bims-imicid 2022-03-27 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022–03–27
twenty-two papers selected by
Dylan Ryan, University of Cambridge

Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue.
Intestinal Tuft-2 cells exert antimicrobial immunity via sensing bacterial metabolite N-undecanoylglycine.
Hexokinase 1 cellular localization regulates the metabolic fate of glucose.
The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming.
CD5 Deficiency Alters Helper T Cell Metabolic Function and Shifts the Systemic Metabolome.
A matter of time: temporal structure and functional relevance of macrophage metabolic rewiring.
Integrated metabolomic and transcriptomic analysis identifies benzo[a]pyrene-induced characteristic metabolic reprogramming during accumulation of lipids and reactive oxygen species in macrophages.
Fungal sensing enhances neutrophil metabolic fitness by regulating antifungal Glut1 activity.
Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis.
1,25-dihydroxyvitamin D3 suppresses CD4+ T cell effector functionality by inhibition of glycolysis.
Lactate metabolism in rheumatoid arthritis: Pathogenic mechanisms and therapeutic intervention with natural compounds.
sEH-derived metabolites of linoleic acid drive pathologic inflammation while impairing key innate immune cell function in burn injury.
Succinate Is a Natural Suppressor of Antiviral Immune Response by Targeting MAVS.
Gut-derived bacterial toxins impair memory CD4 T-cell mitochondrialfunction in HIV-1infection.
Metabolic Messengers: bile acids.
Macrophage mitochondrial bioenergetics and tissue invasion are boosted by an Atossa-Porthos axis in Drosophila.
Itaconate or how I learned to stop avoiding the study of immunometabolism.
Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion.
Microbial metabolite butyrate promotes induction of IL-10+IgM+ plasma cells.
Intracellular metabolic adaptation of intraepithelial CD4+CD8αα+ T lymphocytes.
Iron deficiency linked to altered bile acid metabolism promotes Helicobacter pylori-induced inflammation-driven gastric carcinogenesis.
Elevated ATP via enhanced miRNA-30b, 30c, and 30e downregulates the expression of CD73 in CD8+ T cells of HIV-infected individuals.

Cell Metab. 2022 Mar 15. pii: S1550-4131(22)00088-2. [Epub ahead of print]

Ejection of damaged mitochondria and their removal by macrophages ensure efficient thermogenesis in brown adipose tissue.

Marco Rosina, Veronica Ceci, Riccardo Turchi, Li Chuan, Nicholas Borcherding, Francesca Sciarretta, María Sánchez-Díaz, Flavia Tortolici, Keaton Karlinsey, Valerio Chiurchiù, Claudia Fuoco, Rocky Giwa, Rachael L Field, Matteo Audano, Simona Arena, Alessandro Palma, Federica Riccio, Farnaz Shamsi, Giovanni Renzone, Martina Verri, Anna Crescenzi, Salvatore Rizza, Fiorella Faienza, Giuseppe Filomeni, Sander Kooijman, Stefano Rufini, Antoine A F de Vries, Andrea Scaloni, Nico Mitro, Yu-Hua Tseng, Andrés Hidalgo, Beiyan Zhou, Jonathan R Brestoff, Katia Aquilano, Daniele Lettieri-Barbato.

  Recent findings have demonstrated that mitochondria can be transferred between cells to control metabolic homeostasis. Although the mitochondria of brown adipocytes comprise a large component of the cell volume and undergo reorganization to sustain thermogenesis, it remains unclear whether an intercellular mitochondrial transfer occurs in brown adipose tissue (BAT) and regulates adaptive thermogenesis. Herein, we demonstrated that thermogenically stressed brown adipocytes release extracellular vesicles (EVs) that contain oxidatively damaged mitochondrial parts to avoid failure of the thermogenic program. When re-uptaken by parental brown adipocytes, mitochondria-derived EVs reduced peroxisome proliferator-activated receptor-γ signaling and the levels of mitochondrial proteins, including UCP1. Their removal via the phagocytic activity of BAT-resident macrophages is instrumental in preserving BAT physiology. Depletion of macrophages in vivo causes the abnormal accumulation of extracellular mitochondrial vesicles in BAT, impairing the thermogenic response to cold exposure. These findings reveal a homeostatic role of tissue-resident macrophages in the mitochondrial quality control of BAT.

Keywords:  adipose tissue; brown adipocytes; extracellular vesicles; homeostasis; immunometabolism; macrophages; mitochondria; mitochondrial quality control; thermogenesis

DOI:  https://doi.org/10.1016/j.cmet.2022.02.016
Immunity. 2022 Mar 15. pii: S1074-7613(22)00124-8. [Epub ahead of print]

Intestinal Tuft-2 cells exert antimicrobial immunity via sensing bacterial metabolite N-undecanoylglycine.

Zhen Xiong, Xiaoxiao Zhu, Jingjing Geng, Yuwei Xu, Runyuan Wu, Cunzhen Li, Dongdong Fan, Xiwen Qin, Ying Du, Yong Tian, Zusen Fan.

  Tuft cells are a type of intestinal epithelial cells that exist in epithelial barriers and play a critical role in immunity against parasite infection. It remains insufficiently clear whether Tuft cells participate in bacterial eradication. Here, we identified Sh2d6 as a signature marker for CD45+ Tuft-2 cells. Depletion of Tuft-2 cells resulted in susceptibility to bacterial infection. Tuft-2 cells quickly expanded in response to bacterial infection and sensed the bacterial metabolite N-undecanoylglycine through vomeronasal receptor Vmn2r26. Mechanistically, Vmn2r26 engaged with N-undecanoylglycine activated G-protein-coupled receptor-phospholipase C gamma2 (GPCR-PLCγ2)-Ca2+ signaling axis, which initiated prostaglandin D2 (PGD2) production. PGD2 enhanced the mucus secretion of goblet cells and induced antibacterial immunity. Moreover, Vmn2r26 signaling also promoted SpiB transcription factor expression, which is responsible for Tuft-2 cell development and expansion in response to bacterial challenge. Our findings reveal an additional function of Tuft-2 cells in immunity against bacterial infection through Vmn2r26-mediated recognition of bacterial metabolites.

Keywords:  N-undecanoylglycine; PGD2; SpiB; Tuft-2 cell; Vmn2r26

DOI:  https://doi.org/10.1016/j.immuni.2022.03.001
Mol Cell. 2022 Mar 14. pii: S1097-2765(22)00166-6. [Epub ahead of print]

Hexokinase 1 cellular localization regulates the metabolic fate of glucose.

Adam De Jesus, Farnaz Keyhani-Nejad, Carolina M Pusec, Lauren Goodman, Justin A Geier, Joshua S Stoolman, Paulina J Stanczyk, Tivoli Nguyen, Kai Xu, Krishna V Suresh, Yihan Chen, Arianne E Rodriguez, Jason S Shapiro, Hsiang-Chun Chang, Chunlei Chen, Kriti P Shah, Issam Ben-Sahra, Brian T Layden, Navdeep S Chandel, Samuel E Weinberg, Hossein Ardehali.

  The product of hexokinase (HK) enzymes, glucose-6-phosphate, can be metabolized through glycolysis or directed to alternative metabolic routes, such as the pentose phosphate pathway (PPP) to generate anabolic intermediates. HK1 contains an N-terminal mitochondrial binding domain (MBD), but its physiologic significance remains unclear. To elucidate the effect of HK1 mitochondrial dissociation on cellular metabolism, we generated mice lacking the HK1 MBD (ΔE1HK1). These mice produced a hyper-inflammatory response when challenged with lipopolysaccharide. Additionally, there was decreased glucose flux below the level of GAPDH and increased upstream flux through the PPP. The glycolytic block below GAPDH is mediated by the binding of cytosolic HK1 with S100A8/A9, resulting in GAPDH nitrosylation through iNOS. Additionally, human and mouse macrophages from conditions of low-grade inflammation, such as aging and diabetes, displayed increased cytosolic HK1 and reduced GAPDH activity. Our data indicate that HK1 mitochondrial binding alters glucose metabolism through regulation of GAPDH.

Keywords:  GAPDH; S-nitrosylation; hexokinase; inflammation; innate immunity; macrophage; metabolism; mitochondria; pentose phosphate pathway; subcellular localization

DOI:  https://doi.org/10.1016/j.molcel.2022.02.028
Cell Metab. 2022 Mar 15. pii: S1550-4131(22)00087-0. [Epub ahead of print]

The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming.

Sophia M Hochrein, Hao Wu, Miriam Eckstein, Laura Arrigoni, Josip S Herman, Fabian Schumacher, Christian Gerecke, Mathias Rosenfeldt, Dominic Grün, Burkhard Kleuser, Georg Gasteiger, Wolfgang Kastenmüller, Bart Ghesquière, Jan Van den Bossche, E Dale Abel, Martin Vaeth.

  Metabolic reprogramming is a hallmark of activated T cells. The switch from oxidative phosphorylation to aerobic glycolysis provides energy and intermediary metabolites for the biosynthesis of macromolecules to support clonal expansion and effector function. Here, we show that glycolytic reprogramming additionally controls inflammatory gene expression via epigenetic remodeling. We found that the glucose transporter GLUT3 is essential for the effector functions of Th17 cells in models of autoimmune colitis and encephalomyelitis. At the molecular level, we show that GLUT3-dependent glucose uptake controls a metabolic-transcriptional circuit that regulates the pathogenicity of Th17 cells. Metabolomic, epigenetic, and transcriptomic analyses linked GLUT3 to mitochondrial glucose oxidation and ACLY-dependent acetyl-CoA generation as a rate-limiting step in the epigenetic regulation of inflammatory gene expression. Our findings are also important from a translational perspective because inhibiting GLUT3-dependent acetyl-CoA generation is a promising metabolic checkpoint to mitigate Th17-cell-mediated inflammatory diseases.

Keywords:  ACLY; ATP-citrate lyase; GLUT1; GLUT3; Th17 cells; acetyl-CoA; glucose metabolism; glycolysis; histone acetylation; immunometabolism

DOI:  https://doi.org/10.1016/j.cmet.2022.02.015
Biomedicines. 2022 Mar 18. pii: 704. [Epub ahead of print]10(3):

CD5 Deficiency Alters Helper T Cell Metabolic Function and Shifts the Systemic Metabolome.

Kiara V Whitley, Claudia M Tellez Freitas, Carlos Moreno, Christopher Haynie, Joshua Bennett, John C Hancock, Tyler D Cox, Brett E Pickett, K Scott Weber.

  Metabolic function plays a key role in immune cell activation, destruction of foreign pathogens, and memory cell generation. As T cells are activated, their metabolic profile is significantly changed due to signaling cascades mediated by the T cell receptor (TCR) and co-receptors found on their surface. CD5 is a T cell co-receptor that regulates thymocyte selection and peripheral T cell activation. The removal of CD5 enhances T cell activation and proliferation, but how this is accomplished is not well understood. We examined how CD5 specifically affects CD4+ T cell metabolic function and systemic metabolome by analyzing serum and T cell metabolites from CD5WT and CD5KO mice. We found that CD5 removal depletes certain serum metabolites, and CD5KO T cells have higher levels of several metabolites. Transcriptomic analysis identified several upregulated metabolic genes in CD5KO T cells. Bioinformatic analysis identified glycolysis and the TCA cycle as metabolic pathways promoted by CD5 removal. Functional metabolic analysis demonstrated that CD5KO T cells have higher oxygen consumption rates (OCR) and higher extracellular acidification rates (ECAR). Together, these findings suggest that the loss of CD5 is linked to CD4+ T cell metabolism changes in metabolic gene expression and metabolite concentration.

Keywords:  CD5; RNA-Seq; T cell co-receptor; T cell metabolism; bioinformatics; helper T cell; metabolomics

DOI:  https://doi.org/10.3390/biomedicines10030704
Trends Endocrinol Metab. 2022 Mar 21. pii: S1043-2760(22)00041-8. [Epub ahead of print]

A matter of time: temporal structure and functional relevance of macrophage metabolic rewiring.

Gretchen L Seim, Jing Fan.

  The response of macrophages to stimulation is a dynamic process which coordinates the orderly adoption and resolution of various immune functions. Accumulating work over the past decade has demonstrated that during the immune response macrophage metabolism is substantially rewired to support important cellular processes, including the production of bioactive molecules, intercellular communication, and the regulation of intracellular signaling and transcriptional programming. In particular, we discuss an important concept emerging from recent studies - metabolic rewiring during the immune response is temporally structured. We review the regulatory mechanisms that drive the dynamic remodeling of metabolism, and examine the functional implications of these metabolic dynamics.

Keywords:  dynamics; immunometabolism; inflammatory response and resolution; macrophage; metabolic regulation

DOI:  https://doi.org/10.1016/j.tem.2022.02.005
Sci Total Environ. 2022 Mar 18. pii: S0048-9697(22)01778-8. [Epub ahead of print] 154685

Integrated metabolomic and transcriptomic analysis identifies benzo[a]pyrene-induced characteristic metabolic reprogramming during accumulation of lipids and reactive oxygen species in macrophages.

Guozhu Ye, Wenjia Lu, Luyun Zhang, Han Gao, Xu Liao, Xu Zhang, Han Zhang, Jinsheng Chen, Qiansheng Huang.

  Polycyclic aromatic hydrocarbon exposure is a major risk factor for cardiovascular diseases. Macrophage lipid accumulation is a characteristic molecular event in the pathophysiology of cardiovascular diseases. Metabolic reprogramming is an intervention target for diseases and toxic effects of environmental pollutants. However, comprehensive metabolic reprogramming related to BaP-induced macrophage lipid accumulation is currently unexplored. Therefore, metabolomics and transcriptomics were conducted to unveil relevant metabolic reprogramming in BaP-exposed macrophages, and to discover potential intervention targets. Metabolomics revealed that most amino acids, nucleotides, monosaccharides, and organic acids were significantly decreased, while most fatty acids and steroids accumulated in BaP-exposed macrophages. Transcriptomics showed that fatty acid synthesis and oxidation, and steroid synthesis and export were decreased, while import of fatty acids and steroids was increased, indicating potential roles of lipid transport in macrophage lipid accumulation following BaP exposure. Meanwhile, alanine, aspartate and glutamate metabolism, branched-chain amino acid degradation, nucleotide synthesis, monosaccharide import, pentose phosphate pathway, citrate synthesis, and glycolysis were decreased, while nucleotide degradation was increased, thus inducing decreases in most amino acids, nucleotides, monosaccharides, and organic acids in BaP-exposed macrophages. Additionally, increases in oxidative stress and the activation of antioxidant systems were observed in BaP-exposed macrophages, which was evinced by increases in reactive oxygen species, and the activation of Fenton reaction, Vdac2/3, Sod2, and Nrf2. Moreover, BaP-induced accumulation of reactive oxygen species and lipids in macrophages could be abolished by epigallocatechin-3-gallate. Quantitative PCR showed that BaP exposure activated aryl hydrocarbon receptor signaling and promoted the proinflammatory phenotype in macrophages, and these effects were inhibited or even abolished by the separate treatment with epigallocatechin-3-gallate or CH-223191, suggesting the regulatory role of aryl hydrocarbon receptor signaling in BaP-induced toxic effects. This study provides novel insights into the toxic effects of polycyclic aromatic hydrocarbons on macrophage metabolism and potential intervention targets.

Keywords:  Amino acid metabolism; Aryl hydrocarbon receptor; Lipid metabolism; Nucleotide metabolism; Redox homeostasis

DOI:  https://doi.org/10.1016/j.scitotenv.2022.154685
Cell Host Microbe. 2022 Mar 15. pii: S1931-3128(22)00103-2. [Epub ahead of print]

Fungal sensing enhances neutrophil metabolic fitness by regulating antifungal Glut1 activity.

De-Dong Li, Chetan V Jawale, Chunsheng Zhou, Li Lin, Giraldina J Trevejo-Nunez, Syed A Rahman, Steven J Mullet, Jishnu Das, Stacy G Wendell, Greg M Delgoffe, Michail S Lionakis, Sarah L Gaffen, Partha S Biswas.

  Combating fungal pathogens poses metabolic challenges for neutrophils, key innate cells in anti-Candida albicans immunity, yet how host-pathogen interactions cause remodeling of the neutrophil metabolism is unclear. We show that neutrophils mediate renal immunity to disseminated candidiasis by upregulating glucose uptake via selective expression of glucose transporter 1 (Glut1). Mechanistically, dectin-1-mediated recognition of β-glucan leads to activation of PKCδ, which triggers phosphorylation, localization, and early glucose transport by a pool of pre-formed Glut1 in neutrophils. These events are followed by increased Glut1 gene transcription, leading to more sustained Glut1 accumulation, which is also dependent on the β-glucan/dectin-1/CARD9 axis. Card9-deficient neutrophils show diminished glucose incorporation in candidiasis. Neutrophil-specific Glut1-ablated mice exhibit increased mortality in candidiasis caused by compromised neutrophil phagocytosis, reactive oxygen species (ROS), and neutrophil extracellular trap (NET) formation. In human neutrophils, β-glucan triggers metabolic remodeling and enhances candidacidal function. Our data show that the host-pathogen interface increases glycolytic activity in neutrophils by regulating Glut1 expression, localization, and function.

Keywords:  Candida albicans; fungus; glucose; glucose transporter 1; immunometabolism; kidney; neutrophils

DOI:  https://doi.org/10.1016/j.chom.2022.02.017
Viruses. 2022 Mar 14. pii: 602. [Epub ahead of print]14(3):

Hallmarks of Metabolic Reprogramming and Their Role in Viral Pathogenesis.

Charles N S Allen, Sterling P Arjona, Maryline Santerre, Bassel E Sawaya.

  Metabolic reprogramming is a hallmark of cancer and has proven to be critical in viral infections. Metabolic reprogramming provides the cell with energy and biomass for large-scale biosynthesis. Based on studies of the cellular changes that contribute to metabolic reprogramming, seven main hallmarks can be identified: (1) increased glycolysis and lactic acid, (2) increased glutaminolysis, (3) increased pentose phosphate pathway, (4) mitochondrial changes, (5) increased lipid metabolism, (6) changes in amino acid metabolism, and (7) changes in other biosynthetic and bioenergetic pathways. Viruses depend on metabolic reprogramming to increase biomass to fuel viral genome replication and production of new virions. Viruses take advantage of the non-metabolic effects of metabolic reprogramming, creating an anti-apoptotic environment and evading the immune system. Other non-metabolic effects can negatively affect cellular function. Understanding the role metabolic reprogramming plays in viral pathogenesis may provide better therapeutic targets for antivirals.

Keywords:  Warburg effect; amino acid metabolism; biomass; biosynthetic and bioenergetic pathways; glutaminolysis; glycolysis; lipid metabolism; metabolic reprogramming; mitochondria; pentose phosphate pathway; viral replication; virus

DOI:  https://doi.org/10.3390/v14030602
Immunology. 2022 Mar 23.

1,25-dihydroxyvitamin D3 suppresses CD4+ T cell effector functionality by inhibition of glycolysis.

E L Bishop, N Gudgeon, G Mackie, D Chauss, J Roberts, D A Tennant, K M Maslowski, B Afzali, M Hewison, S Dimeloe.

  In CD4+ T helper cells, the active form of vitamin D3 , 1,25-dihydroxyvitamin D3 (1,25D) suppresses production of inflammatory cytokines, including interferon-gamma (IFN-γ), but the mechanisms for this are not yet fully defined. In innate immune cells, response to 1,25D has been linked to metabolic reprogramming. It is unclear whether 1,25D has similar effects on CD4+ T cells, although it is known that antigen stimulation of these cells promotes an anabolic metabolic phenotype, characterised by high rates of aerobic glycolysis to support clonal expansion and effector cytokine expression. Here, we performed in-depth analysis of metabolic capacity and pathway usage, employing extracellular flux and stable isotope-based tracing approaches, in CD4+ T cells treated with 1,25D. We report that 1,25D significantly decreases rates of aerobic glycolysis in activated CD4+ T cells, whilst exerting a lesser effect on mitochondrial glucose oxidation. This is associated with transcriptional repression of Myc, but not repression of mTOR activity under these conditions. Consistent with the modest effect of 1,25D on mitochondrial activity, it also did not impact CD4+ T cell mitochondrial mass or membrane potential. Finally, we demonstrate that inhibition of aerobic glycolysis by 1,25D substantially contributes to its immune-regulatory capacity in CD4+ T cells, since the suppression of IFN-γ expression was significantly blunted in the absence of aerobic glycolysis. This article is protected by copyright. All rights reserved.

Keywords:  T cell; glycolysis; immunometabolism; metabolism; vitamin D

DOI:  https://doi.org/10.1111/imm.13472
Phytomedicine. 2022 Mar 15. pii: S0944-7113(22)00126-X. [Epub ahead of print]100 154048

Lactate metabolism in rheumatoid arthritis: Pathogenic mechanisms and therapeutic intervention with natural compounds.

Ouyang Yi, Ye Lin, Mingyue Hu, Shengtao Hu, Zhaoli Su, Jin Liao, Bin Liu, Liang Liu, Xiong Cai.

   BACKGROUND: Rheumatoid arthritis (RA) is a common chronic and systemic autoimmune disease characterized by persistent inflammation and hyperplasia of the synovial membrane, the degradation of cartilage, and the erosion of bones in diarthrodial joints. The inflamed joints of patients with RA have been recognized to be a site of hypoxic microenvironment which results in an imbalance of lactate metabolism and the accumulation of lactate. Lactate is no longer considered solely a metabolic waste product of glycolysis, but also a combustion aid in the progression of RA from the early stages of inflammation to the late stages of bone destruction.
PURPOSE: To review the pathogenic mechanisms of lactate metabolism in RA and investigate the potential of natural compounds for treating RA linked to the regulation of imbalance in lactate metabolism.
METHODS: Research advances in our understanding of lactate metabolism in the pathogenesis of RA and novel pharmacological approaches of natural compounds by targeting lactate metabolic signaling were comprehensively reviewed and deeply discussed.
RESULTS: Lactate produced by RA synovial fibroblasts (RASFs) acts on targeted cells such as T cells, macrophages, dendritic cells and osteoclasts, and affects their differentiation, activation and function to accelerate the development of RA. Many natural compounds show therapeutic potential for RA by regulating glycolytic rate-limiting enzymes to limit lactate production, and affecting monocarboxylate transporter and acetyl-CoA carboxylase to inhibit lactate transport and conversion.
CONCLUSION: Regulation of imbalance in lactate metabolism offers novel therapeutic approaches for RA, and natural compounds capable of targeting lactate metabolic signaling constitute potential candidates for development of drugs RA.

Keywords:  Hypoxic microenvironment; Lactate metabolism; Natural compounds; Rheumatoid arthritis; Synovial fibroblasts

DOI:  https://doi.org/10.1016/j.phymed.2022.154048
Proc Natl Acad Sci U S A. 2022 Mar 29. 119(13): e2120691119

sEH-derived metabolites of linoleic acid drive pathologic inflammation while impairing key innate immune cell function in burn injury.

Christian B Bergmann, Cindy B McReynolds, Debin Wan, Nalin Singh, Holly Goetzman, Charles C Caldwell, Dorothy M Supp, Bruce D Hammock.

  SignificanceOxylipins alter immune cell function and potentially drive pathophysiology in burn and sepsis patients. Past and recent data reveal a correlation between increased systemic EpOME levels and reduced survival in human burn trauma and sepsis. This work extends these studies and provides evidence that the downstream sEH-derived metabolites, DiHOMEs, are driving worsening outcomes by altering the immune response. Inhibiting DiHOME metabolite formation with the sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), restored immune function by increasing immune cell survival and function. These data support the hypothesis that sEH-derived linoleic acid diols are responsible for increased mortality in burn and sepsis patients and also provide a rationale for testing the therapeutic blockage of DiHOME generation in burn and sepsis patients to improve their outcomes.

Keywords:  DiHOME; TPPU; burn injury; soluble epoxide hydrolase

DOI:  https://doi.org/10.1073/pnas.2120691119
Front Immunol. 2022 ;13 816378

Succinate Is a Natural Suppressor of Antiviral Immune Response by Targeting MAVS.

Yue Xiao, Xinyi Chen, Zhun Wang, Jiazheng Quan, Xibao Zhao, Haimei Tang, Han Wu, Qianqian Di, Zherui Wu, Weilin Chen.

  Succinate is at the crossroads of multiple metabolic pathways and plays a role in several immune responses acting as an inflammation signal. However, whether succinate regulates antiviral immune response remains unclear. Here, we found that the production of succinate was reduced in RAW264.7 cells during vesicular stomatitis virus (VSV) infection. Using diethyl succinate to pretreat the mouse peritoneal macrophages and RAW264.7 cells before VSV infection, the production of interferon-β (IFN-β), chemokine (C-X-C motif) ligand 10 (CXCL-10), and IFN-stimulated genes 15 (ISG15) was significantly decreased, following which the VSV replication in diethyl succinate-pretreated cells was obviously increased. Moreover, succinate decreased the expression of IFN-β in serum, lung, and spleen derived from the VSV-infected mice. The overall survival rate in the VSV-infected mice with diethyl succinate pretreatment was also remarkably downregulated. Furthermore, we identified that succinate inhibited the activation of MAVS-TBK1-IRF3 signaling by suppressing the formation of MAVS aggregates. Our findings provide previously unrecognized roles of succinate in antiviral immune response and establish a novel link between metabolism and innate immune response.

Keywords:  MAVS; VSV; antiviral immune response; metabolism; succinate

DOI:  https://doi.org/10.3389/fimmu.2022.816378
J Clin Invest. 2022 Mar 22. pii: e149571. [Epub ahead of print]

Gut-derived bacterial toxins impair memory CD4 T-cell mitochondrialfunction in HIV-1infection.

Brian Ferrari, Amanda Cabral Da Silva, Ken H Liu, Evgeniya V Saidakova, Larisa B Korolevskaya, Konstantin V Shmagel, Carey Shive, Gabriela Pacheco Sanchez, Mauricio Retuerto, Ashish Arunkumar Sharma, Khader Ghneim, Laura Noel-Romas, Benigno Rodriguez, Mahmoud A Ghannoum, Peter P Hunt, Steven G Deeks, Adam D Burgener, Dean P Jones, Mirela A Dobre, Vincent C Marconi, Rafick-Pierre Sekaly, Souheil-Antoine Younes.

  People living with HIV (PLWH) who are Immune Non-Responders (INR) persons are at greater risk of comorbidity and mortality than are Immune Responders (IR) who restore their CD4 T cells count (IR) after anti-retroviral therapy (ART). INR have low CD4-T cell counts (<350 c/ul), heightened systemic inflammation, and increased CD4-T cell cycling (Ki67+). Here we report the findings that memory CD4-T cells and plasma samples of INR from several cohorts are enriched in gut-derived bacterial solutes (GDBS) p-cresol-sulfate (PCS) and indoxyl sulfate (IS) that both negatively correlated with CD4-T cell counts. In vitro PCS or IS blocked CD4-T cell proliferation, induced apoptosis, and diminished the expression of mitochondrial proteins. Electron microscopy imaging (EMI) revealed perturbations of mitochondria networks similar to those found in INR following incubation of healthy memory CD4-T cells with PCS. Using the bacterial 16S rDNA, INR stool samples were found enriched with proteolytic bacterial genera that metabolize tyrosine and phenylalanine amino acids to produce PCS. We propose that toxic solutes from the gut bacterial flora may impair CD4-T cell recovery during ART and may contribute to CD4-T cell lymphopenia characteristic of INR.

Keywords:  AIDS/HIV; Apoptosis; Infectious disease; Mitochondria; T cell development

DOI:  https://doi.org/10.1172/JCI149571
Nat Metab. 2022 Mar 25.

Metabolic Messengers: bile acids.

Alessia Perino, Kristina Schoonjans.

DOI: https://doi.org/10.1038/s42255-022-00559-z
EMBO J. 2022 Mar 23. e109049

Macrophage mitochondrial bioenergetics and tissue invasion are boosted by an Atossa-Porthos axis in Drosophila.

Shamsi Emtenani, Elliot T Martin, Attila Gyoergy, Julia Bicher, Jakob-Wendelin Genger, Thomas Köcher, Maria Akhmanova, Mariana Guarda, Marko Roblek, Andreas Bergthaler, Thomas R Hurd, Prashanth Rangan, Daria E Siekhaus.

  Cellular metabolism must adapt to changing demands to enable homeostasis. During immune responses or cancer metastasis, cells leading migration into challenging environments require an energy boost, but what controls this capacity is unclear. Here, we study a previously uncharacterized nuclear protein, Atossa (encoded by CG9005), which supports macrophage invasion into the germband of Drosophila by controlling cellular metabolism. First, nuclear Atossa increases mRNA levels of Porthos, a DEAD-box protein, and of two metabolic enzymes, lysine-α-ketoglutarate reductase (LKR/SDH) and NADPH glyoxylate reductase (GR/HPR), thus enhancing mitochondrial bioenergetics. Then Porthos supports ribosome assembly and thereby raises the translational efficiency of a subset of mRNAs, including those affecting mitochondrial functions, the electron transport chain, and metabolism. Mitochondrial respiration measurements, metabolomics, and live imaging indicate that Atossa and Porthos power up OxPhos and energy production to promote the forging of a path into tissues by leading macrophages. Since many crucial physiological responses require increases in mitochondrial energy output, this previously undescribed genetic program may modulate a wide range of cellular behaviors.

Keywords:  immune cell infiltration; mitochondrial bioenergetics; oxidative phosphorylation; protein translation; transcription factor

DOI:  https://doi.org/10.15252/embj.2021109049
PLoS Pathog. 2022 Mar;18(3): e1010361

Itaconate or how I learned to stop avoiding the study of immunometabolism.

Carolina Coelho.

DOI: https://doi.org/10.1371/journal.ppat.1010361
Nat Commun. 2022 Mar 21. 13(1): 1511

Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion.

Nian Jiang, Bowen Xie, Wenwu Xiao, Ming Fan, Shanxiu Xu, Yixin Duan, Yamah Hamsafar, Angela C Evans, Jie Huang, Weibing Zhou, Xuelei Lin, Ningrong Ye, Siyi Wanggou, Wen Chen, Di Jing, Ruben C Fragoso, Brittany N Dugger, Paul F Wilson, Matthew A Coleman, Shuli Xia, Xuejun Li, Lun-Quan Sun, Arta M Monjazeb, Aijun Wang, William J Murphy, Hsing-Jien Kung, Kit S Lam, Hong-Wu Chen, Jian Jian Li.

Glioblastoma multiforme (GBM) remains the top challenge to radiotherapy with only 25% one-year survival after diagnosis. Here, we reveal that co-enhancement of mitochondrial fatty acid oxidation (FAO) enzymes (CPT1A, CPT2 and ACAD9) and immune checkpoint CD47 is dominant in recurrent GBM patients with poor prognosis. A glycolysis-to-FAO metabolic rewiring is associated with CD47 anti-phagocytosis in radioresistant GBM cells and regrown GBM after radiation in syngeneic mice. Inhibition of FAO by CPT1 inhibitor etomoxir or CRISPR-generated CPT1A-/-, CPT2-/-, ACAD9-/- cells demonstrate that FAO-derived acetyl-CoA upregulates CD47 transcription via NF-κB/RelA acetylation. Blocking FAO impairs tumor growth and reduces CD47 anti-phagocytosis. Etomoxir combined with anti-CD47 antibody synergizes radiation control of regrown tumors with boosted macrophage phagocytosis. These results demonstrate that enhanced fat acid metabolism promotes aggressive growth of GBM with CD47-mediated immune evasion. The FAO-CD47 axis may be targeted to improve GBM control by eliminating the radioresistant phagocytosis-proofing tumor cells in GBM radioimmunotherapy.

DOI: https://doi.org/10.1038/s41467-022-29137-3
PLoS One. 2022 ;17(3): e0266071

Microbial metabolite butyrate promotes induction of IL-10+IgM+ plasma cells.

Bandik Föh, Jana Sophia Buhre, Hanna B Lunding, Maria E Moreno-Fernandez, Peter König, Christian Sina, Senad Divanovic, Marc Ehlers.

The microbially-derived short-chain fatty acid butyrate is a central inhibitor of inflammatory innate and adaptive immune responses. Emerging evidence suggests that butyrate induces differentiation of IL-10-producing (IL-10+) regulatory B cells. However, the underlying mechanisms of butyrate-driven modulation of B cell differentiation are not fully defined. Given the dominant role of regulatory plasma cells (PCs) as the main source of anti-inflammatory cytokines including IL-10 and the observation that butyrate also induces the differentiation of PCs, we here investigated the effect of the microbial metabolite butyrate on the induction of regulatory IL-10+ PCs and underlying mechanisms. Here we show that butyrate induces the differentiation of IL-10+IgM+ PCs. Ex vivo, butyrate, but hardly propionate, another microbially-derived short-chain fatty acid, induced the differentiation of IL-10+IgM+ CD138high PCs from isolated splenic murine B cells. In vivo, administration of butyrate via drinking water or by daily intraperitoneal injection increased the number of IL-10+IgM+ CD138high PCs in the spleens of Ovalbumin (Ova)/complete Freund's adjuvant-immunized mice. The induction of these regulatory PCs was associated with an increase of anti-Ova IgM, but a reduction of anti-Ova class-switched pathogenic IgG2b serum antibodies. Based on the knowledge that butyrate inhibits histone deacetylases (HDACs) thereby increasing histone acetylation, we identified here that HDAC3 inhibition was sufficient to induce PC differentiation and IL-10+ expression. Furthermore, reduced mitochondrial superoxide levels following butyrate treatment and HDAC3 inhibition were necessary for PC differentiation, but not IL-10 expression. In summary, the microbial metabolite butyrate promotes the differentiation of IgM+ PCs and their expression of IL-10. HDAC3 inhibition may be involved as an underlying pathway for both PC differentiation and IL-10 expression, while reduced mitochondrial superoxide levels are crucial only for PC differentiation. The induction of regulatory IL-10+IgM+ PCs and the inhibition of class switching to antigen-specific pathogenic IgG subclasses might represent important pathways of butyrate to limit inflammation.

DOI: https://doi.org/10.1371/journal.pone.0266071
iScience. 2022 Apr 15. 25(4): 104021

Intracellular metabolic adaptation of intraepithelial CD4+CD8αα+ T lymphocytes.

Yosuke Harada, Tomohisa Sujino, Kentaro Miyamoto, Ena Nomura, Yusuke Yoshimatsu, Shun Tanemoto, Satoko Umeda, Keiko Ono, Yohei Mikami, Nobuhiro Nakamoto, Kaoru Takabayashi, Naoki Hosoe, Haruhiko Ogata, Tuneo Ikenoue, Atsushi Hirao, Yoshiaki Kubota, Takanori Kanai.

  Intestinal intraepithelial lymphocytes (IELs), the first line of defense against microbial and dietary antigens, are classified as natural or induced based on their origin and receptor expression. Induced CD4+CD8αα+TCRβ+ T cells (double positive, DPIELs) originated from CD4+CD8α-TCRβ+ T cells (single positive, SPIELs) increase with aging. However, the metabolic requirements and the metabolic-related genes in IEL development remain unclear. We determined that the intraepithelial compartment is hypoxic in the presence of microbes and DPIELs increased more than natural IELs in this location. Moreover, DPIELs consumed less oxygen and glucose and exhibited unique alterations in mitochondria. Using inhibitors and genetically modified mice, we revealed that DPIELs adapt to their surrounding oxygen-deprived environment in peripheral tissues by modulating specific genes, including hypoxia-inducible factor, mammalian target of rapamycin complexes (mTORC), phosphorylated ribosomal protein S6 (pS6), and other glycolytic factors. Our findings provide valuable insight into the metabolic properties of IELs.

Keywords:  Biological sciences; Cell biology; Components of the immune system; Immunology

DOI:  https://doi.org/10.1016/j.isci.2022.104021
J Clin Invest. 2022 Mar 22. pii: e147822. [Epub ahead of print]

Iron deficiency linked to altered bile acid metabolism promotes Helicobacter pylori-induced inflammation-driven gastric carcinogenesis.

Jennifer M Noto, M Blanca Piazuelo, Shailja C Shah, Judith Romero-Gallo, Jessica L Hart, Chao Di, James D Carmichael, Alberto G Delgado, Alese E Halvorson, Robert A Greevy, Lydia E Wroblewski, Ayushi Sharma, Annabelle B Newton, Margaret M Allaman, Keith T Wilson, M Kay Washington, M Wade Calcutt, Kevin L Schey, Bethany P Cummings, Charles R Flynn, Joseph P Zackular, Richard M Peek.

  Gastric carcinogenesis is mediated by complex interactions among Helicobacter pylori, host, and environmental factors. We now demonstrate that H. pylori augments gastric injury in INS-GAS mice under iron deficient conditions. Mechanistically, these phenotypes were not driven by alterations in the gastric microbiota; however, discovery-based and targeted metabolomics revealed that bile acids were significantly altered in H. pylori-infected mice with iron deficiency, with significant upregulation of deoxycholic acid (DCA), a carcinogenic bile acid. Severity of gastric injury was further augmented when H. pylori-infected mice were treated with DCA, and, in vitro, DCA increased translocation of the H. pylori oncoprotein CagA into host cells. Conversely, bile acid sequestration attenuated H. pylori-induced injury under conditions of iron deficiency. To translate these findings into human populations, the association between bile acid-sequestrant use and gastric cancer risk was evaluated in a large human cohort. Among 416,885 individuals, a significant dose-dependent reduction in risk was associated with cumulative bile acid-sequestrant use. Further, expression of the bile acid receptor TGR5 paralleled the severity of carcinogenic lesions in humans. These data demonstrate that increased H. pylori-induced injury within the context of iron deficiency is tightly linked to altered bile acid metabolism, which may promote gastric carcinogenesis.

Keywords:  Bacterial infections; Gastric cancer; Gastroenterology; Infectious disease; Mouse models

DOI:  https://doi.org/10.1172/JCI147822
PLoS Pathog. 2022 Mar;18(3): e1010378

Elevated ATP via enhanced miRNA-30b, 30c, and 30e downregulates the expression of CD73 in CD8+ T cells of HIV-infected individuals.

Shima Shahbaz, Isobel Okoye, Gregg Blevins, Shokrollah Elahi.

CD8+ T cells play a crucial role against chronic viral infections, however, their effector functions are influenced by the expression of co-stimulatory/inhibitory receptors. For example, CD73 works with CD39 to convert highly inflammatory ATP to adenosine. However, its expression on T cells in the context of viral infections has not been well defined. Here, we analyzed the expression of CD73 on human T cells in a cohort of 102 HIV-infected individuals including those on antiretroviral therapy (ART), ART-naïve, and long-term non-progressors who were not on ART. We found that the frequency of CD73+ T cells was markedly lower among T cell subsets (e.g. naïve, effector or memory) in the peripheral blood of all HIV-infected individuals. Notably, CD73 was decreased at the cell surface, intracellular and gene levels. Functionally, CD8+CD73+ T cells exhibited decreased cytokine expression (TNF-α, IFN-γ and IL-2) upon global or antigen-specific stimulation and impaired expression of cytolytic molecules at the gene and protein levels. In contrast, CD8+CD73+ T cells expressed elevated levels of homing receptors such as CCR7, α4β7 integrin, which suggests a migratory advantage for these cells as observed in vitro. We also observed significant migration of CD73+CD8+ T cells into the cerebrospinal fluids of multiple sclerosis (MS) patients at the time of disease relapse. Moreover, we found that elevated levels of ATP in the plasma of HIV-infected individuals upregulates the expression of miRNA30b-e in T cells in vitro. In turn, inhibition of miRNAs (30b, 30c and 30e) resulted in significant upregulation of CD73 mRNA in CD8+ T cells. Therefore, we provide a novel mechanism for the downregulation of CD73 via ATP-induced upregulation of miRNA30b, 30c and 30e in HIV infection. Finally, these observations imply that ATP-mediated downregulation of CD73 mainly occurs via its receptor, P2X1/P2RX1. Our results may in part explain why HIV-infected individuals have reduced risk of developing MS considering the role of CD73 for efficient T cell entry into the central nervous system.

DOI: https://doi.org/10.1371/journal.ppat.1010378