bims-imicid 2024-08-18 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2024–08–18
nineteen papers selected by
Dylan Ryan, University of Cambridge

High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases.
Functional overlap of inborn errors of immunity and metabolism genes defines T cell metabolic vulnerabilities.
Type I interferon governs immunometabolic checkpoints that coordinate inflammation during Staphylococcal infection.
Itaconate suppresses house dust mite-induced allergic airways disease and Th2 cell differentiation.
ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses.
Impaired microglial glycolysis promotes inflammatory responses after intracerebral haemorrhage via HK2-dependent mitochondrial dysfunction.
Broad-spectrum antibiotics disrupt homeostatic efferocytosis.
Metabolic alterations in vitamin D deficient systemic lupus erythematosus patients.
Autocrine VEGF-B signaling maintains lipid synthesis and mitochondrial fitness to support T cell immune responses.
The influence of metabolic disorders on adaptive immunity.
Macrophage-mediated myelin recycling fuels brain cancer malignancy.
The CCR6-CCL20 axis promotes regulatory T cell glycolysis and immunosuppression in tumors.
Platelet Ido1 expression is induced during Plasmodium yoelii infection, altering plasma tryptophan metabolites.
Cysteine depletion triggers adipose tissue thermogenesis and weight-loss.
Proviral and antiviral roles of phosphofructokinase family of glycolytic enzymes in TBSV replication.
NAD+ metabolism reprogramming mediated irradiation-induced immunosuppressive polarization of macrophages.
Microbiota-derived butyrate inhibits cDC development via HDAC inhibition, diminishing their ability to prime T cells.
Staphylococcus aureus adapts to exploit collagen-derived proline during chronic infection.
Interleukin-10 suppresses lipid metabolism-mediated intestinal inflammation.

Cell. 2024 Aug 06. pii: S0092-8674(24)00800-6. [Epub ahead of print]

High expression of oleoyl-ACP hydrolase underpins life-threatening respiratory viral diseases.

Xiaoxiao Jia, Jeremy Chase Crawford, Deborah Gebregzabher, Ebony A Monson, Robert C Mettelman, Yanmin Wan, Yanqin Ren, Janet Chou, Tanya Novak, Hayley A McQuilten, Michele Clarke, Annabell Bachem, Isabelle J Foo, Svenja Fritzlar, Julio Carrera Montoya, Alice M Trenerry, Shuai Nie, Michael G Leeming, Thi H O Nguyen, Lukasz Kedzierski, Dene R Littler, Andrew Kueh, Tina Cardamone, Chinn Yi Wong, Luca Hensen, Aira Cabug, Jaime Gómez Laguna, Mona Agrawal, Tim Flerlage, David F Boyd, Lee-Ann Van de Velde, Jennifer R Habel, Liyen Loh, Hui-Fern Koay, Carolien E van de Sandt, Igor E Konstantinov, Stuart P Berzins, Katie L Flanagan, Linda M Wakim, Marco J Herold, Amanda M Green, Heather S Smallwood, Jamie Rossjohn, Ryan S Thwaites, Christopher Chiu, Nichollas E Scott, Jason M Mackenzie, Sammy Bedoui, Patrick C Reading, Sarah L Londrigan, Karla J Helbig, Adrienne G Randolph, Paul G Thomas, Jianqing Xu, Zhongfang Wang, Brendon Y Chua, Katherine Kedzierska.

  Respiratory infections cause significant morbidity and mortality, yet it is unclear why some individuals succumb to severe disease. In patients hospitalized with avian A(H7N9) influenza, we investigated early drivers underpinning fatal disease. Transcriptomics strongly linked oleoyl-acyl-carrier-protein (ACP) hydrolase (OLAH), an enzyme mediating fatty acid production, with fatal A(H7N9) early after hospital admission, persisting until death. Recovered patients had low OLAH expression throughout hospitalization. High OLAH levels were also detected in patients hospitalized with life-threatening seasonal influenza, COVID-19, respiratory syncytial virus (RSV), and multisystem inflammatory syndrome in children (MIS-C) but not during mild disease. In olah-/- mice, lethal influenza infection led to survival and mild disease as well as reduced lung viral loads, tissue damage, infection-driven pulmonary cell infiltration, and inflammation. This was underpinned by differential lipid droplet dynamics as well as reduced viral replication and virus-induced inflammation in macrophages. Supplementation of oleic acid, the main product of OLAH, increased influenza replication in macrophages and their inflammatory potential. Our findings define how the expression of OLAH drives life-threatening viral disease.

Keywords:  MIS-C; OLAH; SARS-CoV-2 and RSV; fatal avian A/H7N9 influenza disease; influenza mouse model; life-threatening seasonal influenza; olah(−/−) mice; olah-driven macrophage-mediated disease severity; oleoyl-ACP hydrolase as key early driver of disease severity

DOI:  https://doi.org/10.1016/j.cell.2024.07.026
Sci Immunol. 2024 Aug 16. 9(98): eadh0368

Functional overlap of inborn errors of immunity and metabolism genes defines T cell metabolic vulnerabilities.

Andrew R Patterson, Gabriel A Needle, Ayaka Sugiura, Erin Q Jennings, Channing Chi, KayLee K Steiner, Emilie L Fisher, Gabriella L Robertson, Caroline Bodnya, Janet G Markle, Ryan D Sheldon, Russell G Jones, Vivian Gama, Jeffrey C Rathmell.

Inborn errors of metabolism (IEMs) and immunity (IEIs) are Mendelian diseases in which complex phenotypes and patient rarity have limited clinical understanding. Whereas few genes have been annotated as contributing to both IEMs and IEIs, immunometabolic demands suggested greater functional overlap. Here, CRISPR screens tested IEM genes for immunologic roles and IEI genes for metabolic effects and found considerable previously unappreciated crossover. Analysis of IEMs showed that N-linked glycosylation and the hexosamine pathway enzyme Gfpt1 are critical for T cell expansion and function. Further, T helper (TH1) cells synthesized uridine diphosphate N-acetylglucosamine more rapidly and were more impaired by Gfpt1 deficiency than TH17 cells. Screening IEI genes found that Bcl11b promotes the CD4 T cell mitochondrial activity and Mcl1 expression necessary to prevent metabolic stress. Thus, a high degree of functional overlap exists between IEM and IEI genes, and immunometabolic mechanisms may underlie a previously underappreciated intersection of these disorders.

DOI: https://doi.org/10.1126/sciimmunol.adh0368
Cell Rep. 2024 Aug 09. pii: S2211-1247(24)00957-4. [Epub ahead of print]43(8): 114607

Type I interferon governs immunometabolic checkpoints that coordinate inflammation during Staphylococcal infection.

Mack B Reynolds, Benjamin Klein, Michael J McFadden, Norah K Judge, Hannah E Navarrete, Britton C Michmerhuizen, Dominik Awad, Tracey L Schultz, Paul W Harms, Li Zhang, Teresa R O'Meara, Jonathan Z Sexton, Costas A Lyssiotis, J Michelle Kahlenberg, Mary X O'Riordan.

  Macrophage metabolic plasticity is central to inflammatory programming, yet mechanisms of coordinating metabolic and inflammatory programs during infection are poorly defined. Here, we show that type I interferon (IFN) temporally guides metabolic control of inflammation during methicillin-resistant Staphylococcus aureus (MRSA) infection. We find that staggered Toll-like receptor and type I IFN signaling in macrophages permit a transient energetic state of combined oxidative phosphorylation (OXPHOS) and aerobic glycolysis followed by inducible nitric oxide synthase (iNOS)-mediated OXPHOS disruption. This disruption promotes type I IFN, suppressing other pro-inflammatory cytokines, notably interleukin-1β. Upon infection, iNOS expression peaks at 24 h, followed by lactate-driven Nos2 repression via histone lactylation. Type I IFN pre-conditioning prolongs infection-induced iNOS expression, amplifying type I IFN. Cutaneous MRSA infection in mice constitutively expressing epidermal type I IFN results in elevated iNOS levels, impaired wound healing, vasculopathy, and lung infection. Thus, kinetically regulated type I IFN signaling coordinates immunometabolic checkpoints that control infection-induced inflammation.

Keywords:  CP: Immunology; CP: Metabolism; Staphylococcus aureus; epigenetics; immunometabolism; inflammation; innate immunity; interferon; lactate; macrophage; nitric oxide; respiratory complex

DOI:  https://doi.org/10.1016/j.celrep.2024.114607
Mucosal Immunol. 2024 Aug 13. pii: S1933-0219(24)00082-5. [Epub ahead of print]

Itaconate suppresses house dust mite-induced allergic airways disease and Th2 cell differentiation.

Yiran Li, Shilpi Singh, Haley A Breckenridge, Tracy X Cui, Thomas M Vigil, Jordan E Kreger, Jing Lei, Harrison K A Wong, Peter Sajjakulnukit, Xiaofeng Zhou, J Kelley Bentley, Costas A Lyssiotis, Richard M Mortensen, Marc B Hershenson.

  Itaconate was initially identified as an antimicrobial compound produced by myeloid cells. Beyond its antimicrobial role, itaconate may also serve as a crucial metabolic and immune modulator. We therefore examined the roles of aconitate decarboxylase 1 (Acod1) and itaconate in house dust mite (HDM)-sensitized and -challenged mice, a model of T helper 2 (Th2)-driven allergic airways disease. HDM treatment induced lung Acod1 mRNA expression and bronchoalveolar lavage (BAL) itaconate levels in wild-type C57BL/6 mice. Acod1 knockout mice (Acod1-KO) with negligible BAL itaconate showed heightened HDM-induced type 2 cytokine expression, increased serum IgE, and enhanced recruitment of Th2 cells in the lung, indicating a shift towards a more pronounced Th2 immune response. Acod1-KO mice also showed increased eosinophilic airway inflammation and hyperresponsiveness. Experiments in chimeric mice demonstrated that bone marrow from Acod1-KO mice is sufficient to increase type 2 cytokine expression in wild-type mice, and that restitution of bone marrow from wild type mice attenuates mRNA expression of Th2 cytokines in Acod1-KO mice. Specific deletion of Acod1 in lysozyme-secreting macrophages (LysM-cre+Acod1flox/flox) recapitulated the exaggerated phenotype observed in whole-body Acod1-KO mice. Adoptive transfer of Acod1-KO bone marrow-derived macrophages also increased lung mRNA expression of Th2 cytokines. In addition, treatment of Th2-polarized CD4 cells with itaconate impeded Th2 cell differentiation, as shown by reduced expression of Gata3 and decreased release of IL-5 and IL-13. Finally, public datasets of human samples show lower Acod1 expression in subjects with allergic asthma, consistent with a protective role of itaconate in asthma pathogenesis. Together, these data suggest that itaconate plays a protective, immunomodulatory role in limiting airway type 2 inflammation after allergen challenge by attenuating T cell responses.

Keywords:  Aconitate decarboxylase 1; Allergen; Asthma; House dust mite; Itaconate; Macrophage

DOI:  https://doi.org/10.1016/j.mucimm.2024.08.001
J Exp Med. 2024 Sep 02. pii: e20231820. [Epub ahead of print]221(9):

ACLY and ACSS2 link nutrient-dependent chromatin accessibility to CD8 T cell effector responses.

Irem Kaymak, McLane J Watson, Brandon M Oswald, Shixin Ma, Benjamin K Johnson, Lisa M DeCamp, Batsirai M Mabvakure, Katarzyna M Luda, Eric H Ma, Kin Lau, Zhen Fu, Brejnev Muhire, Susan M Kitchen-Goosen, Alexandra Vander Ark, Michael S Dahabieh, Bozena Samborska, Matthew Vos, Hui Shen, Zi Peng Fan, Thomas P Roddy, Gillian A Kingsbury, Cristovão M Sousa, Connie M Krawczyk, Kelsey S Williams, Ryan D Sheldon, Susan M Kaech, Dominic G Roy, Russell G Jones.

Coordination of cellular metabolism is essential for optimal T cell responses. Here, we identify cytosolic acetyl-CoA production as an essential metabolic node for CD8 T cell function in vivo. We show that CD8 T cell responses to infection depend on acetyl-CoA derived from citrate via the enzyme ATP citrate lyase (ACLY). However, ablation of ACLY triggers an alternative, acetate-dependent pathway for acetyl-CoA production mediated by acyl-CoA synthetase short-chain family member 2 (ACSS2). Mechanistically, acetate fuels both the TCA cycle and cytosolic acetyl-CoA production, impacting T cell effector responses, acetate-dependent histone acetylation, and chromatin accessibility at effector gene loci. When ACLY is functional, ACSS2 is not required, suggesting acetate is not an obligate metabolic substrate for CD8 T cell function. However, loss of ACLY renders CD8 T cells dependent on acetate (via ACSS2) to maintain acetyl-CoA production and effector function. Together, ACLY and ACSS2 coordinate cytosolic acetyl-CoA production in CD8 T cells to maintain chromatin accessibility and T cell effector function.

DOI: https://doi.org/10.1084/jem.20231820
J Adv Res. 2024 Aug 12. pii: S2090-1232(24)00359-X. [Epub ahead of print]

Impaired microglial glycolysis promotes inflammatory responses after intracerebral haemorrhage via HK2-dependent mitochondrial dysfunction.

Yin Li, Hang Zhou, Xuchao He, Lingji Jin, Yuhan Zhu, Libin Hu, Majing Feng, Jun Zhu, Liang Wang, Yonghe Zheng, Shiwei Li, Zhiyuan Yan, Peili Cen, Junwen Hu, Zihang Chen, Xiaobo Yu, Xiongjie Fu, Chaoran Xu, Shenglong Cao, Yang Cao, Gao Chen, Lin Wang.

   INTRODUCTION: Intracerebral haemorrhage (ICH) is a devastating disease that leads to severe neurological deficits. Microglia are the first line of defence in the brain and play a crucial role in neurological recovery after ICH, whose activities are primarily driven by glucose metabolism. However, little is known regarding the status of glucose metabolism in microglia and its interactions with inflammatory responses after ICH.
OBJECTIVES: This study investigated microglial glycolysis and its mechanistic effects on microglial inflammation after ICH.
METHODS: We explored the status of glucose metabolism in the ipsilateral region and in fluorescence-activated-cell-sorting-isolated (FACS-isolated) microglia via 2-deoxy-[18F]fluoro-D-glucose positron emission tomography (FDG-PET) analyses and gamma emission, respectively. Energy-related targeted metabolomics, along with 13C-glucose isotope tracing, was utilised to analyse glycolytic products in microglia. Mitochondrial membrane potential and mitochondrial reactive oxygen species (MitoROS) accumulation was assessed by flow cytometry. Behavioural, western blotting, gene regulation, and enzymatic activity analyses were conducted with a focus on microglia.
RESULTS: Neurological dysfunction was strongly correlated with decreased FDG-PET signals in the perihaematomal region, where microglial uptake of FDG was reduced. The decreased quantity of glucose-6-phosphate (G-6-P) in microglia was attributed to the downregulation of glucose transporter 1 (GLUT1) and hexokinase 2 (HK2). Enhanced inflammatory responses were driven by HK2 suppression via decreased mitochondrial membrane potential, which could be rescued by MitoROS scavengers. HK inhibitors aggravated neurological injury by suppressing FDG uptake and enhancing microglial inflammation in ICH mice.
CONCLUSION: These findings indicate an unexpected metabolic status in pro-inflammatory microglia after ICH, consisting of glycolysis impairment caused by the downregulation of GLUT1 and HK2. Additionally, HK2 suppression promotes inflammatory responses by disrupting mitochondrial function, providing insight into the mechanisms by which inflammation may be facilitated after ICH and indicating that metabolic enzymes as potential targets for ICH treatment.

Keywords:  Glycolysis; Hexokinase 2; Inflammation; Intracerebral haemorrhage; Microglia; Mitochondria

DOI:  https://doi.org/10.1016/j.jare.2024.08.016
Nat Metab. 2024 Aug 09.

Broad-spectrum antibiotics disrupt homeostatic efferocytosis.

Pedro H V Saavedra, Alissa J Trzeciak, Allie Lipshutz, Andrew W Daman, Anya J O'Neal, Zong-Lin Liu, Zhaoquan Wang, Jesús E Romero-Pichardo, Waleska Saitz Rojas, Giulia Zago, Marcel R M van den Brink, Steven Z Josefowicz, Christopher D Lucas, Christopher J Anderson, Alexander Y Rudensky, Justin S A Perry.

The clearance of apoptotic cells, termed efferocytosis, is essential for tissue homeostasis and prevention of autoimmunity1. Although past studies have elucidated local molecular signals that regulate homeostatic efferocytosis in a tissue2,3, whether signals arising distally also regulate homeostatic efferocytosis remains elusive. Here, we show that large peritoneal macrophage (LPM) display impairs efferocytosis in broad-spectrum antibiotics (ABX)-treated, vancomycin-treated and germ-free mice in vivo, all of which have a depleted gut microbiota. Mechanistically, the microbiota-derived short-chain fatty acid butyrate directly boosts efferocytosis efficiency and capacity in mouse and human macrophages, and rescues ABX-induced LPM efferocytosis defects in vivo. Bulk messenger RNA sequencing of butyrate-treated macrophages in vitro and single-cell messenger RNA sequencing of LPMs isolated from ABX-treated and butyrate-rescued mice reveals regulation of efferocytosis-supportive transcriptional programmes. Specifically, we find that the efferocytosis receptor T cell immunoglobulin and mucin domain containing 4 (TIM-4, Timd4) is downregulated in LPMs of ABX-treated mice but rescued by oral butyrate. We show that TIM-4 is required for the butyrate-induced enhancement of LPM efferocytosis capacity and that LPM efferocytosis is impaired beyond withdrawal of ABX. ABX-treated mice exhibit significantly worse disease in a mouse model of lupus. Our results demonstrate that homeostatic efferocytosis relies on distal metabolic signals and suggest that defective homeostatic efferocytosis may explain the link between ABX use and inflammatory disease4-7.

DOI: https://doi.org/10.1038/s42255-024-01107-7
Sci Rep. 2024 08 14. 14(1): 18879

Metabolic alterations in vitamin D deficient systemic lupus erythematosus patients.

Yunxia Yan, Fangyuan Yu, Qi Li, Xuebing Feng, Linyu Geng, Lingyun Sun.

  Vitamin D deficiency is increasingly common in systemic lupus erythematosus (SLE) patients and is associated with the disease activity and proteinuria. Recently, alterations in metabolism have been recognized as key regulators of SLE pathogenesis. Our objective was to identify differential metabolites in the serum metabolome of SLE with vitamin D deficiency. In this study, serum samples from 31 SLE patients were collected. Levels of 25(OH)D3 were assayed by ELISA. Patients were divided into two groups according to their vitamin D level (20 ng/ml). Untargeted metabolomics were used to study the metabolite profiles in serum by high-performance liquid chromatography-tandem mass spectrometry. Subsequently, we performed metabolomics profiling analysis to identify 52 significantly altered metabolites in vitamin D deficient SLE patients. The area under the curve (AUC) from ROC analyses was calculated to assess the diagnostic potential of each candidate metabolite biomarker. Lipids accounted for 66.67% of the differential metabolites in the serum, highlighted the disruption of lipid metabolism. The 52 differential metabolites were mapped to 27 metabolic pathways, with fat digestion and absorption, as well as lipid metabolism, emerging as the most significant pathways. The AUC of (S)-Oleuropeic acid and 2-Hydroxylinolenic acid during ROC analysis were 0.867 and 0.833, respectively, indicating their promising diagnostic potential. In conclusion, our results revealed vitamin D deficiency alters SLE metabolome, impacting lipid metabolism, and thrown insights into the pathogenesis and diagnosis of SLE.

Keywords:  Lipids; Metabolism; Systemic lupus erythematosus; Vitamin D

DOI:  https://doi.org/10.1038/s41598-024-67588-4
J Clin Invest. 2024 Aug 15. pii: e176586. [Epub ahead of print]134(16):

Autocrine VEGF-B signaling maintains lipid synthesis and mitochondrial fitness to support T cell immune responses.

Jianli He, Yalan Chen, Huihua Ding, Jin-An Zhou, Zhengcao Xing, Xinyu Yang, Qiuju Fan, Yong Zuo, Tianshi Wang, Jinke Cheng.

  T cells rewire their metabolic activities to meet the demand of immune responses, but how to coordinate the immune response by metabolic regulators in activated T cells is unknown. Here, we identified autocrine VEGF-B as a metabolic regulator to control lipid synthesis and maintain the integrity of the mitochondrial inner membrane for the survival of activated T cells. Disruption of autocrine VEGF-B signaling in T cells reduced cardiolipin mass, resulting in mitochondrial damage, with increased apoptosis and reduced memory development. The addition of cardiolipin or modulating VEGF-B signaling improved T cell mitochondrial fitness and survival. Autocrine VEGF-B signaling through GA-binding protein α (GABPα) induced sentrin/SUMO-specific protease 2 (SENP2) expression, which further de-SUMOylated PPARγ and enhanced phospholipid synthesis, leading to a cardiolipin increase in activated T cells. These data suggest that autocrine VEGF-B mediates a signal to coordinate lipid synthesis and mitochondrial fitness with T cell activation for survival and immune response. Moreover, autocrine VEGF-B signaling in T cells provides a therapeutic target against infection and tumors as well as an avenue for the treatment of autoimmune diseases.

Keywords:  Adaptive immunity; Growth factors; Immunology; T cells

DOI:  https://doi.org/10.1172/JCI176586
Cell Mol Immunol. 2024 Aug 12.

The influence of metabolic disorders on adaptive immunity.

Thomas J C Collins, Pooranee K Morgan, Kevin Man, Graeme I Lancaster, Andrew J Murphy.

  The immune system plays a crucial role in protecting the body from invading pathogens and maintaining tissue homoeostasis. Maintaining homoeostatic lipid metabolism is an important aspect of efficient immune cell function and when disrupted immune cell function is impaired. There are numerous metabolic diseases whereby systemic lipid metabolism and cellular function is impaired. In the context of metabolic disorders, chronic inflammation is suggested to be a major contributor to disease progression. A major contributor to tissue dysfunction in metabolic disease is ectopic lipid deposition, which is generally caused by diet and genetic factors. Thus, we propose the idea, that similar to tissue and organ damage in metabolic disorders, excessive accumulation of lipid in immune cells promotes a dysfunctional immune system (beyond the classical foam cell) and contributes to disease pathology. Herein, we review the evidence that lipid accumulation through diet can modulate the production and function of immune cells by altering cellular lipid content. This can impact immune cell signalling, activation, migration, and death, ultimately affecting key aspects of the immune system such as neutralising pathogens, antigen presentation, effector cell activation and resolving inflammation.

Keywords:  Cancer; Cell Metabolism; Immunity; Immunometabolism; Lipid Metabolism; Metabolic Disorders

DOI:  https://doi.org/10.1038/s41423-024-01206-1
Cell. 2024 Aug 07. pii: S0092-8674(24)00824-9. [Epub ahead of print]

Macrophage-mediated myelin recycling fuels brain cancer malignancy.

Daan J Kloosterman, Johanna Erbani, Menno Boon, Martina Farber, Shanna M Handgraaf, Masami Ando-Kuri, Elena Sánchez-López, Bauke Fontein, Marjolijn Mertz, Marja Nieuwland, Ning Qing Liu, Gabriel Forn-Cuni, Nicole N van der Wel, Anita E Grootemaat, Luuk Reinalda, Sander I van Kasteren, Elzo de Wit, Brian Ruffell, Ewa Snaar-Jagalska, Kevin Petrecca, Dieta Brandsma, Alexander Kros, Martin Giera, Leila Akkari.

  Tumors growing in metabolically challenged environments, such as glioblastoma in the brain, are particularly reliant on crosstalk with their tumor microenvironment (TME) to satisfy their high energetic needs. To study the intricacies of this metabolic interplay, we interrogated the heterogeneity of the glioblastoma TME using single-cell and multi-omics analyses and identified metabolically rewired tumor-associated macrophage (TAM) subpopulations with pro-tumorigenic properties. These TAM subsets, termed lipid-laden macrophages (LLMs) to reflect their cholesterol accumulation, are epigenetically rewired, display immunosuppressive features, and are enriched in the aggressive mesenchymal glioblastoma subtype. Engulfment of cholesterol-rich myelin debris endows subsets of TAMs to acquire an LLM phenotype. Subsequently, LLMs directly transfer myelin-derived lipids to cancer cells in an LXR/Abca1-dependent manner, thereby fueling the heightened metabolic demands of mesenchymal glioblastoma. Our work provides an in-depth understanding of the immune-metabolic interplay during glioblastoma progression, thereby laying a framework to unveil targetable metabolic vulnerabilities in glioblastoma.

Keywords:  cancer immunity; cholesterol; glioblastoma; lipid metabolism; macrophages; myelin recycling; tumor microenvironment

DOI:  https://doi.org/10.1016/j.cell.2024.07.030
Cancer Immunol Res. 2024 Aug 12.

The CCR6-CCL20 axis promotes regulatory T cell glycolysis and immunosuppression in tumors.

Ayush Pant, Aanchal Jain, Yiyun Chen, Kisha Patel, Laura Saleh, Stephany Tzeng, Ryan T Nitta, Liang Zhao, Caren Yu-Ju Wu, Maria Bederson, William Lee Wang, Brandon Hwa-Lin Bergsneider, John Choi, Ravi Medikonda, Rohit Verma, Kwang Bog Cho, Lily H Kim, Jennifer E Kim, Eli Yazigi, Si Yeon Lee, Sakthi Rajendran, Prajwal Rajappa, Crystal L Mackall, Gordon Li, Betty Tyler, Henry Brem, Drew M Pardoll, Michael Lim, Christopher M Jackson.

Regulatory T cells (Tregs) are important players in the tumor microenvironment. However, the mechanisms behind their immunosuppressive effects are poorly understood. We found that CCR6-CCL20 activity in tumor-infiltrating Tregs is associated with greater glycolytic activity and ablation of Ccr6 reduced glycolysis and lactic acid production while increasing compensatory glutamine metabolism. Immunosuppressive activity towards CD8+ T cells was abrogated in Ccr6-/- Tregs due to reduction in activation-induced glycolysis. Furthermore, Ccr6-/- mice exhibited improved survival across multiple tumor models compared to wildtype mice, and Treg and CD8+ T-cell depletion abrogated the improvement. In addition, Ccr6 ablation further promoted the efficacy of anti-PD-1 therapy in a preclinical glioma model. Follow-up knockdown of Ccl20 with siRNA also demonstrated improvement in antitumor efficacy. Our results unveil CCR6 as a marker and regulator of Treg-induced immunosuppression and identify approaches to target the metabolic determinants of Treg immunosuppressive activity.

DOI: https://doi.org/10.1158/2326-6066.CIR-24-0230
Blood Adv. 2024 Aug 12. pii: bloodadvances.2024013175. [Epub ahead of print]

Platelet Ido1 expression is induced during Plasmodium yoelii infection, altering plasma tryptophan metabolites.

Sara K Blick-Nitko, Sara K Ture, Xenia L Schafer, Joshua C Munger, Alison Claire Livada, Chen Li, Preeti Maurya, Matthew T Rondina, Craig N Morrell.

Platelets are immune responsive in many diseases as noted by changes in platelet mRNA in conditions such as sepsis1, atherosclerosis2, COVID-193,4, and many other inflammatory and infectious etiologies5. The malaria causing Plasmodium parasite is a persistent public health threat and significant evidence shows that platelets participate in host responses to infection. Using a mouse model of non-lethal/uncomplicated malaria, P. yoelii XNL (PyNL), infected, but not control mouse platelets expressed Ido1, a rate limiting enzyme in tryptophan metabolism that increases kynurenine at the expense of serotonin. Interferon-gamma (IFN) is a potent inducer of Ido1 and mice treated with recombinant IFN had increased platelet Ido1 and IDO1 activity. PyNL infected mice treated with anti-IFN antibody had similar platelet Ido1 and metabolic profiles to that of uninfected controls. PyNL infected mice become thrombocytopenic by day 7 post-infection and transfusion of platelets from IFN treated wild type mice, but not Ido1-/- mice, increased the plasma kynurenine to tryptophan ratio, indicating platelets are a source of post-infection IDO1 activity. We generated platelet specific Ido1 knockout mice to assess the contribution of platelet Ido1 during PyNL infection. Platelet specific Ido1-/- mice had increased death and evidence of lung thrombi which were not present in infected WT mice. Platelet Ido1 may be a significant contributor to plasma KYN in IFN driven immune processes and the loss of platelets may limit total Ido1, leading to immune and vascular dysfunction.

DOI: https://doi.org/10.1182/bloodadvances.2024013175
bioRxiv. 2024 Aug 08. pii: 2024.08.06.606880. [Epub ahead of print]

Cysteine depletion triggers adipose tissue thermogenesis and weight-loss.

Aileen H Lee, Lucie Orliaguet, Yun-Hee Youm, Rae Maeda, Tamara Dlugos, Yuanjiu Lei, Daniel Coman, Irina Shchukina, Sairam Andhey, Steven R Smith, Eric Ravussin, Krisztian Stadler, Fahmeed Hyder, Maxim N Artyomov, Yuki Sugiura, Vishwa Deep Dixit.

Dietary interventions such as caloric restriction (CR) 1 and methionine restriction 2 that prolong lifespan induce the 'browning' of white adipose tissue (WAT), an adaptive metabolic response that increases heat production to maintain health 3,4 . However, how diet influences adipose browning and metabolic health is unclear. Here, we identified that weight-loss induced by CR in humans 5 reduces cysteine concentration in WAT suggesting depletion of this amino-acid may be involved in metabolic benefits of CR. To investigate the role of cysteine on organismal metabolism, we created a cysteine-deficiency mouse model in which dietary cysteine was eliminated and cystathionine γ-lyase (CTH) 6 , the enzyme that synthesizes cysteine was conditionally deleted. Using this animal model, we found that systemic cysteine-depletion causes drastic weight-loss with increased fat utilization and browning of adipose tissue. The restoration of dietary cysteine in cysteine-deficient mice rescued weight loss together with reversal of adipose browning and increased food-intake in an on-demand fashion. Mechanistically, cysteine deficiency induced browning and weight loss is dependent on sympathetic nervous system derived noradrenaline signaling via β3-adrenergic-receptors and does not require UCP1. Therapeutically, in high-fat diet fed obese mice, one week of cysteine-deficiency caused 30% weight-loss and reversed inflammation. These findings thus establish that cysteine is essential for organismal metabolism as removal of cysteine in the host triggers adipose browning and rapid weight loss.

DOI: https://doi.org/10.1101/2024.08.06.606880
Virology. 2024 Aug 05. pii: S0042-6822(24)00211-3. [Epub ahead of print]599 110190

Proviral and antiviral roles of phosphofructokinase family of glycolytic enzymes in TBSV replication.

Yuyan Liu, Wenwu Lin, Peter D Nagy.

  Positive-strand RNA viruses build viral replication organelles (VROs) with the help of co-opted host factors. The biogenesis of the membranous VROs requires major metabolic changes in infected cells. Previous studies showed that tomato bushy stunt virus (TBSV) hijacks several glycolytic enzymes to produce ATP locally within VROs. In this work, we demonstrate that the yeast Pfk2p phosphofructokinase, which performs a rate-limiting and highly regulated step in glycolysis, interacts with the TBSV p33 replication protein. Deletion of PFK2 reduced TBSV replication in yeast, suggesting proviral role for Pfk2p. TBSV also co-opted two plant phosphofructokinases, which supported viral replication and ATP production within VROs, thus acting as proviral factors. Three other phosphofructokinases inhibited TBSV replication and they reduced ATP production within VROs, thus functioning as antiviral factors. Altogether, different phosphofructokinases have proviral or antiviral roles. This suggests on-going arms race between tombusviruses and their hosts to control glycolysis pathway in infected cells.

Keywords:  ATP generation; Antiviral factor; Glycolysis; Host factor; Nicotiana benthamiana; Proviral factor; Replication; Tomato bushy stunt virus; Virus-host interaction; Yeast

DOI:  https://doi.org/10.1016/j.virol.2024.110190
Int J Radiat Oncol Biol Phys. 2024 Aug 08. pii: S0360-3016(24)03176-6. [Epub ahead of print]

NAD+ metabolism reprogramming mediated irradiation-induced immunosuppressive polarization of macrophages.

Wanrong Meng, Ling Li, Yaying Hao, Miaomiao Tang, Chang Cao, Jialu He, Linlin Wang, Bangrong Cao, Yongqing Zhang, Longjiang Li, Guiquan Zhu.

   PURPOSE: radiotherapy stands as an important complementary treatment for head and neck squamous cell carcinoma (HNSCC), yet it does not invariably result in complete tumor regression. The infiltration of immunosuppressive macrophages is believed to mediate the radiotherapy resistance, which mechanism remains largely unexplored. This study aimed to elucidate the role of immunosuppressive macrophages during radiotherapy and the associated underlying mechanisms.
MATERIALS AND METHODS: Male C3H mice bearing syngeneic SCC-VII tumor were received irradiation (2 × 8Gy). The impact of irradiation on tumor-infiltrating macrophages were assessed. Bone marrow derived macrophages were evaluated in differentiation, proliferation, migration, and inflammatory cytokines after treatment of irradiated tumor culture medium (irCM) and irradiated tumor derived extracellular vesicles (irTEVs). A comprehensive metabolomics profiling of the irTEVs was conducted using liquid chromatography-mass spectrometry, while key metabolites were investigated the mechanism in macrophage in vitro and in vivo.
RESULTS: Radiotherapy on SCC-VII syngeneic graft tumors increased polarization of both M1 and M2 macrophages in tumor microenvironment and drove infiltrated macrophages towards an immunosuppressive phenotype. Irradiation-induced polarization and immunosuppression of macrophages were dependent on irTEVs which delivered an increased amount of nicotinamide (NAM) to macrophages. NAM directly bound to the NF-κB transcriptional activity regulator USP7, through which NAM reduced translocation of NF-κB into the nucleus, thereby decreasing the release of cytokines IL6 and IL8. Increased enzyme activity of nicotinamide phosphoribosyl transferase (NAMPT) which is the rate-limiting enzyme of NAD+ metabolism, contributed to the irradiation-induced accumulation levels of NAM in irradiated HNSCC and irTEVs. Inhibition of NAMPT decreased NAM levels in irTEVs and increased radiotherapy sensitivity through alleviating immunosuppressive function of macrophages.
CONCLUSIONS: Radiotherapy could induce NAD+ metabolic reprogramming of HNSCC cells, which regulate macrophage towards an immunosuppressive phenotype. Pharmacological targeting NAD+ metabolism might be a promising strategy for radiotherapy sensitization of HNSCC.

Keywords:  Head and neck squamous cell carcinomas; extracellular vesicles; macrophages; metabolomics; radiotherapy resistance

DOI:  https://doi.org/10.1016/j.ijrobp.2024.07.2327
Mucosal Immunol. 2024 Aug 12. pii: S1933-0219(24)00084-9. [Epub ahead of print]

Microbiota-derived butyrate inhibits cDC development via HDAC inhibition, diminishing their ability to prime T cells.

Anna Andrusaite, Jennifer Lewis, Annika Frede, Andrew Farthing, Verena Kästele, Jennifer Montgomery, Allan Mowat, Elizabeth Mann, Simon Milling.

Conventional dendritic cells (cDC) are central to maintaining the balance between protective immune responses and tolerance to harmless antigens, especially in the intestine. Short chain fatty acids (SCFAs) such as butyrate play critical roles in regulating intestinal immunity, but the underlying mechanisms remain unclear. Here we demonstrate that microbiota-derived butyrate alters intestinal cDC populations in vivo resulting in decreased numbers of the cDC2 lineage. By establishing a novel in vitro culture model, we show that butyrate has a direct and selective ability to repress the development of cDC2 from cDC precursors, an effect that is independent of G-protein coupled receptors (GPCRs) and is due to inhibition of histone deacetylase 3. Finally, cDC derived from pre-cDC in the presence of butyrate in vitro express lower levels of costimulatory molecules and have a decreased ability to prime naïve T cells. Together, our data show that butyrate affects the developmental trajectory of cDC, selectively repressing the cDC2 lineage and reducing their ability to stimulate T cells. These properties may help explain the ability of butyrate to maintain homeostasis in the intestine.

DOI: https://doi.org/10.1016/j.mucimm.2024.08.003
Nat Microbiol. 2024 Aug 12.

Staphylococcus aureus adapts to exploit collagen-derived proline during chronic infection.

Andreacarola Urso, Ian R Monk, Ying-Tsun Cheng, Camilla Predella, Tania Wong Fok Lung, Erin M Theiller, Jack Boylan, Sofya Perelman, Swikrity U Baskota, Ahmed M Moustafa, Gaurav Lohia, Ian A Lewis, Benjamin P Howden, Timothy P Stinear, Nicolino V Dorrello, Victor Torres, Alice S Prince.

Staphylococcus aureus is a pulmonary pathogen associated with substantial human morbidity and mortality. As vaccines targeting virulence determinants have failed to be protective in humans, other factors are likely involved in pathogenesis. Here we analysed transcriptomic responses of human clinical isolates of S. aureus from initial and chronic infections. We observed upregulated collagenase and proline transporter gene expression in chronic infection isolates. Metabolomics of bronchiolar lavage fluid and fibroblast infection, growth assays and analysis of bacterial mutant strains showed that airway fibroblasts produce collagen during S. aureus infection. Host-adapted bacteria upregulate collagenase, which degrades collagen and releases proline. S. aureus then imports proline, which fuels oxidative metabolism via the tricarboxylic acid cycle. Proline metabolism provides host-adapted S. aureus with a metabolic benefit enabling out-competition of non-adapted strains. These data suggest that clinical settings characterized by airway repair processes and fibrosis provide a milieu that promotes S. aureus adaptation and supports infection.

DOI: https://doi.org/10.1038/s41564-024-01769-9
Life Metab. 2024 Jun;pii: loae011. [Epub ahead of print]3(3):

Interleukin-10 suppresses lipid metabolism-mediated intestinal inflammation.

Tristram A J Ryan, Ivan Zanoni.

In a recent paper published in Nature, York et al. reported that the anti-inflammatory cytokine IL-10 regulates sphingolipid metabolism to limit NF-κB-mediated inflammation. Deletion of Il10 in mice, or genetic mutation of IL10 in humans, predisposes to inflammatory bowel disease, which may be overcome by restoring homeostatic sphingolipid metabolism.

DOI: https://doi.org/10.1093/lifemeta/loae011