bims-imicid 2024-11-03 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–11–03
27 papers selected by
Dylan Ryan, University of Cambridge

Rhythmic IL-17 production by γδ T cells maintains adipose de novo lipogenesis.
Targeting metabolic pathway enhance CAR-T potency for solid tumor.
Methylmalonic acid induces metabolic abnormalities and exhaustion in CD8+ T cells to suppress anti-tumor immunity.
Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.
Fatty acids promote migration of CD4+ T cells through calcium release-activated calcium modulator ORAI1 sensitive glycolysis in dairy cows.
The immunometabolic roots of aging.
HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells.
HIF-1α regulates mitochondrial function in bone marrow-derived macrophages, but not in tissue-resident alveolar macrophages.
Blocking the HIF-1α/glycolysis axis inhibits allergic airway inflammation by reducing ILC2 metabolism and function.
Stimulation of neutral lipid synthesis via viral growth factor signaling and ATP citrate lyase during vaccinia virus infection.
Sepsis-induced changes in pyruvate metabolism: insights and potential therapeutic approaches.
Metabolic reprogramming tips vaccinia virus infection outcomes by stabilizing interferon-γ induced IRF1.
Nanoparticle-based itaconate treatment recapitulates low-cholesterol/low-fat diet-induced atherosclerotic plaque resolution.
The Role of Natural Killer Cells and Their Metabolism in HIV-1 Infection.
E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic Dysfunction-Associated Steatohepatitis.
Glycolysis inhibition functionally reprograms T follicular helper cells and reverses lupus.
Glut3 promotes cellular O-GlcNAcylation as a distinctive tumor-supportive feature in Treg cells.
Antitumoral Activity and Metabolic Signatures of Dichloroacetate, 6-Aminonicotinamide and Etomoxir in Breast-Tumor-Educated Macrophages.
Tumor-derived lactic acid promotes acetylation of histone H3K27 and differentiation of IL-10-producing regulatory B cells through direct and indirect signaling pathways.
Acid affairs in anti-tumour immunity.
Metabolic gatekeepers: harnessing tumor-derived metabolites to optimize T cell-based immunotherapy efficacy in the tumor microenvironment.
Altered serum metabolome is associated with disease activity and immune responses in rheumatoid arthritis.
Metabolomic alterations in the plasma of patients with various clinical manifestations of COVID-19.
Upregulation of Cullin1 neddylation promotes glycolysis and M1 polarization of macrophage via NF-κB p65 pathway in sepsis.
Lactobacillaceae differentially impact butyrate-producing gut microbiota to drive CNS autoimmunity.
Immune Checkpoint VISTA Negatively Regulates Microglia Glycolysis and Activation via TRIM28-Mediated Ubiquitination of HK2 in Sepsis-Associated Encephalopathy.
The zinc transporter Slc30a1 (ZnT1) in macrophages plays a protective role against attenuated Salmonella.

Nature. 2024 Oct 30.

Rhythmic IL-17 production by γδ T cells maintains adipose de novo lipogenesis.

Aaron Douglas, Brenneth Stevens, Miguel Rendas, Harry Kane, Evan Lynch, Britta Kunkemoeller, Karl Wessendorf-Rodriguez, Emily A Day, Caroline Sutton, Martin Brennan, Katie O'Brien, Ayano C Kohlgruber, Hannah Prendeville, Amanda E Garza, Luke A J O'Neill, Kingston H G Mills, Christian M Metallo, Henrique Veiga-Fernandes, Lydia Lynch.

The circadian rhythm of the immune system helps to protect against pathogens1-3; however, the role of circadian rhythms in immune homeostasis is less well understood. Innate T cells are tissue-resident lymphocytes with key roles in tissue homeostasis4-7. Here we use single-cell RNA sequencing, a molecular-clock reporter and genetic manipulations to show that innate IL-17-producing T cells-including γδ T cells, invariant natural killer T cells and mucosal-associated invariant T cells-are enriched for molecular-clock genes compared with their IFNγ-producing counterparts. We reveal that IL-17-producing γδ (γδ17) T cells, in particular, rely on the molecular clock to maintain adipose tissue homeostasis, and exhibit a robust circadian rhythm for RORγt and IL-17A across adipose depots, which peaks at night. In mice, loss of the molecular clock in the CD45 compartment (Bmal1∆Vav1) affects the production of IL-17 by adipose γδ17 T cells, but not cytokine production by αβ or IFNγ-producing γδ (γδIFNγ) T cells. Circadian IL-17 is essential for de novo lipogenesis in adipose tissue, and mice with an adipocyte-specific deficiency in IL-17 receptor C (IL-17RC) have defects in de novo lipogenesis. Whole-body metabolic analysis in vivo shows that Il17a-/-Il17f-/- mice (which lack expression of IL-17A and IL-17F) have defects in their circadian rhythm for de novo lipogenesis, which results in disruptions to their whole-body metabolic rhythm and core-body-temperature rhythm. This study identifies a crucial role for IL-17 in whole-body metabolic homeostasis and shows that de novo lipogenesis is a major target of IL-17.

DOI: https://doi.org/10.1038/s41586-024-08131-3
Int Immunopharmacol. 2024 Oct 24. pii: S1567-5769(24)01934-9. [Epub ahead of print]143(Pt 2): 113412

Targeting metabolic pathway enhance CAR-T potency for solid tumor.

Wenying Li, Jiannan Chen, Zhigang Guo.

  Chimeric antigen receptor (CAR) T cells have great potential in cancer therapy, particularly in treating hematologic malignancies. However, their efficacy in solid tumors remains limited, with a significant proportion of patients failing to achieve long-term complete remission. One major challenge is the premature exhaustion of CAR-T cells, often due to insufficient metabolic energy. The survival, function and metabolic adaptation of CAR-T cells are key determinants of their therapeutic efficacy. We explore how targeting metabolic pathways in the tumor microenvironment can enhance CAR-T cell therapy by addressing metabolic competition and immunosuppression that impair CAR-T cell function. Tumors undergo metabolically reprogrammed to meet their rapid proliferation, thereby modulating metabolic pathways in immune cells to promote immunosuppression. The distinct metabolic requirements of tumors and T cells create a competitive environment, affecting the efficacy of CAR-T cell therapy. Recent research on glucose, lipid and amino acid metabolism, along with the interactions between tumor and immune cell metabolism, has revealed that targeting these metabolic processes can enhance antitumor immune responses. Combining metabolic interventions with existing antitumor therapies can fulfill the metabolic demands of immune cells, providing new ideas for tumor immunometabolic therapies. This review discusses the latest advances in the immunometabolic mechanisms underlying tumor immunosuppression, their implications for immunotherapy, and summarizes potential metabolic targets to improve the efficacy of CAR-T therapy.

Keywords:  CAR-T cell therapy; Immunotherapy; Metabolism reprogramming; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.intimp.2024.113412
Oncogene. 2024 Oct 29.

Methylmalonic acid induces metabolic abnormalities and exhaustion in CD8+ T cells to suppress anti-tumor immunity.

Joanne D Tejero, Rebecca S Hesterberg, Stanislav Drapela, Didem Ilter, Devesh Raizada, Felicia Lazure, Hossein Kashfi, Min Liu, Leonardo Silvane, Dorina Avram, Juan Fernández-García, John M Asara, Sarah-Maria Fendt, John L Cleveland, Ana P Gomes.

Systemic levels of methylmalonic acid (MMA), a byproduct of propionate metabolism, increase with age and MMA promotes tumor progression via its direct effects in tumor cells. However, the role of MMA in modulating the tumor ecosystem remains to be investigated. The proliferation and function of CD8+ T cells, key anti-tumor immune cells, declines with age and in conditions of vitamin B12 deficiency, which are the two most well-established conditions that lead to increased systemic levels of MMA. Thus, we hypothesized that increased circulatory levels of MMA would lead to a suppression of CD8+ T cell immunity. Treatment of primary CD8+ T cells with MMA induced a dysfunctional phenotype characterized by robust immunosuppressive transcriptional reprogramming and marked increases in the expression of the exhaustion regulator, TOX. Accordingly, MMA treatment upregulated exhaustion markers in CD8+ T cells and decreased their effector functions, which drove the suppression of anti-tumor immunity in vitro and in vivo. Mechanistically, MMA-induced CD8+ T cell exhaustion was associated with a suppression of NADH-regenerating reactions in the TCA cycle and concomitant defects in mitochondrial function. Thus, MMA has immunomodulatory roles, thereby highlighting MMA as an important link between aging, immune dysfunction, and cancer.

DOI: https://doi.org/10.1038/s41388-024-03191-1
bioRxiv. 2024 Oct 14. pii: 2024.10.10.617261. [Epub ahead of print]

Glucose-dependent glycosphingolipid biosynthesis fuels CD8+ T cell function and tumor control.

Joseph Longo, Lisa M DeCamp, Brandon M Oswald, Robert Teis, Alfredo Reyes-Oliveras, Michael S Dahabieh, Abigail E Ellis, Michael P Vincent, Hannah Damico, Kristin L Gallik, Shelby E Compton, Colt D Capan, Kelsey S Williams, Corinne R Esquibel, Zachary B Madaj, Hyoungjoo Lee, Dominic G Roy, Connie M Krawczyk, Brian B Haab, Ryan D Sheldon, Russell G Jones.

  Glucose is essential for T cell proliferation and function, yet its specific metabolic roles in vivo remain poorly defined. Here, we identify glycosphingolipid (GSL) biosynthesis as a key pathway fueled by glucose that enables CD8+ T cell expansion and cytotoxic function in vivo. Using 13C-based stable isotope tracing, we demonstrate that CD8+ effector T cells use glucose to synthesize uridine diphosphate-glucose (UDP-Glc), a precursor for glycogen, glycan, and GSL biosynthesis. Inhibiting GSL production by targeting the enzymes UGP2 or UGCG impairs CD8+ T cell expansion and cytolytic activity without affecting glucose-dependent energy production. Mechanistically, we show that glucose-dependent GSL biosynthesis is required for plasma membrane lipid raft integrity and aggregation following TCR stimulation. Moreover, UGCG-deficient CD8+ T cells display reduced granzyme expression and tumor control in vivo. Together, our data establish GSL biosynthesis as a critical metabolic fate of glucose-independent of energy production-required for CD8+ T cell responses in vivo.

Keywords:  CD8+ T cells; UGCG; cytotoxic function; glucose; glycosphingolipids; immunometabolism; lipid rafts; lipidomics; metabolomics; nucleotide sugar metabolism

DOI:  https://doi.org/10.1101/2024.10.10.617261
J Dairy Sci. 2024 Oct 28. pii: S0022-0302(24)01243-8. [Epub ahead of print]

Fatty acids promote migration of CD4+ T cells through calcium release-activated calcium modulator ORAI1 sensitive glycolysis in dairy cows.

Bingbing Zhang, Jianan Wen, Ming Li, Jingjing Wang, Ziwei Ji, Xinquan Lv, Muhammad Usman, John Mauck, Juan J Loor, Wei Yang, Guihua Wang, Jinzhu Ma, Chuang Xu.

  Nutritional and metabolic state in dairy cows are important determinants of the immune response. During the periparturient period, a state of negative energy balance in the cow increases plasma concentrations of fatty acids, which are associated with inflammation. Among immune cells, CD4+ T are able to function under high fatty acid (High-FA) conditions, but the underlying mechanisms regulating these events remain unclear. The objective of this study was to clarify the functional mechanisms of CD4+ T cells under High-FA conditions. Effects of glycolysis and calcium release-activated calcium modulator 1 (ORAI1) on migration of CD4+ T cells exposed to High-FA were investigated in vivo and in vitro. CD4+ T cells were isolated from peripheral blood of healthy (n = 9) and High-FA (n = 9) Holstein cows (average 2.5 ± 0.2 lactations, 12.3 ± 0.8 d in milk). In the first experiment, real-time quantitative PCR (RT-qPCR) was used to assess chemokine receptors in isolated CD4+ T cells and migration capacity. The relative mRNA measurements results revealed downregulation of CCR1 and CXCR2, and upregulation of CCR2, CCR4, CCR5, CCR7, CCR8, CCR10, CXCR1, CXCR3, CXCR4, CX3CR1. Among them, the expression of CXCR4 was relatively high. Therefore, CXCL12, a ligand chemokine of CXCR4, was an inducer of CD4+ T cell migration. CD4+ T cells were inoculated in the upper chamber and CXCL12 (100 ng/mL, Peprotech) in RPMI1640 was added to the lower chamber and transmigrate for 3 h at 37°C and 5% CO2. The cell migration assay revealed that migration capacity of CD4+ T cells from High-FA cows was greater. RT-qPCR indicated greater abundance of the glycolysis-related targets HIF1A, HK2, PKM2, Glut1, GAPDH, LDHA and Western blotting indicated greater abundance of the glycolysis-related targets HIF1A, HK2, PKM2, Glut1, GAPDH and LDHA in CD4+ T cells of High-FA cows. To characterize specific mechanisms of CD4+ T cell migration in vitro, cells from the spleens of 3 newborn healthy female Holstein calves were isolated (1 d old, 40-50 kg) after euthanasia. Inhibition of glycolysis attenuated the migration ability of cells, but had no effect on the protein and mRNA abundance of SOCE-associated ORAI1 and STIM1. In contrast, ORAI1 was upregulated in CD4+ T cells of cows exposed to high-FA. To explore the potential mechanisms whereby an active glycolytic metabolism affects CD4+ T cells under High-FA conditions, we knocked down ORAI1 (siORAI1) using small interfering RNA. Isolated CD4+ T cells from High-FA cows with the siORAI1 had an attenuated glycolytic metabolism and migration capacity. Taken together, these data suggested that calcium ions in CD4+ T cells from cows with High-FA regulate glycolytic metabolism and influence cell migration at least in part by modulating ORAI1. Thus, these studies identified a novel mechanism of Ca2+ regulation of CD4+ T cell glycolytic metabolism affecting their migration through the SOCE pathway.

Keywords:  CD4(+) T cells; Glycolysis; High FA; Migration; SOCE

DOI:  https://doi.org/10.3168/jds.2024-24845
Curr Opin Immunol. 2024 Oct 25. pii: S0952-7915(24)00088-8. [Epub ahead of print]91 102498

The immunometabolic roots of aging.

Pierpaolo Ginefra, Helen C Hope, Girieca Lorusso, Patrizia D'Amelio, Nicola Vannini.

Aging is one of the greatest risk factors for several chronic diseases and is accompanied by a progressive decline of cellular and organ function. Recent studies have highlighted the changes in metabolism as one of the main drivers of organism dysfunctions during aging and how that strongly deteriorate immune cell performance and function. Indeed, a dysfunctional immune system has been shown to have a pleiotropic impact on the organism, accelerating the overall aging process of an individual. Intrinsic and extrinsic factors are responsible for such metabolic alterations. Understanding the contribution, regulation, and connection of these different factors is fundamental to comprehend the process of aging and develop approaches to mitigate age-related immune decline. Here, we describe metabolic perturbations occurring at cellular and systemic levels. Particularly, we emphasize the interplay between metabolism and immunosenescence and describe novel interventions to protect immune function and promote health span.

DOI: https://doi.org/10.1016/j.coi.2024.102498
Nat Commun. 2024 Oct 30. 15(1): 9394

HIF1α-regulated glycolysis promotes activation-induced cell death and IFN-γ induction in hypoxic T cells.

Hongxing Shen, Oluwagbemiga A Ojo, Haitao Ding, Logan J Mullen, Chuan Xing, M Iqbal Hossain, Abdelrahman Yassin, Vivian Y Shi, Zach Lewis, Ewa Podgorska, Shaida A Andrabi, Maciek R Antoniewicz, James A Bonner, Lewis Zhichang Shi.

Hypoxia is a common feature in various pathophysiological contexts, including tumor microenvironment, and IFN-γ is instrumental for anti-tumor immunity. HIF1α has long been known as a primary regulator of cellular adaptive responses to hypoxia, but its role in IFN-γ induction in hypoxic T cells is unknown. Here, we show that the HIF1α-glycolysis axis controls IFN-γ induction in both human and mouse T cells, activated under hypoxia. Specific deletion of HIF1α in T cells (Hif1α-/-) and glycolytic inhibition suppresses IFN-γ induction. Conversely, HIF1α stabilization by hypoxia and VHL deletion in T cells (Vhl-/-) increases IFN-γ production. Hypoxic Hif1α-/- T cells are less able to kill tumor cells in vitro, and tumor-bearing Hif1α-/- mice are not responsive to immune checkpoint blockade (ICB) therapy in vivo. Mechanistically, loss of HIF1α greatly diminishes glycolytic activity in hypoxic T cells, resulting in depleted intracellular acetyl-CoA and attenuated activation-induced cell death (AICD). Restoration of intracellular acetyl-CoA by acetate supplementation re-engages AICD, rescuing IFN-γ production in hypoxic Hif1α-/- T cells and re-sensitizing Hif1α-/- tumor-bearing mice to ICB. In summary, we identify HIF1α-regulated glycolysis as a key metabolic control of IFN-γ production in hypoxic T cells and ICB response.

DOI: https://doi.org/10.1038/s41467-024-53593-8
bioRxiv. 2024 Oct 14. pii: 2024.10.14.618294. [Epub ahead of print]

HIF-1α regulates mitochondrial function in bone marrow-derived macrophages, but not in tissue-resident alveolar macrophages.

Parker S Woods, Rengül Cetin-Atalay, Angelo Y Meliton, Kaitlyn A Sun, Obada R Shamaa, Kun Woo D Shin, Yufeng Tian, Benjamin Haugen, Robert B Hamanaka, Gökhan M Mutlu.

HIF-1α plays a critical role in shaping macrophage phenotype and effector function. We have previously shown that tissue-resident alveolar macrophages (TR-AMs) have extremely low glycolytic capacity at steady-state, but can shift toward glycolysis under hypoxic conditions. Here, using inducible HIF-1α knockout ( Hif1a -/- ) TR-AMs and bone marrow-derived macrophages (BMDMs) and show that TR-AM HIF-1α is required for the glycolytic shift under prolyl hydroxylase inhibition, but is dispensable at steady-state for inflammatory effector function. In contrast, HIF-1α deletion in BMDMs led to diminished glycolytic capacity at steady-state and reduced inflammatory capacity, but higher mitochondrial function. Gene set enrichment analysis revealed enhanced c-Myc transcriptional activity in Hif1a -/- BMDMs, and upregulation of gene pathways related to ribosomal biogenesis and cellular proliferation. The findings highlight the heterogeneity of HIF-1α function in distinct macrophage populations and provide new insight into how HIF-1α regulates gene expression, inflammation, and metabolism in macrophages.

DOI: https://doi.org/10.1101/2024.10.14.618294
Allergy. 2024 Oct 27.

Blocking the HIF-1α/glycolysis axis inhibits allergic airway inflammation by reducing ILC2 metabolism and function.

Xiaogang Zhang, Jingping Liu, Xinyao Li, Guilang Zheng, Tianci Wang, Hengbiao Sun, Zhengcong Huang, Junyu He, Ju Qiu, Zhibin Zhao, Yuxiong Guo, Yumei He.

   BACKGROUND: The role of lung group 2 innate lymphoid cell (ILC2) activation in allergic asthma is increasingly established. However, the regulatory mechanisms underlying hypoxia-inducible factor-1α (HIF-1α)-mediated glycolysis in ILC2-mediated allergic airway inflammation remain unclear.
OBJECTIVE: To investigate the role of the HIF-1α/glycolysis axis in ILC2-mediated allergic airway inflammation.
METHODS: Glycolysis and HIF-1α inhibitors were used to identify their effect on the function and glucose metabolism of mouse and human ILC2s in vivo and vitro. Blocking glycolysis and HIF-1α in mice under interleukin-33 (IL-33) stimulation were performed to test ILC2 responses. Conditional HIF-1α-deficient mice were used to confirm the specific role of HIF-1α in ILC2-driven airway inflammation models. Transcriptomic, metabolic, and chromatin immunoprecipitation analyses were performed to elucidate the underlying mechanism.
RESULTS: HIF-1α is involved in ILC2 metabolism and is crucial in allergic airway inflammation. Single-cell sequencing data analysis and qPCR confirmation revealed a significant upregulation of glycolysis-related genes, particularly HIF-1α, in murine lung ILC2s after IL-33 intranasal administration or injection. Treatment with the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) and the HIF-1α inhibitor 2-methoxyestradiol (2-ME) abrogated inflammation by suppressing ILC2s function. Conditional HIF-1α-deficient mice showed reduced ILC2 response and airway inflammation induced upon IL-33 or house dust mite (HDM) stimulation. Transcriptome and metabolic analyses revealed significantly impaired glycolysis in lung ILC2s in conditional HIF-1α knockout mice compared to that in their littermate controls. Chromatin immunoprecipitation results confirmed the transcriptional downregulation of glycolysis-related genes in HIF-1α-knockout and 2-DG-treated mice. Furthermore, impaired HIF-1α/glycolysis axis activation is correlated with downregulated ILC2 in patients with asthma.
CONCLUSION: The HIF-1α/glycolysis axis is critical for controlling ILC2 responses in allergic airway inflammation and has potential immunotherapeutic value in asthma.

Keywords:  HIF‐1α; allergic lung inflammation; asthma; glycolysis; group 2 innate lymphoid cells

DOI:  https://doi.org/10.1111/all.16361
J Virol. 2024 Oct 30. e0110324

Stimulation of neutral lipid synthesis via viral growth factor signaling and ATP citrate lyase during vaccinia virus infection.

Anil Pant, Djamal Brahim Belhaouari, Lara Dsouza, Zhilong Yang.

  Fatty acid metabolism can provide various products essential for viral infections. How vaccinia virus (VACV), the prototype of poxviruses, modulates fatty acid metabolism is not well understood. Here, we show that VACV infection results in increased neutral lipid droplet synthesis, the organelles that play a crucial role in storing and mobilizing fatty acids for energy production via β-oxidation. Citrate is the first tricarboxylic acid (TCA) cycle intermediate that can be transported to the cytosol to be converted to acetyl-CoA for de novo fatty acid biosynthesis. We found that VACV infection stimulates the S455 phosphorylation of ATP citrate lyase (ACLY), a pivotal enzyme that links citrate metabolism with lipid metabolism. We demonstrate that the inhibition of neutral lipid droplet synthesis and ACLY severely suppresses VACV replication. Remarkably, we found that virus growth factor (VGF)-induced signaling is essential for the VACV-mediated upregulation of ACLY phosphorylation and neutral lipid droplets. Finally, we report that VGF-induced EGFR-Akt pathway and ACLY phosphorylation are important for VACV stimulation of neutral lipid synthesis. These findings identified a new way of rewiring cell metabolism by a virus and a novel function for VGF in the governance of virus-host interactions through the induction of a key enzyme at the crossroads of the TCA cycle and fatty acid metabolism. Our study also provides a mechanism for the role played by VGF and its downstream signaling cascades in the modulation of lipid metabolism in VACV-infected cells.IMPORTANCENeutral lipid droplets are vital players in cellular metabolism. Here, we showed that VACV induces neutral lipid droplet synthesis in infected primary human foreskin fibroblasts and identified the cellular and viral factors needed. We identified VACV encoded growth factor (VGF) as an essential viral factor that induces cellular EGFR-Akt signaling to increase lipid droplets. Interestingly, VACV increases the S455 phosphorylation of ACLY, a key metabolic enzyme that sits at the crossroads of carbohydrate and lipid metabolism in a VGF-EGFR-Akt-dependent manner. We also found that ACLY is vital for VACV-induced lipid droplet synthesis. Our findings identified the modulation of ACLY by a virus and identified it as a potential target for antiviral development against pathogenic poxviruses. Our study also expands the role of growth factor signaling in boosting VACV replication by targeting fatty acid metabolism.

Keywords:  ATP citrate lyase; EGFR; fatty acids; lipid droplets; metabolism; poxvirus; vaccinia virus

DOI:  https://doi.org/10.1128/jvi.01103-24
EMBO Mol Med. 2024 Oct 28.

Sepsis-induced changes in pyruvate metabolism: insights and potential therapeutic approaches.

Louise Nuyttens, Jolien Vandewalle, Claude Libert.

  Sepsis is a heterogeneous syndrome resulting from a dysregulated host response to infection. It is considered as a global major health priority. Sepsis is characterized by significant metabolic perturbations, leading to increased circulating metabolites such as lactate. In mammals, pyruvate is the primary substrate for lactate production. It plays a critical role in metabolism by linking glycolysis, where it is produced, with the mitochondrial oxidative phosphorylation pathway, where it is oxidized. Here, we provide an overview of all cytosolic and mitochondrial enzymes involved in pyruvate metabolism and how their activities are disrupted in sepsis. Based on the available data, we also discuss potential therapeutic strategies targeting these pyruvate-related enzymes leading to enhanced survival.

Keywords:  Lactate; Metabolism; Mitochondria; Pyruvate; Sepsis

DOI:  https://doi.org/10.1038/s44321-024-00155-6
PLoS Pathog. 2024 Oct 30. 20(10): e1012673

Metabolic reprogramming tips vaccinia virus infection outcomes by stabilizing interferon-γ induced IRF1.

Tyron Chang, Jessica Alvarez, Sruthi Chappidi, Stacey Crockett, Mahsa Sorouri, Robert C Orchard, Dustin C Hancks.

Interferon (IFN) induced activities are critical, early determinants of immune responses and infection outcomes. A key facet of IFN responses is the upregulation of hundreds of mRNAs termed interferon-stimulated genes (ISGs) that activate intrinsic and cell-mediated defenses. While primary interferon signaling is well-delineated, other layers of regulation are less explored but implied by aberrant ISG expression signatures in many diseases in the absence of infection. Consistently, our examination of tonic ISG levels across uninfected human tissues and individuals revealed three ISG subclasses. As tissue identity and many comorbidities with increased virus susceptibility are characterized by differences in metabolism, we characterized ISG responses in cells grown in media known to favor either aerobic glycolysis (glucose) or oxidative phosphorylation (galactose supplementation). While these conditions over time had a varying impact on the expression of ISG RNAs, the differences were typically greater between treatments than between glucose/galactose. Interestingly, extended interferon-priming led to divergent expression of two ISG proteins: upregulation of IRF1 in IFN-γ/glucose and increased IFITM3 in galactose by IFN-α and IFN-γ. In agreement with a hardwired response, glucose/galactose regulation of interferon-γ induced IRF1 is conserved in unrelated mouse and cat cell types. In galactose conditions, proteasome inhibition restored interferon-γ induced IRF1 levels to that of glucose/interferon-γ. Glucose/interferon-γ decreased replication of the model poxvirus vaccinia at low MOI and high MOIs. Vaccinia replication was restored by IRF1 KO. In contrast, but consistent with differential regulation of IRF1 protein by glucose/galactose, WT and IRF1 KO cells in galactose media supported similar levels of vaccinia replication regardless of IFN-γ priming. Also associated with glucose/galactose is a seemingly second block at a very late stage in viral replication which results in reductions in herpes- and poxvirus titers but not viral protein expression. Collectively, these data illustrate a novel layer of regulation for the key ISG protein, IRF1, mediated by glucose/galactose and imply unappreciated subprograms embedded in the interferon response. In principle, such cellular circuitry could rapidly adapt immune responses by sensing changing metabolite levels consumed during viral replication and cell proliferation.

DOI: https://doi.org/10.1371/journal.ppat.1012673
Cell Rep. 2024 Oct 27. pii: S2211-1247(24)01262-2. [Epub ahead of print]43(11): 114911

Nanoparticle-based itaconate treatment recapitulates low-cholesterol/low-fat diet-induced atherosclerotic plaque resolution.

Natalie E Hong, Alice Chaplin, Lin Di, Anastasia Ravodina, Graham H Bevan, Huiyun Gao, Courteney Asase, Roopesh Singh Gangwar, Mark J Cameron, Matthew Mignery, Olga Cherepanova, Aloke V Finn, Lalitha Nayak, Andrew A Pieper, Andrei Maiseyeu.

  Current pharmacologic treatments for atherosclerosis do not completely protect patients; additional protection can be achieved by dietary modifications, such as a low-cholesterol/low-fat diet (LCLFD), that mediate plaque stabilization and inflammation reduction. However, this lifestyle modification can be challenging for patients. Unfortunately, incomplete understanding of the underlying mechanisms has thwarted efforts to mimic the protective effects of a LCLFD. Here, we report that the tricarboxylic acid cycle intermediate itaconate (ITA), produced by plaque macrophages, is key to diet-induced plaque resolution. ITA is produced by immunoresponsive gene 1 (IRG1), which we observe is highly elevated in myeloid cells of vulnerable plaques and absent from early or stable plaques in mice and humans. We additionally report development of an ITA-conjugated lipid nanoparticle that accumulates in plaque and bone marrow myeloid cells, epigenetically reduces inflammation via H3K27ac deacetylation, and reproduces the therapeutic effects of LCLFD-induced plaque resolution in multiple atherosclerosis models.

Keywords:  ApoE(−/−) mice; CP: Immunology; TCA cycle; atherosclerosis; cholesterol; itaconate; nanoparticle; plaque resolution

DOI:  https://doi.org/10.1016/j.celrep.2024.114911
Viruses. 2024 Oct 09. pii: 1584. [Epub ahead of print]16(10):

The Role of Natural Killer Cells and Their Metabolism in HIV-1 Infection.

Kewreshini K Naidoo, Marcus Altfeld.

  Natural killer (NK) cells are multifaceted innate effector cells that critically influence antiviral immunity, and several protective NK cell features that modulate HIV-1 acquisition and viral control have been described. Chronic HIV-1 infection leads to NK cell impairment that has been associated with metabolic dysregulations. Therapeutic approaches targeting cellular immune metabolism represent potential novel interventions to reverse defective NK cell function in people living with HIV.

Keywords:  HIV-1 infection; NK cell metabolism; antiviral immunity; immunometabolism; innate immunity; natural killer cells

DOI:  https://doi.org/10.3390/v16101584
Adv Sci (Weinh). 2024 Oct 28. e2410880

E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic Dysfunction-Associated Steatohepatitis.

Zheng Liu, Hao Wang, Yuan Liang, Mu Liu, Qiyuan Huang, Mingming Wang, Jinren Zhou, Qingfa Bu, Haoming Zhou, Ling Lu.

  Macrophages are essential for the development of steatosis, hepatic inflammation, and fibrosis in metabolic dysfunction-associated steatohepatitis(MASH). However, the roles of macrophage E2F2 in the progression of MASH have not been elucidated. This study reveals that the expression of macrophage E2F2 is dramatically downregulated in MASH livers from mice and humans, and that this expression is adversely correlated with the severity of the disease. Myeloid-specific E2F2 depletion aggravates intrahepatic inflammation, hepatic stellate cell activation, and hepatocyte lipid accumulation during MASH progression. Mechanistically, E2F2 can inhibit the SLC7A5 transcription directly. E2F2 deficiency upregulates the expression of SLC7A5 to mediate amino acids flux, resulting in enhanced glycolysis, impaired mitochondrial function, and increased macrophages proinflammatory response in a Leu-mTORC1-dependent manner. Moreover, bioinformatics analysis and CUT &Tag assay identify the direct binding of Nrf2 to E2F2 promoter to promote its transcription and nuclear translocation. Genetic or pharmacological activation of Nrf2 effectively activates E2F2 to attenuate the MASH progression. Finally, patients treated with CDK4/6 inhibitors demonstrate reduced E2F2 activity but increased SLC7A5 activity in PBMCs. These findings indicated macrophage E2F2 suppresses MASH progression by reprogramming amino acid metabolism via SLC7A5- Leu-mTORC1 signaling pathway. Activating E2F2 holds promise as a therapeutic strategy for MASH.

Keywords:  amino acid transportation; glycolysis; macrophage; metabolic dysfunction‐associated steatohepatitis; slc7a5

DOI:  https://doi.org/10.1002/advs.202410880
bioRxiv. 2024 Oct 18. pii: 2024.10.15.618563. [Epub ahead of print]

Glycolysis inhibition functionally reprograms T follicular helper cells and reverses lupus.

Ahmed Elshikha, Yong Ge, Seung Chul Choi, Yuk Pheel Park, Lauren Padilla, Yanan Zhu, William L Clapp, Eric S Sobel, Mansour Mohamadzadeh, Laurence Morel.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which the production of pathogenic autoantibodies depends on T follicular helper (T FH ) cells. This study was designed to investigate the mechanisms by which inhibition of glycolysis with 2-deoxy-d-glucose (2DG) reduces the expansion of T FH cells and the associated autoantibody production in lupus-prone mice. Integrated cellular, transcriptomic, epigenetic and metabolic analyses showed that 2DG reversed the enhanced cell expansion and effector functions, as well as mitochondrial and lysosomal defects in lupus T FH cells, which include an increased chaperone-mediated autophagy induced by TLR7 activation. Importantly, adoptive transfer of 2DG-reprogrammed T FH cells protected lupus-prone mice from disease progression. Orthologs of genes responsive to 2DG in murine lupus T FH cells were overexpressed in the T FH cells of SLE patients, suggesting a therapeutic potential of targeting glycolysis to eliminate aberrant T FH cells and curb the production of autoantibodies inducing tissue damage.

DOI: https://doi.org/10.1101/2024.10.15.618563
Cell Mol Immunol. 2024 Oct 28.

Glut3 promotes cellular O-GlcNAcylation as a distinctive tumor-supportive feature in Treg cells.

Amit Sharma, Garima Sharma, Zhen Gao, Ke Li, Mutong Li, Menglin Wu, Chan Johng Kim, Yingjia Chen, Anupam Gautam, Hong Bae Choi, Jin Kim, Jung-Myun Kwak, Sin Man Lam, Guanghou Shui, Sandip Paul, Yongqiang Feng, Keunsoo Kang, Sin-Hyeog Im, Dipayan Rudra.

  Regulatory T cells (Tregs) establish dominant immune tolerance but obstruct tumor immune surveillance, warranting context-specific mechanistic insights into the functions of tumor-infiltrating Tregs (TIL-Tregs). We show that enhanced posttranslational O-linked N-acetylglucosamine modification (O-GlcNAcylation) of cellular factors is a molecular feature that promotes a tumor-specific gene expression signature and distinguishes TIL-Tregs from their systemic counterparts. We found that altered glucose utilization through the glucose transporter Glut3 is a major facilitator of this process. Treg-specific deletion of Glut3 abrogates tumor immune tolerance, while steady-state immune homeostasis remains largely unaffected in mice. Furthermore, by employing mouse tumor models and human clinical data, we identified the NF-κB subunit c-Rel as one such factor that, through Glut3-dependent O-GlcNAcylation, functionally orchestrates gene expression in Tregs at tumor sites. Together, these results not only identify immunometabolic alterations and molecular events contributing to fundamental aspects of Treg biology, specifically at tumor sites but also reveal tumor-specific cellular properties that can aid in the development of Treg-targeted cancer immunotherapies.

Keywords:  Glut3; O-GlcNAcylation; Regulatory T cells; Treg; Treg metabolism

DOI:  https://doi.org/10.1038/s41423-024-01229-8
J Proteome Res. 2024 Oct 30.

Antitumoral Activity and Metabolic Signatures of Dichloroacetate, 6-Aminonicotinamide and Etomoxir in Breast-Tumor-Educated Macrophages.

Ana S Dias, Catarina R Almeida, Luisa Helguero, Iola F Duarte.

  Pharmacological targeting of metabolic pathways represents an appealing strategy to selectively kill cancer cells while promoting antitumor functions of stromal cells. In this study, we assessed the effectiveness of 13 metabolic drugs (MDs) in steering in vitro generated breast tumor-educated macrophages (TEMs) toward an antitumoral phenotype. For that, the production of vascular endothelial growth factor (VEGF) and tumor necrosis factor α (TNF-α), two important regulators of tumor progression, was evaluated. Notably, dichloroacetate (DCA), 6-aminonicotinamide (6-AN), and etomoxir decreased VEGF production and enhanced TNF-α release. Hence, we further clarified their impact on TEM metabolism using an untargeted NMR-based metabolomics approach. DCA downregulated glycolysis and enhanced the utilization of extracellular substrates like lactate while reconfiguring lipid metabolism. Several DCA-induced changes significantly correlated with heightened TNF-α production in response to pro-inflammatory stimulation. The inhibition of the pentose phosphate pathway by 6-AN was accompanied by enhanced glutaminolysis, which correlated with a decreased level of VEGF production. In etomoxir-treated TEM, inhibition of fatty acid oxidation was compensated through upregulation of glycolysis, catabolism of intracellular amino acids, and consumption of extracellular branched chain alpha-ketoacids (BCKA) and citrate. Overall, our results offer a comprehensive view of the metabolic signature of each MD in breast TEM and highlight putative correlations with phenotypic effects.

Keywords:  Breast cancer; Macrophages; Metabolic Drugs; Nuclear Magnetic Resonance (NMR) Metabolomics; Tumor Microenvironment; VEGF and TNF-α

DOI:  https://doi.org/10.1021/acs.jproteome.4c00654
Int J Cancer. 2024 Oct 31.

Tumor-derived lactic acid promotes acetylation of histone H3K27 and differentiation of IL-10-producing regulatory B cells through direct and indirect signaling pathways.

Satoshi Muraoka, Takashi Baba, Takashi Akazawa, Kei-Ichi Katayama, Hiroki Kusumoto, Shimpei Yamashita, Yasuo Kohjimoto, Sadahiro Iwabuchi, Shinichi Hashimoto, Isao Hara, Norimitsu Inoue.

  Tumor cells are known to enhance glycolysis, even under normoxic conditions, via the Warburg effect, producing excess lactic acid in the tumor microenvironment. Lactic acid enhances the IL-23/IL-17 pathway and induces chronic inflammation. The acidic microenvironment formed by lactic acid suppresses immune cell proliferation and activation. In the present study, we clarified that lactic acid had two novel activities for immune cells. First, lactic acid specifically enhanced acetylation at lysine 27 of histone H3 (H3K27ac) in splenic B cells and monocytes/macrophages, and this epigenetically up-regulates the expression of genes. Acetylation and methylation of other residues of histone H3 were rarely induced. Second, lactic acid induced a particularly-marked enhancement of Il10 gene expression in B cells, leading to an increase in IL-10-producing regulatory B (Breg) cells. Furthermore, two pathways should be involved in both the enhancement of H3K27ac and the induction of Breg cells by lactic acid: a direct pathway that enhances the CD40 signal in B cells, and an indirect pathway that affects B cells by activating the exchange protein directly activated by cAMP (EPAC) 1/2 in non-B cells. In tumor-bearing mice, the levels of H3K27ac of tumor-infiltrating B cells were significantly higher than splenic B cells and were suppressed by intraperitoneal injection of the EPAC1/2 inhibitor. In conclusion, tumor-derived lactic acid increases H3K27ac and IL-10-producing Breg cells, causing the suppression of anti-tumor immunity.

Keywords:  EPAC; H3K27ac; IL‐10; acetylation; histone; lactic acid; regulatory B cells

DOI:  https://doi.org/10.1002/ijc.35229
Cancer Cell Int. 2024 Oct 27. 24(1): 354

Acid affairs in anti-tumour immunity.

Federica Cappellesso, Massimiliano Mazzone, Federico Virga.

  Metabolic rewiring of cancer cells is one of the hallmarks of cancer. As a consequence, the metabolic landscape of the tumour microenvironment (TME) differs compared to correspondent healthy tissues. Indeed, due to the accumulation of acid metabolites, such as lactate, the pH of the TME is generally acidic with a pH drop that can be as low as 5.6. Disruptions in the acid-base balance and elevated lactate levels can drive malignant progression not only through cell-intrinsic mechanisms but also by impacting the immune response. Generally, acidity and lactate dampen the anti-tumour response of both innate and adaptive immune cells favouring tumour progression and reducing the response to immunotherapy. In this review, we summarize the current knowledge on the functional, metabolic and epigenetic effects of acidity and lactate on the cells of the immune system. In particular, we focus on the role of monocarboxylate transporters (MCTs) and other solute carrier transporters (SLCs) that, by mediating the exchange of lactate (among other metabolites) and bicarbonate, participate in pH regulation and lactate transport in the cancer context. Finally, we discuss advanced approaches to target pH or lactate in the TME to enhance the anti-tumour immune response.

Keywords:  Acidity; Epigenetics; Immune response; Immunotherapy; Lactate; SLC; Tumour microenvironment; pH

DOI:  https://doi.org/10.1186/s12935-024-03520-0
Cell Death Dis. 2024 Oct 26. 15(10): 775

Metabolic gatekeepers: harnessing tumor-derived metabolites to optimize T cell-based immunotherapy efficacy in the tumor microenvironment.

Yucheng Zheng, Rongwei Xu, Xu Chen, Ye Lu, Jiarong Zheng, Yunfan Lin, Pei Lin, Xinyuan Zhao, Li Cui.

The tumor microenvironment (TME) orchestrates a complex interplay between tumor cells and immune cells, crucially modulating the immune response. This review delves into the pivotal role of metabolic reprogramming in the TME, highlighting how tumor-derived metabolites influence T lymphocyte functionality and the efficacy of cancer immunotherapies. Focusing on the diverse roles of these metabolites, we examine how lactate, lipids, amino acids, and other biochemical signals act not only as metabolic byproducts but as regulatory agents that can suppress or potentiate T cell-mediated immunity. By integrating recent findings, we underscore the dual impact of these metabolites on enhancing tumor progression and inhibiting immune surveillance. Furthermore, we propose innovative therapeutic strategies that target metabolic pathways to restore immune function within the TME. The insights provided in this review pave the way for the development of metabolic interventions aimed at enhancing the success of immunotherapies in oncology, offering new hope for precision medicine in the treatment of cancer.

DOI: https://doi.org/10.1038/s41419-024-07122-6
Clin Rheumatol. 2024 Nov 01.

Altered serum metabolome is associated with disease activity and immune responses in rheumatoid arthritis.

Xuanlin Cai, Jiayang Jin, Hua Ye, Xiaohong Xiang, Li Luo, Jing Li.

  Rheumatoid arthritis (RA) is widespread globally, with the emergence of metabolites derived from both the host and microbes playing a pivotal role in its pathogenesis. This study aims to elucidate the relationships between serum metabolites and the immunological and clinical features of RA. Serum samples were collected from 35 RA patients and 37 healthy controls (HC). Metabolite profiling was performed using gas chromatography-mass spectrometry (GC/MS). Principal component analysis revealed a significant distinction between the RA and HC cohorts. Employing univariate statistical analysis, we identified 36 differential metabolites. Among these, 9 metabolites, including galactose and glucose, were found to be enriched, while the remaining metabolites, such as citric acid, fumaric acid, and inosine, were depleted in RA. These diverse metabolites encompassed various metabolic processes, including the biosynthesis of fatty acids, amino acids, and glucose. The enrichment of glucose and galactose in RA exhibited a substantial correlation with elevated IgG levels, as determined through correlation analysis. Conversely, the depletion of citric acid was correlated with elevated levels of C3 and CRP. Methionine, which also declined in RA patients, displayed a negative correlation with ESR. Furthermore, galactose and glucose exhibited significant positive correlations with naïve B cells, while the decreased eicosanoic acid level in RA was significantly associated with an increase in natural killer cells. Our findings suggest that the altered serum metabolite profile in RA is closely linked to disease severity and the dysregulated immune responses observed in RA patients. Key Points • Identified nine metabolites with upregulated expression and twenty-seven metabolites with downregulated expression. • Established a correlation between alterations in serum metabolite levels and inflammatory markers in RA patients. • Discovered a significant association between changes in serum metabolites and immune cell profiles in RA patients.

Keywords:  Disease activity; Immune responses; Metabolomics; Rheumatoid arthritis

DOI:  https://doi.org/10.1007/s10067-024-07201-1
Virol J. 2024 Oct 28. 21(1): 266

Metabolomic alterations in the plasma of patients with various clinical manifestations of COVID-19.

Qi Xin, Xiao Liang, Jin Yang, Xiaorui Wang, Fang Hu, Meng Jiang, Yijia Liu, Jin Gong, Yiwen Pan, Lijuan Liu, Jiao Xu, Yuxin Cui, Hongyu Qin, Han Bai, Yixin Li, Junpeng Ma, Chengsheng Zhang, Bingyin Shi.

   BACKGROUND: The metabolomic profiles of individuals with different clinical manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have not been clearly characterized.
METHODS: We performed metabolomics analysis of 166 individuals, including 62 healthy controls, 16 individuals with asymptomatic SARS-CoV-2 infection, and 88 patients with moderate (n = 42) and severe (n = 46) symptomatic 2019 coronavirus disease (COVID-19; 17 with short-term and 34 with long-term nucleic-acid test positivity). By examining differential expression, we identified candidate metabolites associated with different SARS-CoV-2 infection presentations. Functional and machine learning analyses were performed to explore the metabolites' functions and verify their candidacy as biomarkers.
RESULTS: A total of 417 metabolites were detected. We discovered 70 differentially expressed metabolites that may help differentiate asymptomatic infections from healthy controls and COVID-19 patients with different disease severity. Cyclamic acid and N-Acetylneuraminic Acid were identified to distinguish symptomatic infected patients and asymptomatic infected patients. Shikimic Acid, Glycyrrhetinic acid and 3-Hydroxybutyrate can supply significant insights for distinguishing short-term and long-term nucleic-acid test positivity.
CONCLUSION: Metabolomic profiling may highlight novel biomarkers for the identification of individuals with asymptomatic SARS-CoV-2 infection and further our understanding of the molecular pathogenesis of COVID-19.

Keywords:  Asymptomatic infection; COVID-19; Long-term nucleic acid test positive; Metabolomics; SARS-CoV-2

DOI:  https://doi.org/10.1186/s12985-024-02523-7
Funct Integr Genomics. 2024 Oct 30. 24(6): 204

Upregulation of Cullin1 neddylation promotes glycolysis and M1 polarization of macrophage via NF-κB p65 pathway in sepsis.

Fuchuang Qin, Hang Tan, Yang Yang, Liping Xu, Xiaofeng Yang.

  This study aimed to explore the underlying mechanism of neddylation in macrophage polarization during sepsis. A mouse model of sepsis was established by cecal ligation and puncture (CLP). ELISA and Flow cytometry were performed to analyze the generation of pro-inflammatory factors and M1/M2 macrophage polarization, respectively. Western blotting was applied to detect NEDD8-mediated neddylation and glycolysis-related proteins. ECAR method was used to analyze the glycolysis level. HE staining was applied to detect the lung injury. The bacterial load in peritoneal cavity and peripheral blood was determined by counting the colony-forming units. The results showed the upregulated neddylation, M1 polarization and glycolysis of macrophage in patients with sepsis and CLP-challenged mice. NEDD8-mediated Cullin1 neddylation promoted M1 polarization and glycolysis to accelerate inflammation via NF-κB p65 pathway in E.coli-treated Raw264.7 cells. MLN4924 treatment alleviated sepsis by inhibiting neddylation to prevent M1 polarization in CLP-challenged mice. In summary, this study demonstrated that upregulation of NEDD8-mediated Cullin1 neddylation promotes glycolysis and M1 polarization of macrophage via NF-κB p65 pathway, accelerating inflammation in sepsis.

Keywords:  Glycolysis; Inflammation; Macrophage polarization; NF-κB p65; Neddylation; Sepsis

DOI:  https://doi.org/10.1007/s10142-024-01483-z
Gut Microbes. 2024 Jan-Dec;16(1):16(1): 2418415

Lactobacillaceae differentially impact butyrate-producing gut microbiota to drive CNS autoimmunity.

Theresa L Montgomery, Lucinda C Toppen, Korin Eckstrom, Eamonn R Heney, Josephine J Kennedy, Matthew J Scarborough, Dimitry N Krementsov.

   BACKGROUND: Short-chain fatty acids (SCFAs), produced by the gut microbiota, are thought to exert an anti-inflammatory effect on the host immune system. The levels of SCFAs and abundance of the microbiota that produce them are depleted in multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS). The mechanisms leading to this depletion are unknown. Using experimental autoimmune encephalomyelitis (EAE) as a model for MS, we have previously shown that gut microbiomes divergent in their abundance of specific commensal Lactobacillaceae, Limosilactobacillus reuteri (L. reuteri) and Ligilactobacillus murinus (L. murinus), differentially impact CNS autoimmunity. To determine the underlying mechanisms, we employed colonization by L. reuteri and L. murinus in disparate gut microbiome configurations in vivo and in vitro, profiling their impact on gut microbiome composition and metabolism, coupled with modulation of dietary fiber in the EAE model.
RESULTS: We show that stable colonization by L. reuteri, but not L. murinus, exacerbates EAE, in conjunction with a significant remodeling of gut microbiome composition, depleting SCFA-producing microbiota, including Lachnospiraceae, Prevotellaceae, and Bifidobacterium, with a net decrease in bacterial metabolic pathways involved in butyrate production. In a minimal microbiome culture model in vitro, L. reuteri directly inhibited SCFA-producer growth and depleted butyrate. Genomic analysis of L. reuteri isolates revealed an enrichment in bacteriocins with known antimicrobial activity against SCFA-producing microbiota. Functionally, provision of excess dietary fiber, as the prebiotic substrate for SCFA production, elevated SCFA levels and abrogated the ability of L. reuteri to exacerbate EAE.
CONCLUSTIONS: Our data highlight a potential mechanism for reduced SCFAs and their producers in MS through depletion by other members of the gut microbiome, demonstrating that interactions between microbiota can impact CNS autoimmunity in a diet-dependent manner. These data suggest that therapeutic restoration of SCFA levels in MS may require not only dietary intervention, but also modulation of the gut microbiome.

Keywords:  ASF; Microbiome; SCFA; bacteriocin; butyrate; multiple sclerosis

DOI:  https://doi.org/10.1080/19490976.2024.2418415
Mol Neurobiol. 2024 Oct 25.

Immune Checkpoint VISTA Negatively Regulates Microglia Glycolysis and Activation via TRIM28-Mediated Ubiquitination of HK2 in Sepsis-Associated Encephalopathy.

Yuhai Xu, Ying Zhu, Yue Shi, Bo Ye, Lulong Bo, Tianzhu Tao.

  V-domain immunoglobulin suppressor of T cell activation (VISTA) has emerged as a crucial player in the pathogenesis of neurological disorders. However, the specific mechanism by which VISTA regulates microglial activation remains unclear. Septic mice were intracerebroventricularly injected with an agonistic anti-VISTA antibody or isotype control. To investigate the differential gene expression profiles, RNA sequencing was conducted on brain tissues from these mice. In vitro, VISTA was silenced in BV2 microglial cells using shRNA. Co-immunoprecipitation assays were performed to identify protein-protein interactions involving hexokinase 2 (HK2), and ubiquitination assays were used to examine the ubiquitination status of HK2. Additionally, BV2 cells were transfected with either tripartite motif-containing 28 overexpression plasmids (TRIM28-PcDNA3.1( +)) or TRIM28-specific siRNA to assess the impact of TRIM28 on VISTA-mediated microglial activation. The cellular glycolytic activity was measured using extracellular acidification rate assays, and proinflammatory cytokine and chemokines were quantified. Treatment with VISTA antibodies significantly alleviated microglial activation and prevented cognitive impairment in septic mice. In contrast, VISTA silencing in BV2 microglia led to the overexpression of proinflammatory cytokines and enhanced glycolysis in an HK2-dependent manner. Mechanistically, HK2 expression was regulated by the E3 ubiquitin ligase TRIM28 through K63-linked ubiquitination, which targeted HK2 for proteasomal degradation. Furthermore, knockdown of TRIM28 reduced the elevated glycolysis and proinflammatory response observed in VISTA-silenced microglia. VISTA modulates microglial activation in sepsis-associated encephalopathy by regulating HK2 expression through TRIM28-mediated K63-linked ubiquitination. These findings highlight VISTA as a potential therapeutic target for modulating microglial activation in sepsis.

Keywords:  Hexokinase 2 (HK2); Microglia; Sepsis-associated encephalopathy (SAE); V-domain immunoglobulin suppressor of T cell activation (VISTA)

DOI:  https://doi.org/10.1007/s12035-024-04572-z
Elife. 2024 Oct 30. pii: e89509. [Epub ahead of print]13

The zinc transporter Slc30a1 (ZnT1) in macrophages plays a protective role against attenuated Salmonella.

Pinanong Na-Phatthalung, Shumin Sun, Enjun Xie, Jia Wang, Junxia Min, Fudi Wang.

  The zinc transporter Slc30a1 plays an essential role in maintaining cellular zinc homeostasis. Despite this, its functional role in macrophages remains largely unknown. Here, we examine the function of Slc30a1 in host defense using mice models infected with an attenuated stain of Salmonella enterica Typhimurium and primary macrophages infected with the attenuated Salmonella. Bulk transcriptome sequencing in primary macrophages identifies Slc30a1 as a candidate in response to Salmonella infection. Whole-mount immunofluorescence and confocal microscopy imaging of primary macrophage and spleen from Salmonella-infected Slc30a1flag-EGFP mice demonstrate Slc30a1 expression is increased in infected macrophages with localization at the plasma membrane and in the cytosol. Lyz2-Cre-driven Slc30a1 conditional knockout mice (Slc30a1fl/fl;Lyz2-Cre) exhibit increased susceptibility to Salmonella infection compared to control littermates. We demonstrate that Slc30a1-deficient macrophages are defective in intracellular killing, which correlated with reduced activation of nuclear factor kappa B and reduction in nitric oxide (NO) production. Notably, the model exhibits intracellular zinc accumulation, demonstrating that Slc30a1 is required for zinc export. We thus conclude that zinc export enables the efficient NO-mediated antibacterial activity of macrophages to control invading Salmonella.

Keywords:  Salmonella infection; Slc30a1; ZnT1; iNOS; macrophages; medicine; mouse; zinc accumulation

DOI:  https://doi.org/10.7554/eLife.89509