bims-imicid 2024-11-24 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–11–24
twenty-two papers selected by
Dylan Ryan, University of Cambridge

Genetically diverse Mycobacterium tuberculosis isolates manipulate inflammasome activation and IL-1β secretion independently of macrophage metabolic rewiring.
Multiomics reveals age-dependent metabolic reprogramming of macrophages by wound bed niche secreted signals.
Metabolic checkpoints in rheumatoid arthritis.
Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity.
Targeting SphK1/S1PR3 axis ameliorates sepsis-induced multiple organ injury via orchestration of macrophage polarization and glycolysis.
Glucose-independent human cytomegalovirus replication is supported by metabolites that feed upper glycolytic branches.
Polyamines mediate cellular energetics and lipid metabolism through mitochondrial respiration to facilitate virus replication.
Methylglyoxal is an antibacterial effector produced by macrophages during infection.
Polyamine-Enriched Exosomes from Leishmania donovani Drive Host Macrophage Polarization via Immunometabolism Reprogramming.
Fueling neurodegeneration: metabolic insights into microglia functions.
Respiratory bioenergetics is enhanced in human, but not bovine macrophages after exposure to M. bovis PPD: Exploratory insights into overall similar Cellular Metabolic Profiles.
Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.
Differential Effects of Itaconate and its Esters on the Glutathione and Glucose Metabolism of Cultured Primary Rat Astrocytes.
Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity.
Metabolomic Profiling of Cerebrospinal Fluid Reveals Metabolite Biomarkers in Tick-Borne Encephalitis Patient.
rTM reprograms macrophages via the HIF-1α/METTL3/PFKM axis to protect mice against sepsis.
Metabolic Reprogramming of Fibroblastic Reticular Cells in Immunity and Tolerance.
YAP enhances mitochondrial OXPHOS in tumor-infiltrating Treg through upregulating Lars2 on stiff matrix.
The Human Mitochondrial Genome Encodes for an Interferon-Responsive Host Defense Peptide.
Cryptic phosphoribosylase activity of NAMPT restricts the virion incorporation of viral proteins.
UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling.
Host specific sphingomyelin is critical for replication of diverse RNA viruses.

J Infect Dis. 2024 Nov 21. pii: jiae583. [Epub ahead of print]

Genetically diverse Mycobacterium tuberculosis isolates manipulate inflammasome activation and IL-1β secretion independently of macrophage metabolic rewiring.

Ana Isabel Fernandes, Alexandre Jorge Pinto, Diogo Silvério, Ulrike Zedler, Carolina Ferreira, Iola F Duarte, Ricardo Silvestre, Anca Dorhoi, Margarida Saraiva.

  The diversity of Mycobacterium tuberculosis (Mtb) impacts the outcome of tuberculosis. We previously showed that Mtb isolates obtained from patients with severe disease induced low inflammasome activation and IL-1β production by infected macrophages. Here we questioned whether this differential modulation of macrophages by Mtb isolates depended on distinct metabolic reprogramming. We found that the macrophage metabolic landscape was similar regardless of the infecting Mtb isolate. Paralleling single-TLR activated macrophages, glycolysis inhibition during infection impaired IL-1β secretion. However, departing from TLR based models, in infected macrophages, IL-1β secretion was independent of mitochondrial metabolic changes and HIF-1α. Additionally, we found an unappreciated impact of a host metabolic inhibitor on the pathogen, and show that inflammasome activation and IL-1β production by macrophages require metabolically active bacteria. Our study highlights the potential confounding effect of host metabolic inhibitors on the pathogen and uncouples Mtb-inflammasome modulation from the host metabolic reprogramming.

Keywords:   Mycobacterium tuberculosis ; immunometabolism; inflammasome; macrophage

DOI:  https://doi.org/10.1093/infdis/jiae583
bioRxiv. 2024 Nov 03. pii: 2024.10.30.621159. [Epub ahead of print]

Multiomics reveals age-dependent metabolic reprogramming of macrophages by wound bed niche secreted signals.

Maria Fernanda Forni, Gabriela A Pizzurro, Will Krause, Amanda F Alexander, Kate Bridges, Yiting Xu, Olivia Justynski, Anthony Gabry, Niels Olsen Saraiva Camara, Kathryn Miller-Jensen, Valerie Horsley.

The cellular metabolism of macrophages depends on tissue niches and can control macrophage inflammatory or resolving phenotypes. Yet, the identity of signals within tissue niches that control macrophage metabolism is not well understood. Here, using single-cell RNA sequencing of macrophages in early mouse wounds, we find that, rather than gene expression of canonical inflammatory or resolving polarization markers, metabolic gene expression defines distinct populations of early wound macrophages. Single-cell secretomics and transcriptomics identify inflammatory and resolving cytokines expressed by early wound macrophages, and we show that these signals drive metabolic inputs and mitochondrial metabolism in an age-dependent manner. We show that aging alters the metabolome of early wound macrophages and rewires their metabolism from mitochondria to glycolysis. We further show that macrophage-derived Chi3l3 and IGF-1 can induce metabolic inputs and mitochondrial mass/metabolism in aged and bone marrow-derived macrophages. Together, these findings reveal that macrophage-derived signals drive the mitochondrial metabolism of macrophages within early wounds in an age-dependent manner and have implications for inflammatory diseases, chronic injuries, and age-related inflammatory diseases.
In Brief: This study reveals that macrophage subsets in early inflammatory stages of skin wound healing are defined by their metabolic profiles rather than polarization phenotype. Using single-cell secretomics, we establish key macrophage cytokines that comprise the in vivo wound niche and drive mitochondrial-based metabolism. Aging significantly alters macrophage heterogeneity and increases glycolytic metabolism, which can be restored to OxPHOS-based metabolism with young niche cytokines. These findings highlight the importance of the tissue niche in driving macrophage phenotypes, with implications for aging-related impairments in wound healing.
Highlights: Single cell transcriptional analysis reveals that reveals that metabolic gene expression identifies distinct macrophage populations in early skin wounds.Single-cell secretomic data show that young macrophages contribute to the wound bed niche by secreting molecules such as IGF-1 and Chi3l3.Old wound macrophages display altered metabolomics, elevated glycolytic metabolism and glucose uptake, and reduced lipid uptake and mitochondrial mass/metabolism.Chi3l3 but not IGF-1 secretion is altered in macrophages in an age dependent manner.Chi3l3 can restore mitochondrial mass/metabolism in aged macrophages.

DOI: https://doi.org/10.1101/2024.10.30.621159
Semin Arthritis Rheum. 2024 Nov 08. pii: S0049-0172(24)00226-9. [Epub ahead of print] 152586

Metabolic checkpoints in rheumatoid arthritis.

Cornelia M Weyand, Jörg J Goronzy.

   BACKGROUND: Rheumatoid Arthritis is a systemic autoimmune disease affecting 0.5-1 % of the population. Despite a growing therapeutic armamentarium, RA remains incurable, and many patients suffer significant morbidity over time. The strongest genetic risk derives from HLA class II polymorphisms, implicating T cells as pathogenic drivers. Innate immune cells, e.g. monocytes and macrophages (Mⱷ) contribute to chronic tissue inflammation through an array of pro-inflammatory functions but also present antigen to autoreactive T cells. Differentiation, survival, and effector functions of both T cells and Mⱷ are ultimately controlled by their bioenergetic and biosynthetic programs, identifying cellular metabolism as a critical disease mechanism in RA.
OBJECTIVES: Summarize current knowledge about metabolic conditions in the RA joint and disease-relevant metabolic circuits shaping the effector repertoire of RA T cells and Mⱷ.
RESULTS: The rheumatoid joint is a glucose deplete tissue environment, selecting for invading immune cells that can survive on non-glucose fuel sources. Inflamed synovium instead offers the amino acid glutamine and RA CD4+T cells and RA Mⱷ rely on glutamine and glutamate to support their pathogenic functions. The metabolic hallmark of RA T cells is their low mitochondrial performance, resulting in low ATP production, low generation of reactive oxygen species (ROS) and low availability of tricarboxylic acid (TCA) cycle intermediates, all shifting RA T cells towards autoreactivity. The underlying defect stems from insufficient repair of mitochondrial DNA (mtDNA). Functional consequences include reversal of the TCA cycle, accumulation of citrate and lack of malate production. Excessive citrate promotes cytoskeletal hyperacetylation, creating hypermigratory and tissue-invasive T cells. Surplus acetyl-CoA supports lipid droplet formation and lipotoxicity. Lack of malate production disrupts the malate-aspartate shuttle, restricts recovery of cytosolic NAD and drives the endoplasmic reticulum (ER) into expansion. The bioenergetically stressed ER accumulates TNF mRNA and turns RA T cells into TNF superproducers. ATP low production renders RA T cells susceptible to cell death, depositing highly inflammatory mtDNA in the tissue. Mitochondrial deficiency leads to a slowdown in glycolysis and pyruvate processing, such that RA CD4+T cells shunt glucose towards the pentose phosphate pathway to support nucleotide synthesis and clonal proliferation. Metabolically deprived CD4+T cells partner with Mⱷ that have highly functional mitochondria. A hallmark of RA Mⱷ is the high expression of the DNA binding protein RFX5, which co-ordinates adaptations to metabolic needs with function. RFX5 upregulates HLA-DR expression and induces the glutaminolytic enzyme glutamate dehydrogenase 1 (GLUD1), providing bioenergetic resources for antigen presentation and survival in the tissue. In essence, RA CD4+T cells and Mⱷ function in a metabolically challenging environment and rewire their cellular metabolism to survive. Metabolic adaptations promote immunostimulation and tissue inflammation, triggering and sustaining rheumatoid synovitis.

Keywords:  ATP; Acetyl-CoA; Aspartate; Cathepsin; Citrate; Cytokines; Glycolysis; Macrophages; Mitochondria; RFX5; T cells; TNF

DOI:  https://doi.org/10.1016/j.semarthrit.2024.152586
Elife. 2024 Nov 20. pii: RP96812. [Epub ahead of print]13

Neurotrophic factor Neuritin modulates T cell electrical and metabolic state for the balance of tolerance and immunity.

Hong Yu, Hiroshi Nishio, Joseph Barbi, Marisa Mitchell-Flack, Paolo D A Vignali, Ying Zheng, Andriana Lebid, Kwang-Yu Chang, Juan Fu, Makenzie Higgins, Ching-Tai Huang, Xuehong Zhang, Zhiguang Li, Lee Blosser, Ada Tam, Charles Drake, Drew Pardoll.

  The adaptive T cell response is accompanied by continuous rewiring of the T cell's electric and metabolic state. Ion channels and nutrient transporters integrate bioelectric and biochemical signals from the environment, setting cellular electric and metabolic states. Divergent electric and metabolic states contribute to T cell immunity or tolerance. Here, we report in mice that neuritin (Nrn1) contributes to tolerance development by modulating regulatory and effector T cell function. Nrn1 expression in regulatory T cells promotes its expansion and suppression function, while expression in the T effector cell dampens its inflammatory response. Nrn1 deficiency in mice causes dysregulation of ion channel and nutrient transporter expression in Treg and effector T cells, resulting in divergent metabolic outcomes and impacting autoimmune disease progression and recovery. These findings identify a novel immune function of the neurotrophic factor Nrn1 in regulating the T cell metabolic state in a cell context-dependent manner and modulating the outcome of an immune response.

Keywords:  Treg; autoimmunity; cell fate; effector T cell; electric state; immunology; inflammation; metabolism; mouse

DOI:  https://doi.org/10.7554/eLife.96812
Biochim Biophys Acta Mol Cell Res. 2024 Nov 14. pii: S0167-4889(24)00220-9. [Epub ahead of print]1872(1): 119877

Targeting SphK1/S1PR3 axis ameliorates sepsis-induced multiple organ injury via orchestration of macrophage polarization and glycolysis.

Dan Wang, Xinwen Bi, Le Zhao, Shijian Xiang, Wenjie Xi, Shushu Yang, Weijie Wu, Tufeng Chen, Lei Zheng, Xinjin Chi, Yang Kang.

  Sepsis is a heterogeneous and imprecise disorder characterized by aberrant response to infection which has been accredited for detrimental impact on immune homeostasis. Recently, macrophage metabolism has been recognized as attractive targets to develop novel immunomodulatory therapy for sepsis research. However, the fine-tuning regulators dictating macrophage functions and the specific mechanisms underlying macrophage metabolic reprogramming remain largely obscure. Sphingosine-1-phosphate (S1P), a metabolic mediator of sphingolipid catabolism, predominantly formed through sphingosine kinase 1 (SphK1) catalyzing, mediates inflammation in sepsis by binding to S1P receptor 3 (S1PR3) expressed in macrophages. Here we demonstrate that SphK1/S1PR3 axis was upregulated in lipopolysaccharide (LPS)-induced macrophages and septic mice lungs, cascading the activation of proglycolytic signaling such as HIF-1α, HK2 and PFKFB3. Targeted inhibition of Sphk1 by PF-543 effectively abrogated upregulated SphK1/S1PR3 axis in vitro and in vivo. In addition, PF-543 significantly suppressed sepsis-related inflammation and multi-organ injury in vivo. Furthermore, PF-543 not only blunted key glycolytic enzymes HIF-1α, HK2, and PFKFB3 in LPS-treated macrophages but also inhibited HK2 and PFKFB3 in septic mice. Silencing or inhibiting SphK1 tempered pro-inflammatory M1 macrophages while boosted anti-inflammatory M2 macrophages. Intriguingly, S1PR3 knockdown proficiently dampened glycolysis-associated markers, retrieved LPS-modulated M1/M2 polarization and attenuated NF-κB p65 activation. In conclusion, our study provides the first evidence that PF-543 orchestrates proportional imbalance of macrophage polarization and the Warburg effect in a SphK1/S1PR3 dependent manner during sepsis, mitigating both hyperinflammation and multi-organ failure, adding a novel puzzle piece to pharmacologically exploitable therapy for sepsis.

Keywords:  Glycolysis; Macrophage polarization; Multiple organ injury; Sepsis; SphK1/S1PR3 signaling pathway

DOI:  https://doi.org/10.1016/j.bbamcr.2024.119877
Proc Natl Acad Sci U S A. 2024 Nov 26. 121(48): e2412966121

Glucose-independent human cytomegalovirus replication is supported by metabolites that feed upper glycolytic branches.

Rebekah L Mokry, John G Purdy.

  Viruses with broad tissue distribution and cell tropism successfully replicate in various nutrient environments in the body. Several viruses reprogram metabolism for viral replication. However, many studies focus on metabolic reprogramming in nutrient-rich conditions that do not recapitulate physiological environments in the body. Here, we investigated how viruses may replicate when a metabolite thought to be essential for replication is limited. We use human cytomegalovirus infection in glucose-free conditions as a model to determine how glucose supports virus replication and how physiologically relevant nutrients contribute to glucose-independent virus production. We find that glucose supports viral genome synthesis, viral protein production and glycosylation, and infectious virus production. Notably, supplement of glucose-free cultures with uridine, ribose, or UDP-GlcNAc-metabolites that feed upper glycolytic branches like the pentose phosphate pathway-results in partially restored virus replication, including low levels of infectious virus production. Supplementing lower glycolysis in glucose-free cultures using pyruvate fails to restore virus replication. These results indicate that nutrients can compensate for glucose via feeding upper glycolytic branches to sustain low levels of virus production. More broadly, our findings suggest that viruses may successfully replicate in diverse metabolic niches, including those in the body with low glucose levels, through alternative nutrient usage.

Keywords:  glycolysis; herpesviruses; human cytomegalovirus; metabolism

DOI:  https://doi.org/10.1073/pnas.2412966121
PLoS Pathog. 2024 Nov 18. 20(11): e1012711

Polyamines mediate cellular energetics and lipid metabolism through mitochondrial respiration to facilitate virus replication.

Yazmin E Cruz-Pulido, Natalie J LoMascolo, Delaina May, Jomana Hatahet, Caroline E Thomas, Andrea K W Chu, Samantha P Stacey, Maria Del Mar Villanueva Guzman, Gregory Aubert, Bryan C Mounce.

Polyamines are critical cellular components that regulate a variety of processes, including translation, cell cycling, and nucleic acid metabolism. The polyamines, putrescine, spermidine, and spermine, are found abundantly within cells and are positively-charged at physiological pH. Polyamine metabolism is connected to distinct other metabolic pathways, including nucleotide and amino acid metabolism. However, the breadth of the effect of polyamines on cellular metabolism remains to be fully understood. We recently demonstrated a role for polyamines in cholesterol metabolism, and following these studies, we measured the impact of polyamines on global lipid metabolism. We find that lipid droplets increase in number and size with polyamine depletion. We further demonstrate that lipid anabolism is markedly decreased, and lipid accumulation is due to reduced mitochondrial fatty acid oxidation. In fact, mitochondrial structure and function are largely ablated with polyamine depletion. To compensate, cells depleted of polyamines switch from aerobic respiration to glycolysis in a polyamine depletion-mediated Warburg-like effect. Finally, we show that inhibitors of lipid metabolism are broadly antiviral, suggesting that polyamines and lipids are promising antiviral targets. Together, these data demonstrate a novel role for polyamines in mitochondrial function, lipid metabolism, and cellular energetics.

DOI: https://doi.org/10.1371/journal.ppat.1012711
bioRxiv. 2024 Nov 03. pii: 2024.11.03.621721. [Epub ahead of print]

Methylglyoxal is an antibacterial effector produced by macrophages during infection.

Andrea Anaya-Sanchez, Samuel B Berry, Scott Espich, Alex Zilinskas, Phuong M Tran, Carolina Agudelo, Helia Samani, K Heran Darwin, Daniel A Portnoy, Sarah A Stanley.

Infected macrophages transition into aerobic glycolysis, a metabolic program crucial for control of bacterial infection. However, antimicrobial mechanisms supported by aerobic glycolysis are unclear. Methylglyoxal is a highly toxic aldehyde that modifies proteins and DNA and is produced as a side-product of glycolysis. Here we show that despite the toxicity of this aldehyde, infected macrophages generate high levels of methylglyoxal during aerobic glycolysis while downregulating the detoxification system. We use targeted mutations in mice to modulate methylglyoxal generation and show that reducing methylglyoxal production by the host promotes survival of Listeria monocytogenes and Mycobacterium tuberculosis , whereas increasing methylglyoxal levels improves control of bacterial infection. Furthermore, we show that bacteria that are unable to detoxify methylglyoxal are avirulent and experience up to 1000-fold greater genomic mutation frequency during infection. Taken together, these results suggest that methylglyoxal is an antimicrobial innate immune effector that defends the host against bacterial pathogens.

DOI: https://doi.org/10.1101/2024.11.03.621721
ACS Infect Dis. 2024 Nov 19.

Polyamine-Enriched Exosomes from Leishmania donovani Drive Host Macrophage Polarization via Immunometabolism Reprogramming.

Prince Sebastian, Madhulika Namdeo, Moodu Devender, Anjali Anand, Krishan Kumar, Jalaja Veronica, Radheshyam Maurya.

  Leishmania donovani (Ld) promastigotes secrete exosomes that are crucial in host-pathogen interactions and intercellular communication by carrying parasite-specific molecules. Although the composition of cargos in Leishmania exosomes is known, the effects of the unique metabolic repertoire on immunometabolism rewiring of macrophage polarization are poorly understood. Interestingly, we found the enrichment of polyamines (PAs) such as spermidine and putrescine in the Ld-exosomes. Herein, we investigate the critical polycationic molecules and their crucial role in parasite survival. Our study shows that PA inhibition or depletion significantly impairs parasite growth and fitness, particularly in drug-resistant strains. Furthermore, we aimed to elucidate the impact of PAs-enriched Ld-exosomes on host macrophages. The data demonstrated that macrophages efficiently internalized these exosomes, leading to heightened phagocytic activity and infectivity. In addition, internalized Ld-exosomes induced M2 macrophage polarization characterized by elevated Arginase-1 expression and activity. The increased expression of the solute carrier gene (SLC3A2) and elevated intracellular spermidine levels suggest that Ld-exosomes contribute to the host PAs pool and create an anti-inflammatory milieu. These findings highlight the essential role of PAs-enriched Ld-exosomes in parasite survival and establishing a pro-parasitic environment in the host macrophage.

Keywords:  Anti-inflammatory; Arginase-1; Exosomes; Immunometabolism; Macrophage polarization; Polyamines

DOI:  https://doi.org/10.1021/acsinfecdis.4c00738
J Neuroinflammation. 2024 Nov 17. 21(1): 300

Fueling neurodegeneration: metabolic insights into microglia functions.

Mohammadamin Sadeghdoust, Aysika Das, Deepak Kumar Kaushik.

  Microglia, the resident immune cells of the central nervous system, emerge in the brain during early embryonic development and persist throughout life. They play essential roles in brain homeostasis, and their dysfunction contributes to neuroinflammation and the progression of neurodegenerative diseases. Recent studies have uncovered an intricate relationship between microglia functions and metabolic processes, offering fresh perspectives on disease mechanisms and possible treatments. Despite these advancements, there are still significant gaps in our understanding of how metabolic dysregulation affects microglial phenotypes in these disorders. This review aims to address these gaps, laying the groundwork for future research on the topic. We specifically examine how metabolic shifts in microglia, such as the transition from oxidative phosphorylation and mitochondrial metabolism to heightened glycolysis during proinflammatory states, impact the disease progression in Alzheimer's disease, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Additionally, we explore the role of iron, fatty and amino acid metabolism in microglial homeostasis and repair. Identifying both distinct and shared metabolic adaptations in microglia across neurodegenerative diseases could reveal common therapeutic targets and provide a deeper understanding of disease-specific mechanisms underlying multiple CNS disorders.

Keywords:  Immunometabolism; Microglia; Neurodegenerative diseases; Neuroinflammation; Therapeutic strategies

DOI:  https://doi.org/10.1186/s12974-024-03296-0
Innate Immun. 2024 Nov 20. 17534259241296630

Respiratory bioenergetics is enhanced in human, but not bovine macrophages after exposure to M. bovis PPD: Exploratory insights into overall similar Cellular Metabolic Profiles.

Marie-Christine Bartens, Sam Willcocks, Dirk Werling, Amanda J Gibson.

  The role of macrophage (MØ) cellular metabolism and reprogramming during TB infection is of great interest due to the influence of Mycobacterium spp. on MØ bioenergetics. Recent studies have shown that M. tuberculosis induces a TLR2-dependent shift towards aerobic glycolysis, comparable to the established LPS induced pro-inflammatory M1 MØ polarisation. Distinct differences in the metabolic profile of murine and human MØ indicates species-specific differences in bioenergetics. So far, studies examining the metabolic potential of bovine MØ are lacking, thus the basic bioenergetics of bovine and human MØ were explored in response to a variety of innate immune stimuli. Cellular energy metabolism kinetics were measured concurrently for both species on a Seahorse XFe96 platform to generate bioenergetic profiles for the response to the bona-fide TLR2 and TLR4 ligands, FSL-1 and LPS respectively. Despite previous reports of species-specific differences in TLR signalling and cytokine production between human and bovine MØ, we observed similar respiratory profiles for both species. Basal respiration remained constant between stimulated MØ and controls, whereas addition of TLR ligands induced increased glycolysis, as measured by the surrogate parameter ECAR. In contrast to MØ stimulation with M. tuberculosis PPD, another TLR2 ligand, M. bovis PPD treatment significantly enhanced basal respiration rates and glycolysis only in human MØ. Respiratory profiling further revealed significant elevation of ATP-linked OCR and maximal respiration suggesting a strong OXPHOS activation upon M. bovis PPD stimulation in human MØ. Our results provide an exploratory set of data elucidating the basic respiratory profile of bovine vs. human MØ that will not only lay the foundation for future studies to investigate host-tropism of the M. tuberculosis complex but may explain inflammatory differences observed for other zoonotic diseases.

Keywords:  BCG; Macrophage; immunometabolism; mycobacteria; tuberculosis

DOI:  https://doi.org/10.1177/17534259241296630
J Clin Invest. 2024 Nov 19. pii: e177824. [Epub ahead of print]

Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.

Kristen E Kay, Juyeun Lee, Ellen S Hong, Julia Beilis, Sahil Dayal, Emily R Wesley, Sofia Mitchell, Sabrina Z Wang, Daniel J Silver, Josephine Volovetz, Sarah Johnson, Mary McGraw, Matthew Grabowski, Tianyao Lu, Lutz Freytag, Vinod K Narayana, Saskia Freytag, Sarah A Best, James R Whittle, Zeneng Wang, Ofer Reizes, Jennifer S Yu, Stanley L Hazen, J Mark Brown, Defne Bayik, Justin Lathia.

  The glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine (SPD) is elevated in the GBM tumor microenvironment. Exogenous administration of SPD drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and reduced cytotoxic function. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+ T cell number and function.

Keywords:  Adaptive immunity; Brain cancer; Immunology; Oncology; Polyamines

DOI:  https://doi.org/10.1172/JCI177824
Neurochem Res. 2024 Nov 20. 50(1): 24

Differential Effects of Itaconate and its Esters on the Glutathione and Glucose Metabolism of Cultured Primary Rat Astrocytes.

Patrick Watermann, Gurleen K Kalsi, Ralf Dringen, Christian Arend.

  Itaconate is produced as endogenous metabolite by decarboxylation of the citric acid cycle intermediate cis-aconitate. As itaconate has anti-microbial and anti-inflammatory properties, this substance is considered as potential therapeutic drug for the treatment of inflammation in various diseases including traumatic brain injury and stroke. To test for potential adverse effects of itaconate on the viability and metabolism of brain cells, we investigated whether itaconate or its membrane permeable derivatives dimethyl itaconate (DI) and 4-octyl itaconate (OI) may affect the basal glucose and glutathione (GSH) metabolism of cultured primary astrocytes. Acute exposure of astrocytes to itaconate, DI or OI in concentrations of up to 300 µM for up to 6 h did not compromise cell viability. Of the tested substances, only OI stimulated aerobic glycolysis as shown by a time- and concentration-dependent increase in glucose-consumption and lactate release. None of the tested itaconates affected the pentose-phosphate pathway-dependent reduction of the water-soluble tetrazolium salt 1 (WST1). In contrast, both DI and OI, but not itaconate, depleted cellular GSH in a time- and concentration-dependent manner. For OI this depletion was accompanied by a matching increase in the extracellular GSH content that was completely prevented in the presence of the multidrug resistance protein 1 (Mrp1)-inhibitor MK571, while in DI-treated cultures GSH was depleted both in cells and medium. These data suggest that OI stimulates Mrp1-mediated astrocytic GSH export, while DI reacts with GSH to a conjugate that is not detectable by the GSH assay applied. The data presented demonstrate that itaconate, DI and OI differ strongly in their effects on the GSH and glucose metabolism of cultured astrocytes. Such results should be considered in the context of the discussed potential use of such compounds as therapeutic agents.

Keywords:  Astrocytes; Glutathione; Glycolysis; Itaconate; Pentose-phosphate pathway

DOI:  https://doi.org/10.1007/s11064-024-04263-0
EMBO Mol Med. 2024 Nov 18.

Salmonella cancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity.

Alastair Copland, Gillian M Mackie, Lisa Scarfe, Elizabeth Jinks, David A J Lecky, Nancy Gudgeon, Riahne McQuade, Masahiro Ono, Manja Barthel, Wolf-Dietrich Hardt, Hiroshi Ohno, Wilma H M Hoevenaar, Sarah Dimeloe, David Bending, Kendle M Maslowski.

  Bacterial cancer therapy (BCT) is a promising therapeutic for solid tumours. Salmonella enterica Typhimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy; instead, STm BCT depends on innate phagocytes for tumour control. Here, we used distal T cell receptor (TCR) and IFNγ reporter mice (Nr4a3-Tocky-Ifnγ-YFP) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic tumour infiltrating lymphocytes (TILs) exhibited a variety of activation defects, including IFN-γ production decoupled from TCR signalling, decreased polyfunctionality and reduced central memory (TCM) formation. Modelling of T-cell-tumour interactions with a tumour organoid platform revealed an intact TCR signalosome, but paralysed metabolic reprogramming due to inhibition of the master metabolic controller, c-Myc. Restoration of c-Myc by deletion of the bacterial asparaginase ansB reinvigorated T cell activation, but at the cost of decreased metabolic control of the tumour by STm. This work shows for the first time that T cells are metabolically defective during BCT, but also that this same phenomenon is inexorably tied to intrinsic tumour suppression by the bacterial vector.

Keywords:   Salmonella ; Asparagine; Cancer Therapy; Immunometabolism; T Cells

DOI:  https://doi.org/10.1038/s44321-024-00159-2
J Med Virol. 2024 Nov;96(11): e70082

Metabolomic Profiling of Cerebrospinal Fluid Reveals Metabolite Biomarkers in Tick-Borne Encephalitis Patient.

Runxin Liang, Yuchang Li, Jing Li, Sen Zhang, Yanhong Gao, Fuli Tan, Ye Feng, Yuehong Chen, Fei Wang, Tao Jiang, Xiaoping Kang.

  Tick-borne encephalitis virus (TBEV) can cause life-threatening central nervous system infection. Changes in cerebrospinal fluid (CSF) metabolites may reflect critical aspects of host responses and end-organ damage in neuro infection and neuroinflammation. In this study, we applied an untargeted metabolomics screen of CSF samples to investigate the metabolites profile and explore biomarkers for TBEV infection. By analyzing CSF samples from 77 patients with TBEV infection and 23 without TBEV infection, tryptophan metabolism and Citrate cycle were found to be the top important metabolic pathways in differentiating the control and case groups; acetoacetate, 5'-deoxy-5'-(methylthio)-adenosine, 3-methyl-2-oxobutanoic acid, and so forth. were identified to be metabolic biomarkers (| log2${\mathrm{log}}_{2}$ FC|> 1, VIP > 1, FDR < 0.05) in CSF and clearly separated the TBEV infection from the noninfected samples. Moreover, four metabolites were identified to be associated with fatal outcome, including kynurenic acid, 5-hydroxyindole-3-acetic acid, DL-tryptophan, indole-3-acrylic acid, demonstrating the potential predictive biomarkers for severe TBEV infection. This study explored the metabolic profile of TBEV infection in CSF samples and identified candidate biomarkers for TBEV infection, which might be useful in target screening for differential diagnosis and therapeutic inter-vention.

Keywords:  cerebrospinal fluid; metabolic biomarker; tick‐borne encephalitis virus

DOI:  https://doi.org/10.1002/jmv.70082
Cell Mol Life Sci. 2024 Nov 16. 81(1): 456

rTM reprograms macrophages via the HIF-1α/METTL3/PFKM axis to protect mice against sepsis.

Chen Yao, Hanyong Zhu, Binbin Ji, Hui Guo, Zimeng Liu, Ni Yang, Qi Zhang, Kangning Hai, Chenbo Gao, Jie Zhao, Xueqin Li, Rongqing Li, Xin Chen, Fandong Meng, Xiucheng Pan, Chunling Fu, Wanpeng Cheng, Fuxing Dong, Jing Yang, Yuchen Pan, Takayuki Ikezoe.

  The metabolic reprogramming of macrophages is a potential therapeutic strategy for sepsis treatment, but the mechanism underlying this reprogramming remains unclear. Since glycolysis can drive macrophage phenotype switching, the rate-limiting enzymes in glycolysis may be key to treating sepsis. Here, we found that, compared with other isoenzymes, the expression of 6-phosphofructokinase, muscle type (PFKM) was the most upregulated in monocytes from septic patients. Recombinant thrombomodulin (rTM) treatment downregulated the protein expression of PFKM in macrophages. Both rTM treatment and Pfkm knockout protected mice from sepsis and reduced the production of the proinflammatory cytokines IL-1β, IL-6, TNF-α, and IL-27, whereas PFKM overexpression increased the production of these cytokines. Mechanistically, rTM treatment inhibited glycolysis in macrophages by decreasing PFKM expression in a hypoxia-inducible factor-1α (HIF-1α)-dependent manner. HIF-1α overexpression increased methyltransferase-like 3 (METTL3) expression, elevated the m6A level on Pfkm, and upregulated the protein expression of PFKM. METTL3 silence attenuated HIF-1α-mediated PFKM expression. These findings provide insight into the underlying mechanism of macrophage reprogramming for the treatment of sepsis.

Keywords:  6-phosphofructokinase; Glycolysis; Macrophages; Methyltransferase-like 3 (METTL3); Muscle type (PFKM); Sepsis; Thrombomodulin

DOI:  https://doi.org/10.1007/s00018-024-05489-5
Eur J Immunol. 2024 Nov 18. e202451321

Metabolic Reprogramming of Fibroblastic Reticular Cells in Immunity and Tolerance.

Dejun Kong, Marina WillsonShirkey, Wenji Piao, Long Wu, Shunqun Luo, Allision Kensiski, Jing Zhao, Young Lee, Reza Abdi, Hong Zheng, Jonathan S Bromberg.

  Fibroblastic reticular cells (FRCs) are pivotal stromal components that maintain the structure of secondary lymphoid tissues and modulate the immune responses within the lymphoid microenvironment. In response to specific immune or inflammatory stimuli, such as infection or autoimmune triggers, FRCs undergo significant metabolic reprogramming. This process, originally characterized in cancer research, involves the regulation of key metabolic enzymes, pathways, and metabolites, resulting in functional transformations of these cells. Specifically, viruses stimulate FRCs to enhance the tricarboxylic acid cycle, while rheumatoid arthritis and sepsis prompt FRCs to increase oxidative phosphorylation. These changes enable FRCs to adapt their functions, such as proliferation or cytokine secretion, thereby effectively regulating the immune microenvironment to meet the dynamic needs of the immune system. This review provides a comprehensive update on the metabolic reprogramming of FRCs, highlighting how these changes support immune tolerance and response under varied physiological conditions.

Keywords:  fibroblastic reticular cells; immune homeostasis; lymph node stromal cell; metabolic reprogramming

DOI:  https://doi.org/10.1002/eji.202451321
J Immunother Cancer. 2024 Nov 17. pii: e010463. [Epub ahead of print]12(11):

YAP enhances mitochondrial OXPHOS in tumor-infiltrating Treg through upregulating Lars2 on stiff matrix.

Jingchao Bai, Meinan Yan, Yihan Xu, Youhui Wang, Yuan Yao, Peng Jin, Yuhan Zhang, Yang Qu, Liling Niu, Hui Li.

   BACKGROUND: Tumor-infiltrating regulatory T cells (TI-Tregs) are well-adapted to thrive in the challenging tumor microenvironment (TME) by undergoing metabolic reprogramming, notably shifting from glycolysis to mitochondrial oxidative phosphorylation (OXPHOS) for energy production. The extracellular matrix is an important component of the TME, contributing to the regulation of both tumor and immune cell metabolism patterns by activating mechanosensors such as YAP. Whether YAP plays a part in regulating TI-Treg mitochondrial function and the underlying mechanisms are yet to be elucidated.
METHODS: To gain insights into the effect of matrix stiffness on YAP activation in Tregs, alterations in stiffness were performed both in vitro and in vivo. YAP conditional knockout mice were used to determine the role of YAP in TI-Tregs. RNA-seq, quantitative PCR, flow cytometry, lentivirus infection and mitochondrial function assay were employed to uncover the mechanism of YAP modulating mitochondrial function in TI-Tregs. A YAP inhibitor and a low leucine diet were applied to tumor-bearing mice to seek the potential antitumor strategy.
RESULTS: In this study, we found that YAP, as a mechanotransducer, was activated by matrix stiffness in TI-Tregs. A deficiency in YAP significantly hindered the immunosuppressive capability of TI-Tregs by disrupting mitochondrial function. Mechanically, YAP enhanced mitochondrial OXPHOS by upregulating the transcription of Lars2 (Leucyl-tRNA synthetase 2, mitochondrial), which was essential for mitochondrial protein translation in TI-Tregs. Since Lars2 relied much on its substrate amino acid, leucine, the combination of a low leucine diet and YAP inhibitor synergistically induced mitochondrial dysfunction in TI-Tregs, ultimately restraining tumor growth.
CONCLUSIONS: This finding uncovered a new understanding of how YAP shapes mitochondrial function in TI-Tregs in response to mechanical signals within the TME, making the combined strategy of traditional medicine and diet adjustment a promising approach for tumor therapy.

Keywords:  Extracellular Matrix; Mitochondria; Solid tumor; T regulatory cell - Treg

DOI:  https://doi.org/10.1136/jitc-2024-010463
bioRxiv. 2024 Nov 01. pii: 2023.03.02.530691. [Epub ahead of print]

The Human Mitochondrial Genome Encodes for an Interferon-Responsive Host Defense Peptide.

M C Rice, M Imun, S W Jung, C Y Park, J S Kim, R W Lai, C R Barr, J M Son, K Tor, E Kim, R J Lu, I Cohen, B A Benayoun, C Lee.

The mitochondrial DNA (mtDNA) can trigger immune responses and directly entrap pathogens, but it is not known to encode for active immune factors. The immune system is traditionally thought to be exclusively nuclear-encoded. Here, we report the identification of a mitochondrial-encoded host defense peptide (HDP) that presumably derives from the primordial proto-mitochondrial bacteria. We demonstrate that MOTS-c (mitochondrial open reading frame from the twelve S rRNA type-c) is a mitochondrial-encoded amphipathic and cationic peptide with direct antibacterial and immunomodulatory functions, consistent with the peptide chemistry and functions of known HDPs. MOTS-c targeted E. coli and methicillin-resistant S. aureus (MRSA), in part, by targeting their membranes using its hydrophobic and cationic domains. In monocytes, IFNγ, LPS, and differentiation signals each induced the expression of endogenous MOTS-c. Notably, MOTS-c translocated to the nucleus to regulate gene expression during monocyte differentiation and programmed them into macrophages with unique transcriptomic signatures related to antigen presentation and IFN signaling. MOTS-c-programmed macrophages exhibited enhanced bacterial clearance and shifted metabolism. Our findings support MOTS-c as a first-in-class mitochondrial-encoded HDP and indicates that our immune system is not only encoded by the nuclear genome, but also by the co-evolved mitochondrial genome.

DOI: https://doi.org/10.1101/2023.03.02.530691
Nat Metab. 2024 Nov 21.

Cryptic phosphoribosylase activity of NAMPT restricts the virion incorporation of viral proteins.

Shu Feng, Na Xie, Yongzhen Liu, Chao Qin, Ali Can Savas, Ting-Yu Wang, Shutong Li, Youliang Rao, Alexandra Shambayate, Tsui-Fen Chou, Charles Brenner, Canhua Huang, Pinghui Feng.

As obligate intracellular pathogens, viruses activate host metabolic enzymes to supply intermediates that support progeny production. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of salvage nicotinamide adenine dinucleotide (NAD+) synthesis, is an interferon-inducible protein that inhibits the replication of several RNA and DNA viruses through unknown mechanisms. Here, we show that NAMPT restricts herpes simplex virus type 1 (HSV-1) replication by impeding the virion incorporation of viral proteins owing to its phosphoribosyl-hydrolase (phosphoribosylase) activity, which is independent of the role of NAMPT in NAD+ synthesis. Proteomics analysis of HSV-1-infected cells identifies phosphoribosylated viral structural proteins, particularly glycoproteins and tegument proteins, which are de-phosphoribosylated by NAMPT in vitro and in cells. Chimeric and recombinant HSV-1 carrying phosphoribosylation-resistant mutations show that phosphoribosylation promotes the incorporation of structural proteins into HSV-1 virions and subsequent virus entry. Loss of NAMPT renders mice highly susceptible to HSV-1 infection. Our work describes an additional enzymatic activity of a metabolic enzyme in viral infection and host defence, offering a system to interrogate the roles of protein phosphoribosylation in metazoans.

DOI: https://doi.org/10.1038/s42255-024-01162-0
Nat Immunol. 2024 Nov 20.

UBXN9 governs GLUT4-mediated spatial confinement of RIG-I-like receptors and signaling.

Andrew G Harrison, Duomeng Yang, Jason G Cahoon, Tingting Geng, Ziming Cao, Timofey A Karginov, Youjia Hu, Xin Li, Conner C Chiari, Yibing Qyang, Anthony T Vella, Zhichao Fan, Sivapriya Kailasan Vanaja, Vijay A Rathinam, Carol A Witczak, Jonathan S Bogan, Penghua Wang.

The cytoplasmic RIG-I-like receptors (RLRs) recognize viral RNA and initiate innate antiviral immunity. RLR signaling also triggers glycolytic reprogramming through glucose transporters (GLUTs), whose role in antiviral immunity is elusive. Here, we unveil that insulin-responsive GLUT4 inhibits RLR signaling independently of glucose uptake in adipose and muscle tissues. At steady state, GLUT4 is trapped at the Golgi matrix by ubiquitin regulatory X domain 9 (UBXN9, TUG). Following RNA virus infection, GLUT4 is released and translocated to the cell surface where it spatially segregates a significant pool of cytosolic RLRs, preventing them from activating IFN-β responses. UBXN9 deletion prompts constitutive GLUT4 translocation, sequestration of RLRs and attenuation of antiviral immunity, whereas GLUT4 deletion heightens RLR signaling. Notably, reduced GLUT4 expression is uniquely associated with human inflammatory myopathies characterized by hyperactive interferon responses. Overall, our results demonstrate a noncanonical UBXN9-GLUT4 axis that controls antiviral immunity via plasma membrane tethering of cytosolic RLRs.

DOI: https://doi.org/10.1038/s41590-024-02004-7
Cell Chem Biol. 2024 Nov 18. pii: S2451-9456(24)00444-6. [Epub ahead of print]

Host specific sphingomyelin is critical for replication of diverse RNA viruses.

Shuo Han, Xiaolei Ye, Jintong Yang, Xuefang Peng, Xiaming Jiang, Jin Li, Xiaojie Zheng, Xinchen Zhang, Yumin Zhang, Lingyu Zhang, Wei Wang, Jiaxin Li, Wenwen Xin, Xiaoai Zhang, Gengfu Xiao, Ke Peng, Leike Zhang, Xuguang Du, Lu Zhou, Wei Liu, Hao Li.

  Lipids and lipid metabolism play an important role in RNA virus replication, which typically occurs on host cell endomembrane structures in the cytoplasm through mechanisms that are not yet fully identified. We conducted genome-scale CRISPR screening and identified sphingomyelin synthase 1 (SMS1; encoded by SGMS1) as a critical host factor for infection by severe fever with thrombocytopenia syndrome virus (SFTSV). SGMS1 knockout reduced sphingomyelin (SM) (d18:1/16:1) levels, inhibiting SFTSV replication. A helix-turn-helix motif in SFTSV RNA-dependent RNA polymerase (RdRp) directly binds to SM(d18:1/16:1) in Golgi apparatus, which was also observed in SARS-CoV-2 and lymphocytic choriomeningitis virus (LCMV), both showing inhibited replication in SGMS1-KO cells. SM metabolic disturbance is associated with disease severity of viral infections. We designed a novel SMS1 inhibitor that protects mice against lethal SFTSV infection and reduce SARS-CoV-2 replication and pathogenesis. These findings highlight the critical role of SMS1 and SM(d18:1/16:1) in RNA virus replication, suggesting a broad-spectrum antiviral strategy.

Keywords:  Golgi apparatus; RNA viruses; antivirals; lipid metabolism; replication complex; sphingomyelin

DOI:  https://doi.org/10.1016/j.chembiol.2024.10.009