Liu.
      Gastric cancer (GC) is a malignant tumor of the gastrointestinal tract with a high mortality rate worldwide, a low early detection rate and a poor prognosis. The rise of metabolomics has facilitated the early detection and treatment of GC. Metabolism in the GC tumor microenvironment (TME) mainly includes glucose metabolism, lipid metabolism and amino acid metabolism, which provide energy and nutrients for GC cell proliferation and migration. Abnormal tumor metabolism can influence tumor progression by regulating the functions of immune cells and immune molecules in the TME, thereby contributing to tumor immune escape. Thus, in this review, we summarize the impact of metabolism on the TME during GC progression. We also propose novel strategies to modulate antitumor immune responses by targeting metabolism.
    Keywords:  Cancer immunity; Gastric cancer; Immune microenvironment; Metabolism; TIME
    DOI:  https://doi.org/10.1016/j.biopha.2023.116030
  33. Cell Rep. 2023 Dec 19. pii: S2211-1247(23)01643-1. [Epub ahead of print]43(1): 113632
    Lipid accumulation-mediated histone hypoacetylation drives persistent NK cell dysfunction in anti-tumor immunity.
    Deyan Jiao, Renhui Sun, Xiaolei Ren, Yingchun Wang, Panpan Tian, Yuzhen Wang, Detian Yuan, Xuetian Yue, Zhuanchang Wu, Chunyang Li, Lifen Gao, Chunhong Ma, Xiaohong Liang.
      
    DOI:  https://doi.org/10.1016/j.celrep.2023.113632
  34. Cell Death Discov. 2023 Dec 22. 9(1): 469
    Squaramides enhance NLRP3 inflammasome activation by lowering intracellular potassium.
    Paula I Seoane, James A Beswick, Andrew G Leach, Tessa Swanton, Lucy V Morris, Kevin Couper, Martin Lowe, Sally Freeman, David Brough.
      The NLRP3 inflammasome is a component of the inflammatory response to infection and injury, orchestrating the maturation and release of the pro-inflammatory cytokines interleukin-1β (IL-1β), IL-18, and triggering pyroptotic cell death. Appropriate levels of NLRP3 activation are needed to avoid excessive tissue damage while ensuring host protection. Here we report a role for symmetrical diarylsquaramides as selective K+ efflux-dependent NLRP3 inflammasome enhancers. Treatment of macrophages with squaramides potentiated IL-1β secretion and ASC speck formation in response to K+ efflux-dependent NLRP3 inflammasome activators without affecting priming, endosome cargo trafficking, or activation of other inflammasomes. The squaramides lowered intracellular K+ concentration which enabled cells to respond to a below-threshold dose of the inflammasome activator nigericin. Taken together these data further highlight the role of ion flux in inflammasome activation and squaramides as an interesting platform for therapeutic development in conditions where enhanced NLRP3 activity could be beneficial.
    DOI:  https://doi.org/10.1038/s41420-023-01756-9
  35. Cell Metab. 2023 Dec 05. pii: S1550-4131(23)00420-5. [Epub ahead of print]
    Central glucagon-like peptide 1 receptor activation inhibits Toll-like receptor agonist-induced inflammation.
    Chi Kin Wong, Brent A McLean, Laurie L Baggio, Jacqueline A Koehler, Rola Hammoud, Nikolaj Rittig, Julian M Yabut, Randy J Seeley, Theodore J Brown, Daniel J Drucker.
      Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert anti-inflammatory effects relevant to the chronic complications of type 2 diabetes. Although GLP-1RAs attenuate T cell-mediated gut and systemic inflammation directly through the gut intraepithelial lymphocyte GLP-1R, how GLP-1RAs inhibit systemic inflammation in the absence of widespread immune expression of the GLP-1R remains uncertain. Here, we show that GLP-1R activation attenuates the induction of plasma tumor necrosis factor alpha (TNF-α) by multiple Toll-like receptor agonists. These actions are not mediated by hematopoietic or endothelial GLP-1Rs but require central neuronal GLP-1Rs. In a cecal slurry model of polymicrobial sepsis, GLP-1RAs similarly require neuronal GLP-1Rs to attenuate detrimental responses associated with sepsis, including sickness, hypothermia, systemic inflammation, and lung injury. Mechanistically, GLP-1R activation leads to reduced TNF-α via α1-adrenergic, δ-opioid, and κ-opioid receptor signaling. These data extend emerging concepts of brain-immune networks and posit a new gut-brain GLP-1R axis for suppression of peripheral inflammation.
    Keywords:  G protein-coupled receptor; autonomic nervous system; diabetes; glucagon-like peptides; gut-brain axis; immune; inflammation; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.009
  36. Sci Immunol. 2023 Dec 22. 8(90): eadf4699
    KCNN4 links PIEZO-dependent mechanotransduction to NLRP3 inflammasome activation.
    Li Ran, Tao Ye, Eric Erbs, Stephan Ehl, Nathalie Spassky, Izabela Sumara, Zhirong Zhang, Romeo Ricci.
      Immune cells sense the microenvironment to fine-tune their inflammatory responses. Patients with cryopyrin-associated periodic syndrome (CAPS), caused by mutations in the NLRP3 gene, develop autoinflammation triggered by nonantigenic cues such as from the environment. However, the underlying mechanisms are poorly understood. Here, we uncover that KCNN4, a calcium-activated potassium channel, links PIEZO-mediated mechanotransduction to NLRP3 inflammasome activation. Yoda1, a PIEZO1 agonist, lowered the threshold for NLRP3 inflammasome activation. PIEZO-mediated sensing of stiffness and shear stress increased NLRP3-dependent inflammation. Myeloid-specific deletion of PIEZO1/2 protected mice from gouty arthritis. Mechanistically, activation of PIEZO1 triggers calcium influx, which activates KCNN4 to evoke potassium efflux and promotes NLRP3 inflammasome activation. Activation of PIEZO signaling was sufficient to activate the inflammasome in cells expressing CAPS-causing NLRP3 mutants via KCNN4. Last, pharmacological inhibition of KCNN4 alleviated autoinflammation in cells of patients with CAPS and in mice bearing a CAPS mutation. Thus, PIEZO-dependent mechanical inputs boost inflammation in NLRP3-dependent diseases, including CAPS.
    DOI:  https://doi.org/10.1126/sciimmunol.adf4699
  37. Viruses. 2023 Nov 29. pii: 2347. [Epub ahead of print]15(12):
    Cholesterol Metabolism in Antigen-Presenting Cells and HIV-1 Trans-Infection of CD4+ T Cells.
    Daniel Okpaise, Nicolas Sluis-Cremer, Giovanna Rappocciolo, Charles R Rinaldo.
      Antiretroviral therapy (ART) provides an effective method for managing HIV-1 infection and preventing the onset of AIDS; however, it is ineffective against the reservoir of latent HIV-1 that persists predominantly in resting CD4+ T cells. Understanding the mechanisms that facilitate the persistence of the latent reservoir is key to developing an effective cure for HIV-1. Of particular importance in the establishment and maintenance of the latent viral reservoir is the intercellular transfer of HIV-1 from professional antigen-presenting cells (APCs-monocytes/macrophages, myeloid dendritic cells, and B lymphocytes) to CD4+ T cells, termed trans-infection. Whereas virus-to-cell HIV-1 cis infection is sensitive to ART, trans-infection is impervious to antiviral therapy. APCs from HIV-1-positive non-progressors (NPs) who control their HIV-1 infection in the absence of ART do not trans-infect CD4+ T cells. In this review, we focus on this unique property of NPs that we propose is driven by a genetically inherited, altered cholesterol metabolism in their APCs. We focus on cellular cholesterol homeostasis and the role of cholesterol metabolism in HIV-1 trans-infection, and notably, the link between cholesterol efflux and HIV-1 trans-infection in NPs.
    Keywords:  HIV-1; antigen-presenting cells; antiretroviral therapy; cholesterol metabolism; immunometabolism; latent reservoir; non-progressor; trans-infection
    DOI:  https://doi.org/10.3390/v15122347
  38. Cell Metab. 2023 Dec 13. pii: S1550-4131(23)00444-8. [Epub ahead of print]
    Apoptosis releases hydrogen sulfide to inhibit Th17 cell differentiation.
    Qianmin Ou, Xinhua Qiao, Zhengshi Li, Luhan Niu, Fangcao Lei, Ruifeng Cheng, Ting Xie, Ning Yang, Yao Liu, Ling Fu, Jing Yang, Xueli Mao, Xiaoxing Kou, Chang Chen, Songtao Shi.
      Over 50 billion cells undergo apoptosis each day in an adult human to maintain immune homeostasis. Hydrogen sulfide (H2S) is also required to safeguard the function of immune response. However, it is unknown whether apoptosis regulates H2S production. Here, we show that apoptosis-deficient MRL/lpr (B6.MRL-Faslpr/J) and Bim-/- (B6.129S1-Bcl2l11tm1.1Ast/J) mice exhibit significantly reduced H2S levels along with aberrant differentiation of Th17 cells, which can be rescued by the additional H2S. Moreover, apoptotic cells and vesicles (apoVs) express key H2S-generating enzymes and generate a significant amount of H2S, indicating that apoptotic metabolism is an important source of H2S. Mechanistically, H2S sulfhydrates selenoprotein F (Sep15) to promote signal transducer and activator of transcription 1 (STAT1) phosphorylation and suppress STAT3 phosphorylation, leading to the inhibition of Th17 cell differentiation. Taken together, this study reveals a previously unknown role of apoptosis in maintaining H2S homeostasis and the unique role of H2S in regulating Th17 cell differentiation via sulfhydration of Sep15C38.
    Keywords:  SLE; Th17 cells; apoVs; apoptosis; apoptotic vesicles; hydrogen sulfide; systemic lupus erythematosus
    DOI:  https://doi.org/10.1016/j.cmet.2023.11.012
  39. Circulation. 2023 Dec 21.
    Single-Cell RNA Sequencing Reveals Metabolic Stress-Dependent Activation of Cardiac Macrophages in a Model of Dyslipidemia-Induced Diastolic Dysfunction.
    Cristina Panico, Arianna Felicetta, Paolo Kunderfranco, Marco Cremonesi, Nicolò Salvarani, Pierluigi Carullo, Federico Colombo, Alessandra Idini, Mauro Passaretti, Riccardo Doro, Marcello Rubino, Alessandro Villaschi, Giorgio Da Rin, Clelia Peano, Marinos Kallikourdis, Carolina M Greco, Gianluigi Condorelli.
       BACKGROUND: Metabolic distress is often associated with heart failure with preserved ejection fraction (HFpEF) and represents a therapeutic challenge. Metabolism-induced systemic inflammation links comorbidities with HFpEF. How metabolic changes affect myocardial inflammation in the context of HFpEF is not known.
    METHODS: We found that ApoE knockout mice fed a Western diet recapitulate many features of HFpEF. Single-cell RNA sequencing was used for expression analysis of CD45+ cardiac cells to evaluate the involvement of inflammation in diastolic dysfunction. We focused bioinformatics analysis on macrophages, obtaining high-resolution identification of subsets of these cells in the heart, enabling us to study the outcomes of metabolic distress on the cardiac macrophage infiltrate and to identify a macrophage-to-cardiomyocyte regulatory axis. To test whether a clinically relevant sodium glucose cotransporter-2 inhibitor could ameliorate the cardiac immune infiltrate profile in our model, mice were randomized to receive the sodium glucose cotransporter-2 inhibitor dapagliflozin or vehicle for 8 weeks.
    RESULTS: ApoE knockout mice fed a Western diet presented with reduced diastolic function, reduced exercise tolerance, and increased pulmonary congestion associated with cardiac lipid overload and reduced polyunsaturated fatty acids. The main immune cell types infiltrating the heart included 4 subpopulations of resident and monocyte-derived macrophages, determining a proinflammatory profile exclusively in ApoE knockout- Western diet mice. Lipid overload had a direct effect on inflammatory gene activation in macrophages, mediated through endoplasmic reticulum stress pathways. Investigation of the macrophage-to-cardiomyocyte regulatory axis revealed the potential effects on cardiomyocytes of multiple inflammatory cytokines secreted by macrophages, affecting pathways such as hypertrophy, fibrosis, and autophagy. Finally, we describe an anti-inflammatory effect of sodium glucose cotransporter-2 inhibitor in this model.
    CONCLUSIONS: Using single-cell RNA sequencing , in a model of diastolic dysfunction driven by hyperlipidemia, we have determined the effects of metabolic distress on cardiac inflammatory cells, in particular on macrophages, and suggest sodium glucose cotransporter-2 inhibitors as potential therapeutic agents for the targeting of a specific phenotype of HFpEF.
    Keywords:  SLC5A2 protein, human; heart failure; heart failure, diastolic; inflammation; macrophages
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.122.062984
  40. bioRxiv. 2023 Dec 04. pii: 2023.12.01.569598. [Epub ahead of print]
    A ketogenic diet reduces age-induced chronic neuroinflammation in mice.
    Mitsunori Nomura, Natalia Faraj Murad, Sidharth S Madhavan, Brenda Eap, Thelma Y Garcia, Carlos Galicia Aguirre, Eric Verdin, Lisa Ellerby, David Furman, John C Newman.
      Beta-hydroxybutyrate (BHB) is a ketone body synthesized during fasting or strenuous exercise. Our previous study demonstrated that a cyclic ketogenic diet (KD), which induces BHB levels similar to fasting every other week, reduces midlife mortality and improves memory in aging mice. BHB actively regulates gene expression and inflammatory activation through non-energetic signaling pathways. Neither of these activities has been well-characterized in the brain and they may represent mechanisms by which BHB affects brain function during aging. First, we analyzed hepatic gene expression in an aging KD-treated mouse cohort using bulk RNA-seq. In addition to the downregulation of TOR pathway activity, cyclic KD reduces inflammatory gene expression in the liver. We observed via flow cytometry that KD also modulates age-related systemic T cell functions. Next, we investigated whether BHB affects brain cells transcriptionally in vitro . Gene expression analysis in primary human brain cells (microglia, astrocytes, neurons) using RNA-seq shows that BHB causes a mild level of inflammation in all three cell types. However, BHB inhibits the more pronounced LPS-induced inflammatory gene activation in microglia. Furthermore, we confirmed that BHB similarly reduces LPS-induced inflammation in primary mouse microglia and bone marrow-derived macrophages (BMDMs). BHB is recognized as an inhibitor of histone deacetylase (HDAC), an inhibitor of NLRP3 inflammasome, and an agonist of the GPCR Hcar2. Nevertheless, in microglia, BHB's anti-inflammatory effects are independent of these known mechanisms. Finally, we examined the brain gene expression of 12-month-old male mice fed with one-week and one-year cyclic KD. While a one-week KD increases inflammatory signaling, a one-year cyclic KD reduces neuroinflammation induced by aging. In summary, our findings demon-strate that BHB mitigates the microglial response to inflammatory stimuli, like LPS, possibly leading to decreased chronic inflammation in the brain after long-term KD treatment in aging mice.
    DOI:  https://doi.org/10.1101/2023.12.01.569598
  41. Virol J. 2023 Dec 19. 20(1): 305
    Untargeted metabolomics of the intestinal tract of DEV-infected ducks.
    Haiqing Cai, Xia Yang, Yunyun Yang, Yi Feng, Anlin Wen, Ying Yang, Ming Wen, Deyuan Ou.
       INTRODUCTION: Duck enteritis virus (DEV) mainly causes infectious diseases characterized by intestinal haemorrhage, inflammation and parenchymal organ degeneration in ducks and other poultry. However, the mechanism by which it causes intestinal damage in ducks is not well understood. Metabolomics can provide an in-depth understanding of the full complexity of the disease.
    METHODS: In this study, 24 clinically healthy green-shell ducks (weight 1.5 kg ± 20 g) were randomly divided into 2 groups (experimental group, 18; control group, 6). The experimental group was intramuscularly injected with 0.2 mL of DEV virus in solution (TCID50 3.16 × 108 PFU/mL), and the control group was injected with 0.2 mL of sterile normal saline. Duck duodenum and ileum tissue samples were collected at 66 h, 90 h and 114 h post-injection (12 h of fasting before killing), and metabolomics analysis of duck duodenum and ileum tissues at the three time points (66, 90, 114 h) was performed by liquid chromatography-mass spectrometry (LC-MS) to screen for and analyse the potential differentiated metabolites and related signalling pathways.
    RESULTS: Screening was performed in the positive/negative mode (Pos: Positive ion mode; the ionization of substances at the ion source with positive ions such as H+, NH4+, Na+ and K+; Neg: Negative ion mode; the ionization of substances at the ion source with negative ions such as Cl-, OAc-), and compound abundance was compared to that in the control group. The total number of differentially abundant compounds in the duodenum at 66 h, 90 h and 114 h of DEV infection gradually increased, and metabolites such as cytidine, 2'-deoxyriboside and 4-guanidinobutyric acid were differentially abundant metabolites common to all three time periods. The metabolic pathways related to inflammatory response and immune response were tryptophan acid metabolism, cysteine-methionine metabolism, histidine metabolism and other amino acid metabolism and fat metabolism. Among them, the metabolic pathways with more differentially abundant metabolites were amino acid biosynthesis, cysteine and methionine metabolism, tryptophan metabolism, unsaturated fatty acid biosynthesis and purine metabolism, and the metabolic pathways with more enrichment factors were the IgA-related intestinal immune network pathway and lysosome pathway. Compared with the control group, there were 16 differentially abundant metabolites in the ileum tissue of DEV-infected ducks at 66 h of infection, 52 at 90 h of infection, and 40 at 14 h of infection with TD114. The metabolic pathways with more enriched differentially abundant metabolites were pyrimidine metabolism, tyrosine metabolism, phenylalanine metabolism and tryptophan biosynthesis. The metabolic pathways with the most enrichment factors were the mTOR signalling pathway, ferroptosis pathway, tryptophan metabolism pathway and caffeine metabolism pathway.
    CONCLUSION: Comparative analysis showed that the number of differentially abundant metabolites in the duodenum and ileum differed to some extent after DEV infection, with significantly more differentially abundant metabolites in duodenal tissues and fewer in ileal tissues; after DEV infection, the highest number of differentially abundant metabolites was obtained at 114 h of DEV infection, followed by the second highest at 90 h of infection and the lowest at 66 h of infection. The common differentially abundant metabolites in duodenal and ileal tissues were prostaglandins, arachidonic acid, and arachidonic ethanolamine. The main metabolic pathways in the duodenum were the IgA-associated intestinal immune network pathway and the lysosomal pathway, and the metabolic pathways with more enriched factors in the ileum were the mTOR signalling pathway, the ferroptosis pathway, and the tryptophan metabolism pathway.
    Keywords:  Differentially abundant metabolites; Duck; Duck enteritis virus; Gut; Nontargeted metabolomics
    DOI:  https://doi.org/10.1186/s12985-023-02266-x
  42. Nat Rev Cardiol. 2023 Dec 19.
    Bone marrow adipocytes support fatty acid metabolism during MI-mediated emergency haematopoiesis.
    Karina Huynh.
      
    DOI:  https://doi.org/10.1038/s41569-023-00987-8
  43. bioRxiv. 2023 Dec 08. pii: 2023.12.08.570852. [Epub ahead of print]
    Host autophagy is exploited by the intracellular parasite Toxoplasma gondii to enhance amino acids levels.
    Matthew D White, Rajendra K Angara, Leticia Torres Dias, Dhananjay D Shinde, Vinai C Thomas, Leonardo Augusto.
      Toxoplasma gondii, a widespread parasite, has the ability to infect nearly any nucleated cell in warm-blooded vertebrates. It is estimated that around 2 billion people globally have been infected by this pathogen. Although most healthy individuals can effectively control parasite replication, certain parasites may evade the immune response, establishing cysts in the brain that are refractory to the immune system and resistance to available drugs. For its chronic persistence in the brain, the parasite relies on host cells' nutrients, particularly amino acids and lipids. Therefore, understanding how latent parasites persist in the brain is crucial for identifying potential drug targets against chronic forms. While shielded within parasitophorous vacuoles (PVs) or cysts, Toxoplasma exploits the host endoplasmic reticulum (ER) metabolism to sustains its persistence in the brain, resulting in host neurological alterations. In this study, we demonstrate that T. gondii disrupts the host ER homeostasis, resulting in accumulation of unfolded protein with the host ER. The host counters this stress by initiating an autophagic pathway known as ER-phagy, which breaks down unfolded proteins into amino acids, promoting their recycling. Remarkably, the persistence of latent forms in cell culture as well as behavioral changes in mice caused by the latent infection could be successfully reversed by restricting the availability of various amino acids during T. gondi infection. Our findings unveil the underlying mechanisms employed by T. gondii to exploit host ER and lysosomal pathways, enhancing nutrient levels during infection. These insights provide new strategies for the treatment of toxoplasmosis.
    Importance: Intracellular parasites employ several mechanisms to manipulate the cellular environment, enabling them to persist in the host. Toxoplasma gondii , a single-celled parasite, possesses the ability to infect virtually any nucleated cell of warm-blooded vertebrates, including nearly 2 billion people worldwide. Unfortunately, existing treatments and immune responses are not entirely effective in eliminating the chronic persisting forms of the parasite. This study reveals that T. gondii induces the host's autophagic pathway to boost amino acid levels in infected cells. The depletion of amino acids, in turn, influences the persistence of the parasite's chronic forms, resulting in a reduction of neurological alterations caused by chronic infection in mice. Significantly, our investigation establishes the crucial role of host ER-phagy in the parasite's persistence within the host during latent infection.
    DOI:  https://doi.org/10.1101/2023.12.08.570852
  44. Fish Shellfish Immunol. 2023 Dec 19. pii: S1050-4648(23)00808-2. [Epub ahead of print] 109322
    Integrated analysis of transcriptome and metabolome reveals the regulatory mechanism of largemouth bass (Micropterus salmoides) in response to Nocardia seriolae infection.
    Fen Dong, Yu-Long Sun, Yuan-Xin Qian, Qiang Chen, Jia-Le He, Ji-Teng Wang, Tao Han, Xiu-Mei Zhang, Yu-Ting Deng.
      Nocardia seriolae is a severe bacterial pathogen that has seriously affected the development of aquaculture industry. Largemouth bass (Micropterus salmoides) is a commercially significant freshwater fish that suffers a variety of environmental threats, including bacterial pathogens. However, the immune responses and metabolic alterations of largemouth bass to N. seriolae infection remain largely unclear. We discovered that N. seriolae caused pathological alterations in largemouth bass and shifted the transcript of immune-related and apoptotic genes in head kidney after infection. To answer the aforementioned question, a combined transcriptome and metabolome analysis was employed to explore the alterations in genes, metabolites, and metabolic pathways in largemouth bass following bacterial infection. A total of 3579 genes and 1929 metabolites are significant differentially changed in the head kidney post infection. In response to N. seriolae infection, host modifies the PI3K-Akt signaling pathway, TCA cycle, glycolysis, and amino acid metabolism. The integrated analysis of transcriptome and metabolome suggested that with the arginine metabolism pathway as the core, multiple biomarkers (arg gene, arginine) are involved in the antibacterial and immune functions of largemouth bass. Thus, we hypothesized that arginine plays a crucial role in the immune responses of largemouth bass against N. seriolae infection, and increasing arginine levels suitably is beneficial for the host against bacterial infection. Our results shed light on the regulatory mechanism of largemouth bass resistance to N. seriolae infection and contributed to the development of more effective N. seriolae resistance strategies.
    Keywords:  Immune response; Metabolic regulation; Micropterus salmoides; Nocardia seriolae; Transcriptome and metabolome studies
    DOI:  https://doi.org/10.1016/j.fsi.2023.109322
  45. J Nutr Biochem. 2023 Dec 20. pii: S0955-2863(23)00285-1. [Epub ahead of print] 109552
    7-Ketocholesterol plays a key role in cholesterol-induced hepatitis via macrophage and neutrophil infiltration.
    Guoen Li, Hyun-Jung Park, Jae-Hee Suh, Hye-Seon Choi.
      This study sought to explore the role of 7-ketocholesterol (7-KC) in liver damage caused by high cholesterol intake and its potential pathological mechanism in mice. Our in vivo findings indicated that mice fed a high-cholesterol diet had elevated serum levels of 7-KC, accompanied by liver injury and inflammation, similar to human nonalcoholic steatohepatitis. Furthermore, the high-cholesterol diet induced neutrophil infiltration, which played a critical role in liver damage through myeloperoxidase (MPO) activity. Upon stimulation with 7-KC, macrophages exhibited increased expression of C-X-C motif chemokine ligand 1 (CXCL1) and CXCL2, as well as ATP-binding cassette transporter A1 (ABCA1) and ABCG1. Hepatocytes, on the other hand, exhibited increased expression of CXCL2 and ABCG1. The infiltration of neutrophils in the liver was primarily caused by CXCL1 and CXCL2, resulting in hepatocyte cell death due to elevated MPO activity. Our data also revealed that the activation of macrophages by 7-KC via ABCA1 or ABCG1 was not associated with lipid accumulation. Collectively, these findings suggest that high cholesterol-induced hepatitis in mice involves, at least partially, the recruitment of neutrophils to the liver by 7-KC-activated macrophages. This is mediated by increased expression of CXCL1 and CXCL2 through ABCA1 or ABCG1, which act as 7-KC efflux transporters. Additionally, hepatocytes contribute to this process by increased expression of CXCL2 through ABCG1. Therefore, our findings suggest that 7-KC may play a role in high cholesterol-induced hepatitis in mice by activating macrophages and hepatocytes, ultimately leading to neutrophil infiltration.
    Keywords:  7-ketocholesterol; MPO; liver cell death; macrophage; neutrophil infiltration
    DOI:  https://doi.org/10.1016/j.jnutbio.2023.109552
  46. Front Cell Infect Microbiol. 2023 ;13 1327452
    Metabolomics reveals the mechanism of action of meropenem and amikacin combined in the treatment of Pseudomonas aeruginosa.
    Hai Yang, Zhen Huang, Jiali Yue, Jianqi Chen, Mingming Yu, Chengming Qu.
      The treatment of Pseudomonas aeruginosa infection often involves the combined use of β-lactam and aminoglycoside antibiotics. In this study, we employed metabolomic analysis to investigate the mechanism responsible for the synergistic activities of meropenem/amikacin combination therapy against multidrug-resistant P. aeruginosa strains harboring OXA-50 and PAO genes. Antibiotic concentrations for meropenem (2 mg/L) monotherapy, amikacin (16 mg/L) monotherapy, and meropenem/amikacin (2/16 mg/L) combination therapy were selected based on clinical breakpoint considerations. Metabolomic analysis revealed significant alterations in relevant metabolites involved in bacterial cell membrane and cell wall synthesis within 15 min of combined drug administration. These alterations encompassed various metabolic pathways, including fatty acid metabolism, peptidoglycan synthesis, and lipopolysaccharide metabolism. Furthermore, at 1 h and 4 h, the combination therapy exhibited significant interference with amino acid metabolism, nucleotide metabolism, and central carbon metabolism pathways, including the tricarboxylic acid cycle and pentose phosphate pathway. In contrast, the substances affected by single drug administration at 1 h and 4 h demonstrated a noticeable reduction. Meropenem/amikacin combination resulted in notable perturbations of metabolic pathways essential for survival of P. aeruginosa, whereas monotherapies had comparatively diminished impacts.
    Keywords:  LC-MS/MS; Pseudomonas aeruginosa; amikacin; meropenem; metabolomics
    DOI:  https://doi.org/10.3389/fcimb.2023.1327452
  47. Cell Host Microbe. 2023 Dec 09. pii: S1931-3128(23)00465-1. [Epub ahead of print]
    Fecal metabolite profiling identifies liver transplant recipients at risk for postoperative infection.
    Christopher J Lehmann, Nicholas P Dylla, Matthew Odenwald, Ravi Nayak, Maryam Khalid, Jaye Boissiere, Jackelyn Cantoral, Emerald Adler, Matthew R Stutz, Mark Dela Cruz, Angelica Moran, Huaiying Lin, Ramanujam Ramaswamy, Anitha Sundararajan, Ashley M Sidebottom, Jessica Little, Eric G Pamer, Andrew Aronsohn, John Fung, Talia B Baker, Aalok Kacha.
      Metabolites produced by the intestinal microbiome modulate mucosal immune defenses and optimize epithelial barrier function. Intestinal dysbiosis, including loss of intestinal microbiome diversity and expansion of antibiotic-resistant pathobionts, is accompanied by changes in fecal metabolite concentrations and increased incidence of systemic infection. Laboratory tests that quantify intestinal dysbiosis, however, have yet to be incorporated into clinical practice. We quantified fecal metabolites in 107 patients undergoing liver transplantation (LT) and correlated these with fecal microbiome compositions, pathobiont expansion, and postoperative infections. Consistent with experimental studies implicating microbiome-derived metabolites with host-mediated antimicrobial defenses, reduced fecal concentrations of short- and branched-chain fatty acids, secondary bile acids, and tryptophan metabolites correlate with compositional microbiome dysbiosis in LT patients and the relative risk of postoperative infection. Our findings demonstrate that fecal metabolite profiling can identify LT patients at increased risk of postoperative infection and may provide guideposts for microbiome-targeted therapies.
    Keywords:  Enterobacterales; Enterococcus; infection; liver transplant; metabolome; microbiome; multiple-drug-resistant organism; postoperative
    DOI:  https://doi.org/10.1016/j.chom.2023.11.016
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