bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2023–01–15
27 papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. GOT1 regulates CD8+ effector and memory T cell generation.
  2. Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke.
  3. SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism.
  4. Mapping transcriptional heterogeneity and metabolic networks in fatty livers at single-cell resolution.
  5. Control of tumor-associated macrophage responses by nutrient acquisition and metabolism.
  6. Eating macrophages for a healthy anti-NASH meal.
  7. SOD1 is an essential H2S detoxifying enzyme.
  8. Protocol for standardized intrathymic injection in mice.
  9. The Polyamine Putrescine Is a Positive Regulator of Group 3 Innate Lymphocyte Activation.
  10. The aryl hydrocarbon receptor cell intrinsically promotes resident memory CD8+ T cell differentiation and function.
  11. An atlas of substrate specificities for the human serine/threonine kinome.
  12. Enzyme-independent catabolism of cysteine with pyridoxal-5'-phosphate.
  13. Arginine limitation drives a directed codon-dependent DNA sequence evolution response in colorectal cancer cells.
  14. Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan.
  15. Protocol for direct measurement of stability and activity of mitochondria electron transport chain complex II.
  16. Proline and glucose metabolic reprogramming supports vascular endothelial and medial biomass in pulmonary arterial hypertension.
  17. Macrophages modulate stiffness-related foreign body responses through plasma membrane deformation.
  18. Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study.
  19. A critical assessment of the role of creatine in brown adipose tissue thermogenesis.
  20. A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer.
  21. Dysregulated ceramide metabolism in mouse progressive dermatitis resulting from constitutive activation of Jak1.
  22. Nicotinamide N-methyltransferase promotes M2 macrophage polarization by IL6 and MDSC conversion by GM-CSF in gallbladder carcinoma.
  23. STING controls T cell memory fitness during infection through T cell-intrinsic and IDO-dependent mechanisms.
  24. Conserved angio-immune subtypes of the tumor microenvironment predict response to immune checkpoint blockade therapy.
  25. Fluorescence-activated cell sorting and phenotypic characterization of human fibro-adipogenic progenitors.
  26. Metabolites as signalling molecules.
  27. GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology.
  1. Cell Rep. 2023 Jan 12. pii: S2211-1247(22)01891-5. [Epub ahead of print]42(1): 111987
    GOT1 regulates CD8+ effector and memory T cell generation.
    Wei Xu, Chirag H Patel, Liang Zhao, Im-Hong Sun, Min-Hee Oh, Im-Meng Sun, Rachel S Helms, Jiayu Wen, Jonathan D Powell.
      T cell activation, proliferation, function, and differentiation are tightly linked to proper metabolic reprogramming and regulation. By using [U-13C]glucose tracing, we reveal a critical role for GOT1 in promoting CD8+ T cell effector differentiation and function. Mechanistically, GOT1 enhances proliferation by maintaining intracellular redox balance and serine-mediated purine nucleotide biosynthesis. Further, GOT1 promotes the glycolytic programming and cytotoxic function of cytotoxic T lymphocytes via posttranslational regulation of HIF protein, potentially by regulating the levels of α-ketoglutarate. Conversely, genetic deletion of GOT1 promotes the generation of memory CD8+ T cells.
    Keywords:  CP: Metabolism; GOT1; HIF; NADH/NAD; effector and memory CD8(+) T cell; glucose; glutamate; serine
    DOI:  https://doi.org/10.1016/j.celrep.2022.111987
  2. Redox Biol. 2023 Feb;pii: S2213-2317(23)00001-0. [Epub ahead of print]59 102600
    Targeting succinate metabolism to decrease brain injury upon mechanical thrombectomy treatment of ischemic stroke.
    Amin Mottahedin, Hiran A Prag, Andreas Dannhorn, Richard Mair, Christina Schmidt, Ming Yang, Annabel Sorby-Adams, Jordan J Lee, Nils Burger, Duvaraka Kulaveerasingam, Margaret M Huang, Stefano Pluchino, Luca Peruzzotti-Jametti, Richard Goodwin, Christian Frezza, Michael P Murphy, Thomas Krieg.
      Current treatments for acute ischemic stroke aim to reinstate a normal perfusion in the ischemic territory but can also cause significant ischemia-reperfusion (IR) injury. Previous data in experimental models of stroke show that ischemia leads to the accumulation of succinate, and, upon reperfusion, the accumulated succinate is rapidly oxidized by succinate dehydrogenase (SDH) to drive superoxide production at mitochondrial complex I. Despite this process initiating IR injury and causing further tissue damage, the potential of targeting succinate metabolism to minimize IR injury remains unexplored. Using both quantitative and untargeted high-resolution metabolomics, we show a time-dependent accumulation of succinate in both human and mouse brain exposed to ischemia ex vivo. In a mouse model of ischemic stroke/mechanical thrombectomy mass spectrometry imaging (MSI) shows that succinate accumulation is confined to the ischemic region, and that the accumulated succinate is rapidly oxidized upon reperfusion. Targeting succinate oxidation by systemic infusion of the SDH inhibitor malonate upon reperfusion leads to a dose-dependent decrease in acute brain injury. Together these findings support targeting succinate metabolism upon reperfusion to decrease IR injury as a valuable adjunct to mechanical thrombectomy in ischemic stroke.
    DOI:  https://doi.org/10.1016/j.redox.2023.102600
  3. Nat Rev Cardiol. 2023 Jan 06.
    SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism.
    Milton Packer.
      Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure events by direct action on the failing heart that is independent of changes in renal tubular function. In the failing heart, nutrient transport into cardiomyocytes is increased, but nutrient utilization is impaired, leading to deficient ATP production and the cytosolic accumulation of deleterious glucose and lipid by-products. These by-products trigger downregulation of cytoprotective nutrient-deprivation pathways, thereby promoting cellular stress and undermining cellular survival. SGLT2 inhibitors restore cellular homeostasis through three complementary mechanisms: they might bind directly to nutrient-deprivation and nutrient-surplus sensors to promote their cytoprotective actions; they can increase the synthesis of ATP by promoting mitochondrial health (mediated by increasing autophagic flux) and potentially by alleviating the cytosolic deficiency in ferrous iron; and they might directly inhibit glucose transporter type 1, thereby diminishing the cytosolic accumulation of toxic metabolic by-products and promoting the oxidation of long-chain fatty acids. The increase in autophagic flux mediated by SGLT2 inhibitors also promotes the clearance of harmful glucose and lipid by-products and the disposal of dysfunctional mitochondria, allowing for mitochondrial renewal through mitochondrial biogenesis. This Review describes the orchestrated interplay between nutrient transport and metabolism and nutrient-deprivation and nutrient-surplus signalling, to explain how SGLT2 inhibitors reverse the profound nutrient, metabolic and cellular abnormalities observed in heart failure, thereby restoring the myocardium to a healthy molecular and cellular phenotype.
    DOI:  https://doi.org/10.1038/s41569-022-00824-4
  4. iScience. 2023 Jan 20. 26(1): 105802
    Mapping transcriptional heterogeneity and metabolic networks in fatty livers at single-cell resolution.
    Laetitia Coassolo, Tianyun Liu, Yunshin Jung, Nikki P Taylor, Meng Zhao, Gregory W Charville, Silas Boye Nissen, Hannele Yki-Jarvinen, Russ B Altman, Katrin J Svensson.
      Non-alcoholic fatty liver disease is a heterogeneous disease with unclear underlying molecular mechanisms. Here, we perform single-cell RNA sequencing of hepatocytes and hepatic non-parenchymal cells to map the lipid signatures in mice with non-alcoholic fatty liver disease (NAFLD). We uncover previously unidentified clusters of hepatocytes characterized by either high or low srebp1 expression. Surprisingly, the canonical lipid synthesis driver Srebp1 is not predictive of hepatic lipid accumulation, suggestive of other drivers of lipid metabolism. By combining transcriptional data at single-cell resolution with computational network analyses, we find that NAFLD is associated with high constitutive androstane receptor (CAR) expression. Mechanistically, CAR interacts with four functional modules: cholesterol homeostasis, bile acid metabolism, fatty acid metabolism, and estrogen response. Nuclear expression of CAR positively correlates with steatohepatitis in human livers. These findings demonstrate significant cellular differences in lipid signatures and identify functional networks linked to hepatic steatosis in mice and humans.
    Keywords:  Molecular network; Molecular physiology; Systems biology; Transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2022.105802
  5. Immunity. 2023 Jan 10. pii: S1074-7613(22)00639-2. [Epub ahead of print]56(1): 14-31
    Control of tumor-associated macrophage responses by nutrient acquisition and metabolism.
    Xian Zhang, Liangliang Ji, Ming O Li.
      Metazoan tissue specification is associated with integration of macrophage lineage cells in sub-tissular niches to promote tissue development and homeostasis. Oncogenic transformation, most prevalently of epithelial cell lineages, results in maladaptation of resident tissue macrophage differentiation pathways to generate parenchymal and interstitial tumor-associated macrophages that largely foster cancer progression. In addition to growth factors, nutrients that can be consumed, stored, recycled, or converted to signaling molecules have emerged as crucial regulators of macrophage responses in tumor. Here, we review how nutrient acquisition through plasma membrane transporters and engulfment pathways control tumor-associated macrophage differentiation and function. We also discuss how nutrient metabolism regulates tumor-associated macrophages and how these processes may be targeted for cancer therapy.
    Keywords:  engulfment; macrophage; metabolism; nutrient; transporter; tumor
    DOI:  https://doi.org/10.1016/j.immuni.2022.12.003
  6. Immunity. 2023 Jan 10. pii: S1074-7613(22)00647-1. [Epub ahead of print]56(1): 3-5
    Eating macrophages for a healthy anti-NASH meal.
    Yun Sok Lee, Jerrold Olefsky.
      Nonalcoholic steatohepatitis (NASH) is a common liver disease involving interactions between a variety of liver cell types. In this issue of Immunity, Wang et al. show that efferocytosis of dying lipid-laden hepatocytes by hepatic macrophages protects against the development of NASH.
    DOI:  https://doi.org/10.1016/j.immuni.2022.12.011
  7. Proc Natl Acad Sci U S A. 2023 Jan 17. 120(3): e2205044120
    SOD1 is an essential H2S detoxifying enzyme.
    Christopher H Switzer, Shingo Kasamatsu, Hideshi Ihara, Philip Eaton.
      Although hydrogen sulfide (H2S) is an endogenous signaling molecule with antioxidant properties, it is also cytotoxic by potently inhibiting cytochrome c oxidase and mitochondrial respiration. Paradoxically, the primary route of H2S detoxification is thought to occur inside the mitochondrial matrix via a series of relatively slow enzymatic reactions that are unlikely to compete with its rapid inhibition of cytochrome c oxidase. Therefore, alternative or complementary cellular mechanisms of H2S detoxification are predicted to exist. Here, superoxide dismutase [Cu-Zn] (SOD1) is shown to be an efficient H2S oxidase that has an essential role in limiting cytotoxicity from endogenous and exogenous sulfide. Decreased SOD1 expression resulted in increased sensitivity to H2S toxicity in yeast and human cells, while increased SOD1 expression enhanced tolerance to H2S. SOD1 rapidly converted H2S to sulfate under conditions of limiting sulfide; however, when sulfide was in molar excess, SOD1 catalyzed the formation of per- and polysulfides, which induce cellular thiol oxidation. Furthermore, in SOD1-deficient cells, elevated levels of reactive oxygen species catalyzed sulfide oxidation to per- and polysulfides. These data reveal that a fundamental function of SOD1 is to regulate H2S and related reactive sulfur species.
    Keywords:  SOD1; hydrogen sulfide; persulfide; polysulfide; reactive sulfur species
    DOI:  https://doi.org/10.1073/pnas.2205044120
  8. STAR Protoc. 2023 Jan 12. pii: S2666-1667(22)00890-5. [Epub ahead of print]4(1): 102010
    Protocol for standardized intrathymic injection in mice.
    Tsung-Lin Tsai, Pei-Yuan Tsai, Ivan L Dzhagalov, Chia-Lin Hsu.
      Currently available intrathymic injection techniques cause postoperative complications or difficulties in equipment acquisition. Here, we describe a standardized intrathymic injection protocol that requires only basic equipment with a minimally invasive procedure. We detail steps to identify injection sites for intrathymic delivery. We then describe how to visualize a successful intrathymic injection by including Indian ink in the injected solution. For complete details on the use and execution of this protocol, please refer to Tsai et al. (2022).1.
    Keywords:  Developmental Biology; Immunology
    DOI:  https://doi.org/10.1016/j.xpro.2022.102010
  9. Immunohorizons. 2023 Jan 01. 7(1): 41-48
    The Polyamine Putrescine Is a Positive Regulator of Group 3 Innate Lymphocyte Activation.
    Prakash Sah, Lauren A Zenewicz.
      Group 3 innate lymphocytes (ILC3s) rapidly respond to invading pathogens or inflammatory signals, which requires shifting cellular metabolic demands. Metabolic adaptations regulating ILC3 function are not completely understood. Polyamines are polycationic metabolites that have diverse roles in cellular functions and in immunity regulate immune cell biology, including Th17 cells. Whether polyamines play a role in ILC3 activation is unknown. In this article, we report that the polyamine synthesis pathway is important for ILC3 activation. IL-23-activated mouse ILC3s upregulate ornithine decarboxylase, the enzyme catalyzing the rate-limiting step of the conversion of ornithine to putrescine in polyamine synthesis, with a subsequent increase in putrescine levels. Inhibition of ornithine decarboxylase via a specific inhibitor, α-difluoromethylornithine, reduced levels of IL-22 produced by steady-state or IL-23-activated ILC3s in a putrescine-dependent manner. Thus, the polyamine putrescine is a positive regulator of ILC3 activation. Our results suggest that polyamines represent a potential target for therapeutic modulation of ILC3 activation during infection or inflammatory disorders.
    DOI:  https://doi.org/10.4049/immunohorizons.2200097
  10. Cell Rep. 2023 Jan 04. pii: S2211-1247(22)01867-8. [Epub ahead of print]42(1): 111963
    The aryl hydrocarbon receptor cell intrinsically promotes resident memory CD8+ T cell differentiation and function.
    Joseph W Dean, Eric Y Helm, Zheng Fu, Lifeng Xiong, Na Sun, Kristen N Oliff, Marcus Muehlbauer, Dorina Avram, Liang Zhou.
      The Aryl hydrocarbon receptor (Ahr) regulates the differentiation and function of CD4+ T cells; however, its cell-intrinsic role in CD8+ T cells remains elusive. Herein we show that Ahr acts as a promoter of resident memory CD8+ T cell (TRM) differentiation and function. Genetic ablation of Ahr in mouse CD8+ T cells leads to increased CD127-KLRG1+ short-lived effector cells and CD44+CD62L+ T central memory cells but reduced granzyme-B-producing CD69+CD103+ TRM cells. Genome-wide analyses reveal that Ahr suppresses the circulating while promoting the resident memory core gene program. A tumor resident polyfunctional CD8+ T cell population, revealed by single-cell RNA-seq, is diminished upon Ahr deletion, compromising anti-tumor immunity. Human intestinal intraepithelial CD8+ T cells also highly express AHR that regulates in vitro TRM differentiation and granzyme B production. Collectively, these data suggest that Ahr is an important cell-intrinsic factor for CD8+ T cell immunity.
    Keywords:  CD8(+) T cell; CP: Immunology; aryl hydrocarbon receptor; cancer immunology; cytotoxicity; development; differentiation; mucosal immunology; tissue resident memory; tumor infiltrating lymphocyte
    DOI:  https://doi.org/10.1016/j.celrep.2022.111963
  11. Nature. 2023 Jan 11.
    An atlas of substrate specificities for the human serine/threonine kinome.
    Jared L Johnson, Tomer M Yaron, Emily M Huntsman, Alexander Kerelsky, Junho Song, Amit Regev, Ting-Yu Lin, Katarina Liberatore, Daniel M Cizin, Benjamin M Cohen, Neil Vasan, Yilun Ma, Konstantin Krismer, Jaylissa Torres Robles, Bert van de Kooij, Anne E van Vlimmeren, Nicole Andrée-Busch, Norbert F Käufer, Maxim V Dorovkov, Alexey G Ryazanov, Yuichiro Takagi, Edward R Kastenhuber, Marcus D Goncalves, Benjamin D Hopkins, Olivier Elemento, Dylan J Taatjes, Alexandre Maucuer, Akio Yamashita, Alexei Degterev, Mohamed Uduman, Jingyi Lu, Sean D Landry, Bin Zhang, Ian Cossentino, Rune Linding, John Blenis, Peter V Hornbeck, Benjamin E Turk, Michael B Yaffe, Lewis C Cantley.
      Protein phosphorylation is one of the most widespread post-translational modifications in biology1,2. With advances in mass-spectrometry-based phosphoproteomics, 90,000 sites of serine and threonine phosphorylation have so far been identified, and several thousand have been associated with human diseases and biological processes3,4. For the vast majority of phosphorylation events, it is not yet known which of the more than 300 protein serine/threonine (Ser/Thr) kinases encoded in the human genome are responsible3. Here we used synthetic peptide libraries to profile the substrate sequence specificity of 303 Ser/Thr kinases, comprising more than 84% of those predicted to be active in humans. Viewed in its entirety, the substrate specificity of the kinome was substantially more diverse than expected and was driven extensively by negative selectivity. We used our kinome-wide dataset to computationally annotate and identify the kinases capable of phosphorylating every reported phosphorylation site in the human Ser/Thr phosphoproteome. For the small minority of phosphosites for which the putative protein kinases involved have been previously reported, our predictions were in excellent agreement. When this approach was applied to examine the signalling response of tissues and cell lines to hormones, growth factors, targeted inhibitors and environmental or genetic perturbations, it revealed unexpected insights into pathway complexity and compensation. Overall, these studies reveal the intrinsic substrate specificity of the human Ser/Thr kinome, illuminate cellular signalling responses and provide a resource to link phosphorylation events to biological pathways.
    DOI:  https://doi.org/10.1038/s41586-022-05575-3
  12. Sci Rep. 2023 Jan 06. 13(1): 312
    Enzyme-independent catabolism of cysteine with pyridoxal-5'-phosphate.
    Prajakatta Mulay, Cindy Chen, Vijay Krishna.
      Pyridoxal-5'-phosphate (PLP) is a versatile cofactor that assists in different types of enzymatic reactions. PLP has also been reported to react with substrates and catalyze some of these reactions independent of enzymes. One such catalytic reaction is the breakdown of cysteine to produce hydrogen sulfide (H2S) in the presence of multivalent metal ions. However, the enzyme-independent catalytic activity of PLP in catabolizing cysteine in the absence of multivalent ions is unknown. In this study, we show that PLP reacts with cysteine to form a thiazolidine product, which is supported by quantum chemical calculations of the absorption spectrum. The reaction of PLP with cysteine is dependent on ionic strength and pH. The thiazolidine product slowly decomposes to produce H2S and the PLP regenerates to its active form with longer reaction times (> 24 h), suggesting that PLP can act as a catalyst. We propose an enzyme-independent plausible reaction mechanism for PLP catalyzed cysteine breakdown to produce H2S, which proceeds through the formation of thiazolidine ring intermediates that later hydrolyzes slowly to regenerate the PLP. This work demonstrates that PLP catalyzes cysteine breakdown in the absence of enzymes, base, and multivalent metal ions to produce H2S.
    DOI:  https://doi.org/10.1038/s41598-022-26966-6
  13. Sci Adv. 2023 Jan 06. 9(1): eade9120
    Arginine limitation drives a directed codon-dependent DNA sequence evolution response in colorectal cancer cells.
    Dennis J Hsu, Jenny Gao, Norihiro Yamaguchi, Alexandra Pinzaru, Qiushuang Wu, Nandan Mandayam, Maria Liberti, Søren Heissel, Hanan Alwaseem, Saeed Tavazoie, Sohail F Tavazoie.
      Utilization of specific codons varies between organisms. Cancer represents a model for understanding DNA sequence evolution and could reveal causal factors underlying codon evolution. We found that across human cancer, arginine codons are frequently mutated to other codons. Moreover, arginine limitation-a feature of tumor microenvironments-is sufficient to induce arginine codon-switching mutations in human colon cancer cells. Such DNA codon switching events encode mutant proteins with arginine residue substitutions. Mechanistically, arginine limitation caused rapid reduction of arginine transfer RNAs and the stalling of ribosomes over arginine codons. Such selective pressure against arginine codon translation induced an adaptive proteomic shift toward low-arginine codon-containing genes, including specific amino acid transporters, and caused mutational evolution away from arginine codons-reducing translational bottlenecks that occurred during arginine starvation. Thus, environmental availability of a specific amino acid can influence DNA sequence evolution away from its cognate codons and generate altered proteins.
    DOI:  https://doi.org/10.1126/sciadv.ade9120
  14. Cell. 2023 Jan 05. pii: S0092-8674(22)01520-3. [Epub ahead of print]186(1): 63-79.e21
    Cell-cell metabolite exchange creates a pro-survival metabolic environment that extends lifespan.
    Clara Correia-Melo, Stephan Kamrad, Roland Tengölics, Christoph B Messner, Pauline Trebulle, StJohn Townsend, Sreejith Jayasree Varma, Anja Freiwald, Benjamin M Heineike, Kate Campbell, Lucía Herrera-Dominguez, Simran Kaur Aulakh, Lukasz Szyrwiel, Jason S L Yu, Aleksej Zelezniak, Vadim Demichev, Michael Mülleder, Balázs Papp, Mohammad Tauqeer Alam, Markus Ralser.
      Metabolism is deeply intertwined with aging. Effects of metabolic interventions on aging have been explained with intracellular metabolism, growth control, and signaling. Studying chronological aging in yeast, we reveal a so far overlooked metabolic property that influences aging via the exchange of metabolites. We observed that metabolites exported by young cells are re-imported by chronologically aging cells, resulting in cross-generational metabolic interactions. Then, we used self-establishing metabolically cooperating communities (SeMeCo) as a tool to increase metabolite exchange and observed significant lifespan extensions. The longevity of the SeMeCo was attributable to metabolic reconfigurations in methionine consumer cells. These obtained a more glycolytic metabolism and increased the export of protective metabolites that in turn extended the lifespan of cells that supplied them with methionine. Our results establish metabolite exchange interactions as a determinant of cellular aging and show that metabolically cooperating cells can shape the metabolic environment to extend their lifespan.
    Keywords:  chronological aging; eukaryotic longevity; metabolic microenvironment; metabolite exchange interactions
    DOI:  https://doi.org/10.1016/j.cell.2022.12.007
  15. STAR Protoc. 2023 Jan 06. pii: S2666-1667(22)00876-0. [Epub ahead of print]4(1): 101996
    Protocol for direct measurement of stability and activity of mitochondria electron transport chain complex II.
    Himangshu S Bose, Nicole E Doetch.
      Mitochondria electron transport chain (ETC) complex II is essential for steroid metabolism. Here, we present a protocol to measure the stability and activity of mitochondria ETC complex II. We first describe mitochondria isolation from cell lines and tissues. We then detail how to determine the stability of ETC complex II using isothermal calorimetry and quantification of steroidogenesis using activity assays in parallel. Finally, we describe the steps to perform radioimmunoassay (RIA) to confirm the activity of ETC complex II. For complete details on the use and execution of this protocol, please refer to Bose et al. (2020).1.
    Keywords:  Cell Isolation; Cell-based Assays; Metabolism; Protein Biochemistry
    DOI:  https://doi.org/10.1016/j.xpro.2022.101996
  16. JCI Insight. 2023 Jan 10. pii: e163932. [Epub ahead of print]
    Proline and glucose metabolic reprogramming supports vascular endothelial and medial biomass in pulmonary arterial hypertension.
    Bradley M Wertheim, Rui-Sheng Wang, Christelle Guillermier, Christiane Vr Hütter, William M Oldham, Jörg Menche, Matthew L Steinhauser, Bradley A Maron.
      In pulmonary arterial hypertension (PAH), inflammation promotes a fibroproliferative pulmonary vasculopathy. Reductionist studies emphasizing single biochemical reactions suggest a shift toward glycolytic metabolism in PAH; however, key questions remain regarding the metabolic profile of specific cell types within PAH vascular lesions in vivo. We used RNA-seq to profile the transcriptome of pulmonary artery endothelial cells (PAECs) freshly isolated from an inflammatory vascular injury model of PAH ex vivo, and these data were integrated with information from human gene ontology pathways. Network medicine was then used to map all amino acid and glucose pathways to the consolidated human interactome, which includes data on 233,957 physical protein-protein interactions. Glucose and proline pathways were significantly close to the human PAH disease module, suggesting that these pathways are functionally relevant to PAH pathobiology. To test this observation in vivo, we used multi-isotope imaging mass spectrometry (MIMS) to map and quantify utilization of glucose and proline in the PAH pulmonary vasculature at subcellular resolution. Our findings suggest suggest that elevated glucose and proline avidity underlies increased biomass in PAECs and the media of fibrosed PAH pulmonary arterioles. Overall, these data show that anabolic utilization of glucose and proline are fundamental to the vascular pathology of PAH.
    Keywords:  Amino acid metabolism; Cardiology; Endothelial cells; Fibrosis; Pulmonology
    DOI:  https://doi.org/10.1172/jci.insight.163932
  17. Proc Natl Acad Sci U S A. 2023 Jan 17. 120(3): e2213837120
    Macrophages modulate stiffness-related foreign body responses through plasma membrane deformation.
    Yueqi Ni, Haoning Qi, Fanyu Zhang, Shuting Jiang, Qinchao Tang, Wenjin Cai, Wenting Mo, Richard J Miron, Yufeng Zhang.
      Implants are widely used in medical applications and yet macrophage-mediated foreign body reactions caused by implants severely impact their therapeutic effects. Although the extensive use of multiple surface modifications has been introduced to provide some mitigation of fibrosis, little is known about how macrophages recognize the stiffness of the implant and thus influence cell behaviors. Here, we demonstrated that macrophage stiffness sensing leads to differential inflammatory activation, resulting in different degrees of fibrosis. The potential mechanism for macrophage stiffness sensing in the early adhesion stages tends to involve cell membrane deformations on substrates with different stiffnesses. Combining theory and experiments, we show that macrophages exert traction stress on the substrate through adhesion and altered membrane curvature, leading to the uneven distribution of the curvature-sensing protein Baiap2, resulting in cytoskeleton remodeling and inflammation inhibition. This study introduces a physical model feedback mechanism for early cellular stiffness sensing based on cell membrane deformation, offering perspectives for future material design and targeted therapies.
    Keywords:  biomaterial recognition; deformation; foreign body reaction; mechanotransduction; stiffness
    DOI:  https://doi.org/10.1073/pnas.2213837120
  18. Sci Adv. 2023 Jan 13. 9(2): eadd5163
    Nicotinamide riboside improves muscle mitochondrial biogenesis, satellite cell differentiation, and gut microbiota in a twin study.
    Helena A K Lapatto, Minna Kuusela, Aino Heikkinen, Maheswary Muniandy, Birgitta W van der Kolk, Swetha Gopalakrishnan, Noora Pöllänen, Martin Sandvik, Mark S Schmidt, Sini Heinonen, Sina Saari, Juho Kuula, Antti Hakkarainen, Janne Tampio, Tuure Saarinen, Marja-Riitta Taskinen, Nina Lundbom, Per-Henrik Groop, Marja Tiirola, Pekka Katajisto, Marko Lehtonen, Charles Brenner, Jaakko Kaprio, Satu Pekkala, Miina Ollikainen, Kirsi H Pietiläinen, Eija Pirinen.
      Nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide riboside (NR) has emerged as a promising compound to improve obesity-associated mitochondrial dysfunction and metabolic syndrome in mice. However, most short-term clinical trials conducted so far have not reported positive outcomes. Therefore, we aimed to determine whether long-term NR supplementation boosts mitochondrial biogenesis and metabolic health in humans. Twenty body mass index (BMI)-discordant monozygotic twin pairs were supplemented with an escalating dose of NR (250 to 1000 mg/day) for 5 months. NR improved systemic NAD+ metabolism, muscle mitochondrial number, myoblast differentiation, and gut microbiota composition in both cotwins. NR also showed a capacity to modulate epigenetic control of gene expression in muscle and adipose tissue in both cotwins. However, NR did not ameliorate adiposity or metabolic health. Overall, our results suggest that NR acts as a potent modifier of NAD+ metabolism, muscle mitochondrial biogenesis and stem cell function, gut microbiota, and DNA methylation in humans irrespective of BMI.
    DOI:  https://doi.org/10.1126/sciadv.add5163
  19. Nat Metab. 2023 Jan 09.
    A critical assessment of the role of creatine in brown adipose tissue thermogenesis.
    David G Nicholls, Martin D Brand.
      Brown adipose tissue is specialized for non-shivering thermogenesis, combining lipolysis with an extremely active mitochondrial electron transport chain and a unique regulated uncoupling protein, UCP1, allowing unrestricted respiration. Current excitement focuses on the presence of brown adipose tissue in humans and the possibility that it may contribute to diet-induced thermogenesis, countering obesity and obesity-related disease as well as protecting cardio-metabolic health. In common with other tissues displaying a high, variable respiration, the tissue possesses a creatine pool and mitochondrial and cytosolic creatine kinase isoforms. Genetic and pharmacological manipulation of these components have pleiotropic effects that appear to influence diet- and cold-induced metabolism in vivo and modeled in vitro. These findings have been used to advance the concept of a UCP1-independent diet-induced thermogenic mechanism based on a dissipative hydrolysis of phosphocreatine in beige and brown adipose tissue. Here we review the in vivo and in vitro experimental basis for this hypothesis, and explore alternative explanations. We conclude that there is currently no convincing evidence for a significant futile creatine cycle in these tissues.
    DOI:  https://doi.org/10.1038/s42255-022-00718-2
  20. Nat Commun. 2023 Jan 06. 14(1): 98
    A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer.
    Sandra Tietscher, Johanna Wagner, Tobias Anzeneder, Claus Langwieder, Martin Rees, Bettina Sobottka, Natalie de Souza, Bernd Bodenmiller.
      Immune checkpoint therapy in breast cancer remains restricted to triple negative patients, and long-term clinical benefit is rare. The primary aim of immune checkpoint blockade is to prevent or reverse exhausted T cell states, but T cell exhaustion in breast tumors is not well understood. Here, we use single-cell transcriptomics combined with imaging mass cytometry to systematically study immune environments of human breast tumors that either do or do not contain exhausted T cells, with a focus on luminal subtypes. We find that the presence of a PD-1high exhaustion-like T cell phenotype is associated with an inflammatory immune environment with a characteristic cytotoxic profile, increased myeloid cell activation, evidence for elevated immunomodulatory, chemotactic, and cytokine signaling, and accumulation of natural killer T cells. Tumors harboring exhausted-like T cells show increased expression of MHC-I on tumor cells and of CXCL13 on T cells, as well as altered spatial organization with more immature rather than mature tertiary lymphoid structures. Our data reveal fundamental differences between immune environments with and without exhausted T cells within luminal breast cancer, and show that expression of PD-1 and CXCL13 on T cells, and MHC-I - but not PD-L1 - on tumor cells are strong distinguishing features between these environments.
    DOI:  https://doi.org/10.1038/s41467-022-35238-w
  21. J Lipid Res. 2023 Jan 10. pii: S0022-2275(23)00002-0. [Epub ahead of print] 100329
    Dysregulated ceramide metabolism in mouse progressive dermatitis resulting from constitutive activation of Jak1.
    Yudai Iino, Tatsuro Naganuma, Makoto Arita.
      Coordinated lipid metabolism contributes to maintaining skin homeostasis by regulating skin barrier formation, immune reactions, thermogenesis, and perception. Several reports have documented the changes in lipid composition in dermatitis, including in atopic dermatitis (AD); however, the specific mechanism by which these lipid profiles are altered during AD pathogenesis remains unknown. Here, we performed untargeted and targeted lipidomic analyses of an AD-like dermatitis model resulting from constitutive activation of Jak1 (Spade mice) to capture the comprehensive lipidome profile during dermatitis onset and progression. We successfully annotated over 700 skin lipids, including glycerophospholipids, ceramides, neutral lipids, and fatty acids, many of which were found to be present at significantly changed levels after dermatitis onset, as determined by the pruritus and erythema. Among them, we found the levels of ceramides composed of non-hydroxy fatty acids and dihydrosphingosines (Cer[NDS]) containing very long-chain (C22 or more) fatty acids were significantly downregulated before AD onset. Furthermore, in vitro enzyme assays using the skin of Spade mice demonstrated the enhancement of ceramide desaturation. Finally, we reveal topical application of Cer[NDS] before AD onset effectively ameliorated the progression of AD symptoms in Spade mice. Our results suggest that the disruption in epidermal ceramide composition is caused by boosting ceramide desaturation in the initiation phase of AD, which regulates AD pathogenesis.
    Keywords:  Atopic dermatitis; Cer[NDS]; Ceramide desaturation; Ceramides; LC-MS/MS; Lipidomics; Lipids; Skin; Sphingolipids
    DOI:  https://doi.org/10.1016/j.jlr.2023.100329
  22. Hepatology. 2023 Jan 13.
    Nicotinamide N-methyltransferase promotes M2 macrophage polarization by IL6 and MDSC conversion by GM-CSF in gallbladder carcinoma.
    Yang Li, Bo Yang, Huijie Miao, Liguo Liu, Ziyi Wang, Chengkai Jiang, Yang Yang, Shimei Qiu, Xuechuan Li, Yajun Geng, Rong Shao, Yijian Zhang, Yingbin Liu.
       BACKGROUND AND AIMS: Nicotinamide N-methyltransferase (NNMT), an enzyme responsible for the methylation of nicotinamide, is involved in many metabolic pathways in adipose tissue and the liver. However, the role of NNMT in editing the tumor immune microenvironment is not well understood.
    APPROACH AND RESULTS: Here, we identified that NNMT can promote IL6 and CM-CSF expression by decreasing the H3K27me3 levels on the promoters of IL6 and CSF2 (encoding GM-CSF) and CCAAT/Enhancer Binding Protein (CEBPB), an essential transcription factor for IL6 expression, thus promoting differentiation of macrophages into M2 type tumor-associated macrophages (TAMs) and generation of myeloid-derived suppressor cells (MDSCs) from peripheral blood mononuclear cells. Treatment of xenografted tumor models overexpressing NNMT gallbladder carcinoma (GBC) cells with the NNMT inhibitor JBSNF-000088 resulted in compromised tumor development and decreased expression levels of IL6, CSF2, TAM marker CD206 and MDSC marker CD33 but increased expression levels of CD8. In addition, elevated expression of NNMT in tumors of patients with GBC was correlated with increased expression levels of CD206 and CD33 but with decreased levels of CD8 and survival of patients.
    CONCLUSIONS: These data highlight the critical role of NNMT in GBC progression. Inhibition of NNMT by JBSNF-000088 is a potential molecular target for GBC immunotherapy.
    DOI:  https://doi.org/10.1097/HEP.0000000000000028
  23. Proc Natl Acad Sci U S A. 2023 Jan 17. 120(3): e2205049120
    STING controls T cell memory fitness during infection through T cell-intrinsic and IDO-dependent mechanisms.
    Michael J Quaney, Curtis J Pritzl, Dezzarae Luera, Rebecca J Newth, Karin M Knudson, Vikas Saxena, Caitlyn Guldenpfennig, Diana Gil, Chris S Rae, Peter Lauer, Mark A Daniels, Emma Teixeiro.
      Stimulator of interferon genes (STING) signaling has been extensively studied in inflammatory diseases and cancer, while its role in T cell responses to infection is unclear. Using Listeria monocytogenes strains engineered to induce different levels of c-di-AMP, we found that high STING signals impaired T cell memory upon infection via increased Bim levels and apoptosis. Unexpectedly, reduction of TCR signal strength or T cell-STING expression decreased Bim expression, T cell apoptosis, and recovered T cell memory. We found that TCR signal intensity coupled STING signal strength to the unfolded protein response (UPR) and T cell survival. Under strong STING signaling, Indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibition also reduced apoptosis and led to a recovery of T cell memory in STING sufficient CD8 T cells. Thus, STING signaling regulates CD8 T cell memory fitness through both cell-intrinsic and extrinsic mechanisms. These studies provide insight into how IDO and STING therapies could improve long-term T cell protective immunity.
    Keywords:  CD8 T cell memory; STING; TCR
    DOI:  https://doi.org/10.1073/pnas.2205049120
  24. Cell Rep Med. 2023 Jan 09. pii: S2666-3791(22)00475-X. [Epub ahead of print] 100896
    Conserved angio-immune subtypes of the tumor microenvironment predict response to immune checkpoint blockade therapy.
    Madhav Subramanian, Ashraf Ul Kabir, Derek Barisas, Karen Krchma, Kyunghee Choi.
      Immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment. However, only a fraction of patients respond to ICB therapy. Accurate prediction of patients to likely respond to ICB would maximize the efficacy of ICB therapy. The tumor microenvironment (TME) dictates tumor progression and therapy outcome. Here, we classify the TME by analyzing the transcriptome from 11,069 cancer patients based on angiogenesis and T cell activity. We find three distinct angio-immune TME subtypes conserved across 30 non-hematological cancers. There is a clear inverse relationship between angiogenesis and anti-tumor immunity in TME. Remarkably, patients displaying TME with low angiogenesis with strong anti-tumor immunity show the most significant responses to ICB therapy in four cancer types. Re-evaluation of the renal cell carcinoma clinical trials provides compelling evidence that the baseline angio-immune state is robustly predictive of ICB responses. This study offers a rationale for incorporating baseline angio-immune scores for future ICB treatment strategies.
    Keywords:  immune checkpoint blockade; tumor angiogenesis; tumor immunity
    DOI:  https://doi.org/10.1016/j.xcrm.2022.100896
  25. STAR Protoc. 2023 Jan 12. pii: S2666-1667(22)00888-7. [Epub ahead of print]4(1): 102008
    Fluorescence-activated cell sorting and phenotypic characterization of human fibro-adipogenic progenitors.
    Tine Borum Billeskov, Jonas Brorson Jensen, Niels Jessen, Jean Farup.
      The ability of stem cells to activate and differentiate is critical for maintaining the regenerative capacity of skeletal muscle. Here, we detail steps for specific quantification and isolation of primary human fibro-adipogenic progenitors and skeletal muscle stem cells using fluorescence-activated cell sorting. We describe important phenotypic traits such as time to enter the cell cycle and assessment of cell differentiation for the isolated cell populations. The technique has been applied on tissue obtained from surgery and needle biopsies. For complete details on the use and execution of this protocol, please refer to Farup et al. (2021).1.
    Keywords:  Cell Biology; Cell Differentiation; Microscopy; Stem Cells; Tissue Engineering
    DOI:  https://doi.org/10.1016/j.xpro.2022.102008
  26. Nat Rev Mol Cell Biol. 2023 Jan 12.
    Metabolites as signalling molecules.
    Steven Andrew Baker, Jared Rutter.
      Traditional views of cellular metabolism imply that it is passively adapted to meet the demands of the cell. It is becoming increasingly clear, however, that metabolites do more than simply supply the substrates for biological processes; they also provide critical signals, either through effects on metabolic pathways or via modulation of other regulatory proteins. Recent investigation has also uncovered novel roles for several metabolites that expand their signalling influence to processes outside metabolism, including nutrient sensing and storage, embryonic development, cell survival and differentiation, and immune activation and cytokine secretion. Together, these studies suggest that, in contrast to the prevailing notion, the biochemistry of a cell is frequently governed by its underlying metabolism rather than vice versa. This important shift in perspective places common metabolites as key regulators of cell phenotype and behaviour. Yet the signalling metabolites, and the cognate targets and transducers through which they signal, are only beginning to be uncovered. In this Review, we discuss the emerging links between metabolism and cellular behaviour. We hope this will inspire further dissection of the mechanisms through which metabolic pathways and intermediates modulate cell function and will suggest possible drug targets for diseases linked to metabolic deregulation.
    DOI:  https://doi.org/10.1038/s41580-022-00572-w
  27. Immunity. 2023 Jan 10. pii: S1074-7613(22)00645-8. [Epub ahead of print]56(1): 43-57.e10
    GATA4 controls regionalization of tissue immunity and commensal-driven immunopathology.
    Zachary M Earley, Wioletta Lisicka, Joseph J Sifakis, Raúl Aguirre-Gamboa, Anita Kowalczyk, Jacob T Barlow, Dustin G Shaw, Valentina Discepolo, Ineke L Tan, Saideep Gona, Jordan D Ernest, Polly Matzinger, Luis B Barreiro, Andrey Morgun, Albert Bendelac, Rustem F Ismagilov, Natalia Shulzhenko, Samantha J Riesenfeld, Bana Jabri.
      There is growing recognition that regionalization of bacterial colonization and immunity along the intestinal tract has an important role in health and disease. Yet, the mechanisms underlying intestinal regionalization and its dysregulation in disease are not well understood. This study found that regional epithelial expression of the transcription factor GATA4 controls bacterial colonization and inflammatory tissue immunity in the proximal small intestine by regulating retinol metabolism and luminal IgA. Furthermore, in mice without jejunal GATA4 expression, the commensal segmented filamentous bacteria promoted pathogenic inflammatory immune responses that disrupted barrier function and increased mortality upon Citrobacter rodentium infection. In celiac disease patients, low GATA4 expression was associated with metabolic alterations, mucosal Actinobacillus, and increased IL-17 immunity. Taken together, these results reveal broad impacts of GATA4-regulated intestinal regionalization on bacterial colonization and tissue immunity, highlighting an elaborate interdependence of intestinal metabolism, immunity, and microbiota in homeostasis and disease.
    Keywords:  GATA4; IgA; bacterial colonization; celiac disease; immunopathology; infection; intestinal epithelial cells; intestinal regionalization; retinoic acid; segmented filamentous bacteria
    DOI:  https://doi.org/10.1016/j.immuni.2022.12.009
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