bims-imicid 2022-09-25 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2022–09–25
33 papers selected by
Dylan Ryan, University of Cambridge

m1A tRNA modification facilitates rapid T cell proliferation.
NAMPT is a metabolic checkpoint of IFNγ-producing CD4+ T cells in lupus nephritis.
Ion channel Piezo1 activation promotes aerobic glycolysis in macrophages.
The low-density lipoprotein receptor-mTORC1 axis coordinates CD8+ T cell activation.
Tangeretin protects mice from diet-induced metabolic inflammation via activating adipose lactate accumulation and macrophage M2 polarization.
Immunometabolic alterations in lupus: where do they come from and where do we go from there?
Grossamide attenuates inflammation by balancing macrophage polarization through metabolic reprogramming of macrophages in mice.
Stress-mediated attenuation of translation undermines T-cell activity in cancer.
Covalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease.
Metabokines in the regulation of systemic energy metabolism.
Resveratrol reduces lactate production and modifies the ovarian cancer immune microenvironment.
Integrated multi-omics reveals the activated retinal microglia with intracellular metabolic reprogramming contributes to inflammation in STZ-induced early diabetic retinopathy.
Targeting lipid metabolism reprogramming of immunocytes in response to the tumor microenvironment stressor: A potential approach for tumor therapy.
High Glucose and Carbonyl Stress Impair HIF-1-Regulated Responses and the Control of Mycobacterium tuberculosis in Macrophages.
Myeloid TM6SF2 Deficiency Inhibits Atherosclerosis.
The Antiviral Effects of 2-Deoxy-D-glucose (2-DG), a Dual D-Glucose and D-Mannose Mimetic, against SARS-CoV-2 and Other Highly Pathogenic Viruses.
Lipotoxicity as a Barrier for T Cell-Based Therapies.
Protective effects of mitochondrial fission inhibition on ox-LDL induced VSMC foaming via metabolic reprogramming.
Novel Role of CETP in Macrophages: Reduction of Mitochondrial Oxidants Production and Modulation of Cell Immune-Metabolic Profile.
Targeting immunometabolism by active ingredients derived from traditional Chinese medicines for treatment of rheumatoid arthritis.
How do humans resist tuberculosis? With a metabolic protein's help.
Importance of temperature on immuno-metabolic regulation and cancer progression.
Microbial Tryptophan Metabolism Tunes Host Immunity, Metabolism, and Extraintestinal Disorders.
Droplet Microfluidic Technology for the Early and Label-Free Isolation of Highly-Glycolytic, Activated T-Cells.
Isotopic tracing of glucose metabolites in human monocytes to assess changes in inflammatory conditions.
Targeting immunometabolism mediated by the IDO1 Pathway: A new mechanism of immune resistance in endometrial cancer.
A novel gene signature unveils three distinct immune-metabolic rewiring patterns conserved across diverse tumor types and associated with outcomes.
Blockade of PGK1 and ALDOA enhances bilirubin control of Th17 cells in Crohn's disease.
Polarization and β-Glucan Reprogram Immunomodulatory Metabolism in Human Macrophages and Ex Vivo in Human Lung Cancer Tissues.
tRNA-m1A modification promotes T cell expansion via efficient MYC protein synthesis.
Metabolomics analysis identifies glutamic acid and cystine imbalances in COVID-19 patients without comorbid conditions. Implications on redox homeostasis and COVID-19 pathophysiology.
Serum metabolite differences detected by HILIC UHPLC-Q-TOF MS in systemic sclerosis.
Mitochondrial Dysfunction in Rheumatoid Arthritis.

Nat Immunol. 2022 Sep 23.

m1A tRNA modification facilitates rapid T cell proliferation.

DOI: https://doi.org/10.1038/s41590-022-01302-2
Mol Ther. 2022 Sep 21. pii: S1525-0016(22)00567-6. [Epub ahead of print]

NAMPT is a metabolic checkpoint of IFNγ-producing CD4+ T cells in lupus nephritis.

Mengyuan Li, Yimei Lai, Binfeng Chen, Chaohuan Guo, Mianjing Zhou, Siyuan Zhao, Shuyi Wang, Jin Li, Niansheng Yang, Hui Zhang.

  IFNγ produced by T cells represents the featured cytokine and is central to the pathogenesis of lupus nephritis (LN). Here, we identified nicotinamide phosphoribosyltransferase (NAMPT), the rate limiting enzyme in salvage NAD+ biosynthetic pathway, playing a key role in controlling IFNγ production by CD4+ T cells in LN. Our data revealed that CD4+ T cells from LN showed enhanced NAMPT-mediated NAD+ biosynthetic process, which was positively correlated with IFNγ production in CD4+ T cells. NAMPT promoted aerobic glycolysis and mitochondrial respiration in CD4+ T cells from patients with LN or MRL/lpr mice through the production of NAD+. By orchestrating metabolic fitness, NAMPT promoted translational efficiency of Ifng in CD4+ T cells. In vivo, knockdown of NAMPT by siRNA or pharmacological inhibition of NAMPT by FK866 suppressed IFNγ production in CD4+ T cells, leading to reduced inflammatory infiltrates and ameliorated kidney damage in lupus mice. Taken together, this study uncovers a metabolic checkpoint of IFNγ-producing CD4+ T cells in LN that therapeutic targeting NAMPT has the potential to normalize metabolic competence and blunt pathogenicity of CD4+ T cells in LN.

Keywords:  IFNγ expression; NAMPT; lupus nephritis; metabolic checkpoint; translation efficiency

DOI:  https://doi.org/10.1016/j.ymthe.2022.09.013
Front Immunol. 2022 ;13 976482

Ion channel Piezo1 activation promotes aerobic glycolysis in macrophages.

Shaoqiu Leng, Xiaoyu Zhang, Shuwen Wang, Jing Qin, Qiang Liu, Anli Liu, Zi Sheng, Qi Feng, Xiang Hu, Jun Peng.

  Altered microenvironmental stiffness is a hallmark of inflammation. It is sensed by the mechanically activated cation channel Piezo1 in macrophages to induce subsequent immune responses. However, the mechanism by which the mechanosensitive signals shape the metabolic status of macrophages and tune immune responses remains unclear. We revealed that Piezo1-deficient macrophages exhibit reduced aerobic glycolysis in resting or liposaccharide (LPS)-stimulated macrophages with impaired LPS-induced secretion of inflammatory cytokines in vitro. Additionally, pretreatment with the Piezo1 agonist, Yoda1, or cyclical hydrostatic pressure (CHP) upregulated glycolytic activity and enhanced LPS-induced secretion of inflammatory cytokines. Piezo1-deficient mice were less susceptible to dextran sulfate sodium (DSS)-induced colitis, whereas Yoda1 treatment aggravated colitis. Mechanistically, we found that Piezo1 activation promotes aerobic glycolysis through the Ca2+-induced CaMKII-HIF1α axis. Therefore, our study revealed that Piezo1-mediated mechanosensitive signals Piezo1 can enhance aerobic glycolysis and promote the LPS-induced immune response in macrophages.

Keywords:  HIF1 alpha; Piezo1; colitis; glycolysis; macrophage

DOI:  https://doi.org/10.3389/fimmu.2022.976482
J Cell Biol. 2022 Nov 07. pii: e202202011. [Epub ahead of print]221(11):

The low-density lipoprotein receptor-mTORC1 axis coordinates CD8+ T cell activation.

Fabrizia Bonacina, Annalisa Moregola, Monika Svecla, David Coe, Patrizia Uboldi, Sara Fraire, Simona Beretta, Giangiacomo Beretta, Fabio Pellegatta, Alberico Luigi Catapano, Federica M Marelli-Berg, Giuseppe Danilo Norata.

Activation of T cells relies on the availability of intracellular cholesterol for an effective response after stimulation. We investigated the contribution of cholesterol derived from extracellular uptake by the low-density lipoprotein (LDL) receptor in the immunometabolic response of T cells. By combining proteomics, gene expression profiling, and immunophenotyping, we described a unique role for cholesterol provided by the LDLR pathway in CD8+ T cell activation. mRNA and protein expression of LDLR was significantly increased in activated CD8+ compared to CD4+ WT T cells, and this resulted in a significant reduction of proliferation and cytokine production (IFNγ, Granzyme B, and Perforin) of CD8+ but not CD4+ T cells from Ldlr -/- mice after in vitro and in vivo stimulation. This effect was the consequence of altered cholesterol routing to the lysosome resulting in a lower mTORC1 activation. Similarly, CD8+ T cells from humans affected by familial hypercholesterolemia (FH) carrying a mutation on the LDLR gene showed reduced activation after an immune challenge.

DOI: https://doi.org/10.1083/jcb.202202011
Biochem Biophys Res Commun. 2022 Sep 14. pii: S0006-291X(22)01294-3. [Epub ahead of print]630 16-23

Tangeretin protects mice from diet-induced metabolic inflammation via activating adipose lactate accumulation and macrophage M2 polarization.

Yulin Sun, Lu Liu, Chen Qiu.

  Infiltration by adipose tissue macrophages (ATMs) and subsequent metabolic inflammation are the key causes of obesity-induced insulin resistance and metabolic disorders. In this study, we analyzed the potential protective effect of tangeretin, a key flavonoid found extensively in citrus peels, against diet-induced metabolic inflammation. Daily gavages of tangeretin at 20 mg/kg protected the mice from high fat diet (HFD) feeding-induced insulin resistance, ATMs activation, and M1 macrophage polarization. Interestingly, in vitro assays using bone marrow-derived macrophages (BMDMs) showed that tangeretin had only a minimal effect on macrophage polarization. Assays of central carbon metabolism (CCM) in adipose tissue showed that tangeretin treatment rerouted the carbon metabolism and caused lactate accumulation in the microenvironment. Co-culture assays further suggested that tangeretin enhanced M2 polarization of BMDMs when adipocytes were present, whereas blocking the lactate uptake in macrophages reversed the effect of tangeretin on polarization. Taken together, these findings indicated that tangeretin provided indirect protection from diet-induced ATMs activation by reprogramming glucose metabolism and promoting lactate accumulation that subsequently promoted macrophage M2 polarization and reduced inflammation.

Keywords:  Adipocyte; Lactate; Macrophage; Metabolic inflammation; Tangeretin

DOI:  https://doi.org/10.1016/j.bbrc.2022.09.044
Curr Opin Immunol. 2022 Sep 16. pii: S0952-7915(22)00092-9. [Epub ahead of print]78 102245

Immunometabolic alterations in lupus: where do they come from and where do we go from there?

Longhuan Ma, Tracoyia Roach, Laurence Morel.

Systemic lupus erythematosus (SLE) is an autoimmune disease in which the overactivation of the immune system has been associated with metabolic alterations. Targeting the altered immunometabolism has been proposed to treat SLE patients based on their results obtained and mouse models of the disease. Here, we review the recent literature to discuss the possible origins of the alterations in the metabolism of immune cells in lupus, the dominant role of mitochondrial defects, technological advances that may move the field forward, as well as how targeting lupus immunometabolism may have therapeutic potential.

DOI: https://doi.org/10.1016/j.coi.2022.102245
Int Immunopharmacol. 2022 Sep 15. pii: S1567-5769(22)00674-9. [Epub ahead of print]112 109190

Grossamide attenuates inflammation by balancing macrophage polarization through metabolic reprogramming of macrophages in mice.

Wenlong Zhao, Di Xu, Wei Hong, Lin Zhang, Qinyan Wu, Mingzhe Gao, Junsong Wang.

  Macrophages exhibited different phenotypes in response to environmental cues. To meet the needs of rapid response to stimuli, M1-activated macrophages preferred glycolysis to oxidative phosphorylation (OXPHOS) in mitochondria to quickly produce energy and obtain ample raw materials to support cell activation at the same time. Activated macrophages produced free radicals and cytokines to eradicate pathogens but also induced oxidative damage and enhanced inflammation. Grossamide (GSE), a lignanamide from Polygonum multiflorum Thunb., exhibited notable anti-inflammatory effects. In this study, the potential of GSE on macrophage polarization was explored. GSE significantly down-regulated the levels of M1 macrophage biomarkers (Cd32a, Cd80 and Cd86) while increased the levels of M2 indicators (Cd163, Mrc1 and Socs1), showing its potential to inhibit LPS-induced M1 polarization of macrophages. This ability has close a link to its effect on metabolic reprogramming of macrophage. GSE shunted nitric oxide (NO) production from arginine by up-regulation of arginase and down-regulation of inducible nitric oxide synthase, thus attenuated the inhibition of NO on OXPHOS. LPS created three breakpoints in the tricarboxylic acid cycle (TCA) cycle of macrophage as evidenced by down-regulated isocitrate dehydrogenase, accumulation of succinate and the inhibited SDH activity, significantly decreased level of oxoglutarate dehydrogenase expression and its substrate α-ketoglutarate. Thus GSE reduced oxidative stress and amended fragmented TCA cycle. As a result, GSE maintained redox (NAD+/NADH) and energy (ATP/ADP) state, reduced extracellular acidification rate and enhanced the oxygen consumption rate. In addition, GSE decreased the release of inflammatory cytokines by inhibiting the activation of the LPS/TLR4/NF-κB pathway. These findings highlighted the central role of immunometabolism of macrophages in its functional plasticity, which invited future study of mode of action of anti-inflammatory drugs from viewpoint of metabolic reprogramming.

Keywords:  Anti-inflammation; Grossamide; Macrophage polarization; Metabolic reprogramming; TCA cycle

DOI:  https://doi.org/10.1016/j.intimp.2022.109190
Cancer Res. 2022 Sep 20. pii: CAN-22-1744. [Epub ahead of print]

Stress-mediated attenuation of translation undermines T-cell activity in cancer.

Brian P Riesenberg, Elizabeth G Hunt, Megan D Tennant, Katie E Hurst, Alex M Andrews, Lee R Leddy, David M Neskey, Elizabeth G Hill, Guillermo O Rangel Rivera, Chrystal M Paulos, Peng Gao, Jessica E Thaxton.

Protein synthesis supports robust immune responses. Nutrient competition and global cell stressors in the tumor microenvironment (TME) may impact protein translation in T cells and antitumor immunity. Using human and mouse tumors, we demonstrated here that protein translation in T cells is repressed in solid tumors. Reduced glucose availability to T cells in the TME led to activation of the unfolded protein response (UPR) element eIF2a. Genetic mouse models revealed that translation attenuation mediated by activated p-eIF2a undermines the ability of T cells to suppress tumor growth. Reprogramming T cell metabolism was able to alleviate p-eIF2a accumulation and translational attenuation in the TME, allowing for sustained protein translation. Metabolic and pharmacological approaches showed that proteasome activity mitigates induction of p-eIF2a to support optimal antitumor T cell function, protecting from translation attenuation and enabling prolonged cytokine synthesis in solid tumors. Together, these data identify a new therapeutic avenue to fuel the efficacy of tumor immunotherapy.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-1744
Int J Biol Sci. 2022 ;18(14): 5260-5275

Covalent Inhibition of Pyruvate Kinase M2 Reprograms Metabolic and Inflammatory Pathways in Hepatic Macrophages against Non-alcoholic Fatty Liver Disease.

Ni Fan, Xiuying Zhang, Wei Zhao, Jia Zhao, Dan Luo, Yilu Sun, Ding Li, Chenliang Zhao, Yu Wang, Hongjie Zhang, Jianhui Rong.

  Warburg effect of aerobic glycolysis in hepatic M1 macrophages is a major cause for metabolic dysfunction and inflammatory stress in non-alcoholic fatty liver disease (NAFLD). Plant-derived triterpene celastrol markedly inhibited macrophage M1 polarization and adipocyte hypertrophy in obesity. The present study was designed to identify the celastrol-bound proteins which reprogrammed metabolic and inflammatory pathways in M1 macrophages. Pyruvate kinase M2 (PKM2) was determined to be a major celastrol-bound protein. Peptide mapping revealed that celastrol bound to the residue Cys31 while covalent conjugation altered the spatial conformation and inhibited the enzyme activity of PKM2. Mechanistic studies showed that celastrol reduced the expression of glycolytic enzymes (e.g., GLUT1, HK2, LDHA, PKM2) and related signaling proteins (e.g., Akt, HIF-1α, mTOR), shifted aerobic glycolysis to mitochondrial oxidative phosphorylation and skewed macrophage polarization from inflammatory M1 type to anti-inflammatory M2 type. Animal experiments indicated that celastrol promoted weight loss, reduced serum cholesterol level, lipid accumulation and hepatic fibrosis in the mouse model of NAFLD. Collectively, the present study demonstrated that celastrol might alleviate lipid accumulation, inflammation and fibrosis in the liver via covalent modification of PKM2.

Keywords:  celastrol; covalent modification; macrophage polarization; non-alcoholic fatty liver disease; pyruvate kinase M2

DOI:  https://doi.org/10.7150/ijbs.73890
Curr Opin Pharmacol. 2022 Sep 19. pii: S1471-4892(22)00113-8. [Epub ahead of print]67 102286

Metabokines in the regulation of systemic energy metabolism.

Amanda Dv MacCannell, Lee D Roberts.

Metabolism consists of life-sustaining chemical reactions involving metabolites. Historically, metabolites were defined as the intermediates or end products of metabolism and considered to be passive participants changed by metabolic processes. However, recent research has redefined how we view metabolism. There is emerging evidence of metabolites which function to mediate cellular signalling and interorgan crosstalk, regulating local metabolism and systemic physiology. These bioactive metabolite signals have been termed metabokines. Metabokines regulate diverse energy metabolism pathways across multiple tissues, including fatty acid β-oxidation, mitochondrial oxidative phosphorylation, lipolysis, glycolysis and gluconeogenesis. There is increasing impetus to uncover novel metabokine signalling axes to better understand how these may be perturbed in metabolic diseases and determine their utility as therapeutic targets.

DOI: https://doi.org/10.1016/j.coph.2022.102286
Neoplasma. 2022 Sep 22. pii: 220414N410. [Epub ahead of print]

Resveratrol reduces lactate production and modifies the ovarian cancer immune microenvironment.

Jing Chen, Shu-Ting Huang, Jian-Guo Chen, Jian-Hui He, Wu-Mei Lin, Zhi-Hong Huang, Hai-Yan Ye, Shan-Yang He.

Tumor cells show deregulated metabolism leading to an enrichment of lactate in the tumor microenvironment (TME). This lactate-rich environment has been reported to impair effector T cells. However, T-regulatory cells (Tregs) show metabolic advantages in lactate-rich TME that maintain a strong suppression of effector T cells, which leads to tumor immune evasion. Therefore, the glycolytic process of tumors could represent a therapeutic target, and agents that modify the energy metabolism of tumor cells have therapeutic potential. Resveratrol is a naturally occurring polyphenol that has been confirmed to suppress tumor cells' glycolytic metabolism. In this study, we show that resveratrol induces metabolic reprogramming in ovarian cancer cells. Resveratrol increases oxidative and decreases glycolysis, in association with decreased lactate production both in vitro and in vivo. Lactate reduction in TME weakens the suppressive function of Tregs, and subsequently restores anti-tumor immunity. Significantly, combined resveratrol and PD-1 blockade promote anti-tumor efficacy. These data suggest that resveratrol's anti-tumor actions in ovarian cancer could be explained, in part, through modification of the anti-tumor immunity, and indicate a novel treatment strategy for improving immune checkpoint blockade therapy using resveratrol.

DOI: https://doi.org/10.4149/neo_2022_220414N410
Front Immunol. 2022 ;13 942768

Integrated multi-omics reveals the activated retinal microglia with intracellular metabolic reprogramming contributes to inflammation in STZ-induced early diabetic retinopathy.

Kangjia Lv, Hui Ying, Guangyi Hu, Jing Hu, Qizhi Jian, Fang Zhang.

  Diabetic retinopathy (DR) is the leading cause of visual impairment and blindness among working-age people. Inflammation is recognized as a critical driver of the DR process. However, the main retina-specific cell type producing pro-inflammatory cytokines and its mechanism underlying DR are still unclear. Here, we used single-cell sequencing to identify microglia with metabolic pathway alterations that were the main source of IL-1β in STZ-induced DR mice. To profile the full extent of local metabolic shifts in activated microglia and to reveal the metabolic microenvironment contributing to immune mechanisms, we performed integrated metabolomics, lipidomics, and RNA profiling analyses in microglia cell line samples representative of the DR microenvironment. The results showed that activated microglia with IL-1β increase exhibited a metabolic bias favoring glycolysis, purine metabolism, and triacylglycerol synthesis, but less Tricarboxylic acid (TCA). In addition, some of these especially glycolysis was necessary to facilitate their pro-inflammation. These findings suggest that activated microglia with intracellular metabolic reprogramming in retina may contribute to pro-inflammation in the early DR.

Keywords:  Diabetic retinopathy; inflammation; metabolic reprogramming; microglia; multi-omics

DOI:  https://doi.org/10.3389/fimmu.2022.942768
Front Immunol. 2022 ;13 937406

Targeting lipid metabolism reprogramming of immunocytes in response to the tumor microenvironment stressor: A potential approach for tumor therapy.

Ming Zhang, Tingju Wei, Xiaodan Zhang, Danfeng Guo.

  The tumor microenvironment (TME) has become a major research focus in recent years. The TME differs from the normal extracellular environment in parameters such as nutrient supply, pH value, oxygen content, and metabolite abundance. Such changes may promote the initiation, growth, invasion, and metastasis of tumor cells, in addition to causing the malfunction of tumor-infiltrating immunocytes. As the neoplasm develops and nutrients become scarce, tumor cells transform their metabolic patterns by reprogramming glucose, lipid, and amino acid metabolism in response to various environmental stressors. Research on carcinoma metabolism reprogramming suggests that like tumor cells, immunocytes also switch their metabolic pathways, named "immunometabolism", a phenomenon that has drawn increasing attention in the academic community. In this review, we focus on the recent progress in the study of lipid metabolism reprogramming in immunocytes within the TME and highlight the potential target molecules, pathways, and genes implicated. In addition, we discuss hypoxia, one of the vital altered components of the TME that partially contribute to the initiation of abnormal lipid metabolism in immune cells. Finally, we present the current immunotherapies that orchestrate a potent antitumor immune response by mediating the lipid metabolism of immunocytes, highlight the lipid metabolism reprogramming capacity of various immunocytes in the TME, and propose promising new strategies for use in cancer therapy.

Keywords:  immunocyte; immunometabolism; immunotherapy; lipid metabolism reprogramming; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2022.937406
mBio. 2022 Sep 19. e0108622

High Glucose and Carbonyl Stress Impair HIF-1-Regulated Responses and the Control of Mycobacterium tuberculosis in Macrophages.

Graciela Terán, Hanxiong Li, Sergiu-Bogdan Catrina, Ruining Liu, Susanna Brighenti, Xiaowei Zheng, Jakob Grünler, Susanne Nylén, Berit Carow, Martin E Rottenberg.

  Diabetes mellitus (DM) increases the risk of developing tuberculosis (TB), but the mechanisms behind diabetes-TB comorbidity are still undefined. Here, we studied the role of hypoxia-inducible factor-1 (HIF-1), a main regulator of metabolic and inflammatory responses, in the outcome of Mycobacterium tuberculosis infection of bone marrow-derived macrophages (BMM). We observed that M. tuberculosis infection of BMM increased the expression of HIF-1α and HIF-1-regulated genes. Treatment with the hypoxia mimetic deferoxamine (DFO) further increased levels of HIF-1-regulated immune and metabolic molecules and diminished the intracellular bacterial load in BMM and in the lungs of infected mice. The expression of HIF-1-regulated immunometabolic genes was reduced, and the intracellular M. tuberculosis levels were increased in BMM incubated with high-glucose levels or with methylglyoxal (MGO), a reactive carbonyl compound elevated in DM. In line with the in vitro findings, high M. tuberculosis levels and low HIF-1-regulated transcript levels were found in the lungs from hyperglycemic Leprdb/db compared with wild-type mice. The increased intracellular M. tuberculosis growth and the reduced expression of HIF-1-regulated metabolic and inflammatory genes in BMM incubated with MGO or high glucose were reverted by additional treatment with DFO. Hif1a-deficient BMM showed ablated responses of immunometabolic transcripts after mycobacterial infection at normal or high-glucose levels. We propose that HIF-1 may be targeted for the control of M. tuberculosis during DM. IMPORTANCE People living with diabetes who are also infected with M. tuberculosis are more likely to develop tuberculosis disease (TB). Why diabetic patients have an increased risk for developing TB is not well understood. Macrophages, the cell niche for M. tuberculosis, can express microbicidal mechanisms or be permissive to mycobacterial persistence and growth. Here, we showed that high glucose and carbonyl stress, which mediate diabetes pathogenesis, impair the control of intracellular M. tuberculosis in macrophages. Infection with M. tuberculosis stimulated the expression of genes regulated by the transcription factor HIF-1, a major controller of the responses to hypoxia, resulting in macrophage activation. High glucose and carbonyl compounds inhibited HIF-1 responses by macrophages. Mycobacterial control in the presence of glucose or carbonyl stress was restored by DFO, a compound that stabilizes HIF-1. We propose that HIF-1 can be targeted to reduce the risk of developing TB in people with diabetes.

Keywords:  HIF-1; Mycobacterium tuberculosis; diabetes; macrophage

DOI:  https://doi.org/10.1128/mbio.01086-22
Cells. 2022 Sep 15. pii: 2877. [Epub ahead of print]11(18):

Myeloid TM6SF2 Deficiency Inhibits Atherosclerosis.

Wenzhen Zhu, Wenying Liang, Haocheng Lu, Lin Chang, Jifeng Zhang, Y Eugene Chen, Yanhong Guo.

  Genetic variants in transmembrane 6 superfamily member 2 (TM6SF2), such as E167K, are associated with atherosclerotic cardiovascular disease (ASCVD). Chronic inflammation and lipid-laden macrophage foam cell formation are the central pathogeneses in the development of atherosclerosis. This study was undertaken to illustrate the biological function of TM6SF2 in macrophages and its role during atherosclerosis development. We generated myeloid cell-specific Tm6sf2 knockout mice on ApoE-deficient background (LysM Cre+/Tm6sf2fl/fl/ApoE-/-, TM6 mKO) with littermate LysM Cre-/Tm6sf2fl/fl/ApoE-/- (Control) mice as controls. Mice were fed a Western diet for 12 weeks to induce atherosclerosis. Myeloid Tm6sf2 deficiency inhibited atherosclerosis and decreased foam cells in the plaques without changing the plasma lipid profile. RNA sequencing of bone marrow-derived macrophages (BMDMs) from TM6 mKO mice demonstrated the downregulation of genes associated with inflammation, cholesterol uptake, and endoplasmic reticulum (ER) stress. TM6SF2 was upregulated by oxidized low-density lipoprotein (oxLDL) in macrophages. Silencing TM6SF2 in THP-1-derived macrophages and Tm6sf2 deficiency in BMDMs reduced inflammatory responses and ER stress and attenuated cholesterol uptake and foam cell formation, while the overexpression of TM6SF2 showed opposite effects. In conclusion, myeloid TM6SF2 deficiency inhibits atherosclerosis development and is a potential therapeutic target for the treatment of atherogenesis.

Keywords:  ER stress; TM6SF2; atherosclerosis; cholesterol; inflammation; macrophage

DOI:  https://doi.org/10.3390/cells11182877
Molecules. 2022 Sep 12. pii: 5928. [Epub ahead of print]27(18):

The Antiviral Effects of 2-Deoxy-D-glucose (2-DG), a Dual D-Glucose and D-Mannose Mimetic, against SARS-CoV-2 and Other Highly Pathogenic Viruses.

Beata Pająk, Rafał Zieliński, John Tyler Manning, Stanislava Matejin, Slobodan Paessler, Izabela Fokt, Mark R Emmett, Waldemar Priebe.

  Viral infection almost invariably causes metabolic changes in the infected cell and several types of host cells that respond to the infection. Among metabolic changes, the most prominent is the upregulated glycolysis process as the main pathway of glucose utilization. Glycolysis activation is a common mechanism of cell adaptation to several viral infections, including noroviruses, rhinoviruses, influenza virus, Zika virus, cytomegalovirus, coronaviruses and others. Such metabolic changes provide potential targets for therapeutic approaches that could reduce the impact of infection. Glycolysis inhibitors, especially 2-deoxy-D-glucose (2-DG), have been intensively studied as antiviral agents. However, 2-DG's poor pharmacokinetic properties limit its wide clinical application. Herein, we discuss the potential of 2-DG and its novel analogs as potent promising antiviral drugs with special emphasis on targeted intracellular processes.

Keywords:  2-deoxy-D-glucose; SARS-CoV-2; glycolysis; glycosylation; metabolic shift; novel analogs; viral infections

DOI:  https://doi.org/10.3390/molecules27185928
Biomolecules. 2022 Aug 25. pii: 1182. [Epub ahead of print]12(9):

Lipotoxicity as a Barrier for T Cell-Based Therapies.

Romy Böttcher-Loschinski, Judit Rial Saborido, Martin Böttcher, Sascha Kahlfuss, Dimitrios Mougiakakos.

  Nowadays, T-cell-based approaches play an increasing role in cancer treatment. In particular, the use of (genetically engineered) T-cells has heralded a novel era for various diseases with previously poor outcomes. Concurrently, the relationship between the functional behavior of immune cells and their metabolic state, known as immunometabolism, has been found to be an important determinant for the success of immunotherapy. In this context, immune cell metabolism is not only controlled by the expression of transcription factors, enzymes and transport proteins but also by nutrient availability and the presence of intermediate metabolites. The lack of as well as an oversupply of nutrients can be detrimental and lead to cellular dysfunction and damage, potentially resulting in reduced metabolic fitness and/or cell death. This review focusses on the detrimental effects of excessive exposure of T cells to fatty acids, known as lipotoxicity, in the context of an altered lipid tumor microenvironment. Furthermore, implications of T cell-related lipotoxicity for immunotherapy will be discussed, as well as potential therapeutic approaches.

Keywords:  T cell; cell-based therapy; immunometabolism; immunotherapy; lipotoxicity; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/biom12091182
Front Pharmacol. 2022 ;13 970151

Protective effects of mitochondrial fission inhibition on ox-LDL induced VSMC foaming via metabolic reprogramming.

Yijin Fang, Yu Zhu, Yue Wu, Liangming Liu, Huadong Wang.

  Atherosclerosis (AS) is one of the most common diseases in middle-age and elderly population. Lipid metabolism disorder induced foaming of vascular smooth muscle cell (VSMC) is an important pathological process of AS. Mitochondria plays an important role in lipids metabolism. While it is not known whether regulating mitochondrial function can protect ox-LDL induced VSMC foaming via metabolic reprogramming. With ox-LDL induced mouse model of VSMC injury, the injury effect of ox-LDL and the protective effect of mdivi-1, the mitochondrial fission inhibitor on mitochondrial morphology and function of VSMC, and the formation of lipid droplet were observed. With metabonomics and proteomics techniques, the main lipid metabolites and regulation proteins were identified. The results showed that Ox-LDL induced a significant mitochondrial fission and fragmentation of VSMC, and mitochondrial function disorder along with lipid deposition and foaming. Mdivi-1 significantly antagonized the damage effect of ox-LDL on mitochondrial morphology and function of VSMC, and blocked the lipid deposition. Metabonomics analysis found 848 different metabolites between ox-LDL and mdivi-1 treatment group, in which the lipid metabolites were the main, and heptadecanoic acid, palmitoleic acid and myristic acid were the critical metabolites changed most. Proteomics results showed that there were 125 differential expressed proteins between ox-LDL and mdivi-1 treatment, acetyl -CoA carboxylase1 and fatty acid synthase were the main differential expressed proteins. This study suggest that Mitochondrial fission plays an important role in VSMC lipid deposition and foaming. Inhibition of mitochondrial fission may effectively fight against ox-LDL induced lipid deposition and foaming of VSMC via improving mitochondrial function and metabolic reprogramming. This finding provides a new insight for prevention and treatment of AS.

Keywords:  atherosclerosis; foaming; lipid deposition; metabolic reprogramming; mitochondrial fission

DOI:  https://doi.org/10.3389/fphar.2022.970151
Antioxidants (Basel). 2022 Aug 31. pii: 1734. [Epub ahead of print]11(9):

Novel Role of CETP in Macrophages: Reduction of Mitochondrial Oxidants Production and Modulation of Cell Immune-Metabolic Profile.

Gabriel G Dorighello, Leandro H P Assis, Thiago Rentz, Joseane Morari, Monique F M Santana, Marisa Passarelli, Neale D Ridgway, Anibal E Vercesi, Helena C F Oliveira.

  Plasma cholesteryl ester transfer protein (CETP) activity diminishes HDL-cholesterol levels and thus may increase atherosclerosis risk. Experimental evidence suggests CETP may also exhibit anti-inflammatory properties, but local tissue-specific functions of CETP have not yet been clarified. Since oxidative stress and inflammation are major features of atherogenesis, we investigated whether CETP modulates macrophage oxidant production, inflammatory and metabolic profiles. Comparing macrophages from CETP-expressing transgenic mice and non-expressing littermates, we observed that CETP expression reduced mitochondrial superoxide anion production and H2O2 release, increased maximal mitochondrial respiration rates, and induced elongation of the mitochondrial network and expression of fusion-related genes (mitofusin-2 and OPA1). The expression of pro-inflammatory genes and phagocytic activity were diminished in CETP-expressing macrophages. In addition, CETP-expressing macrophages had less unesterified cholesterol under basal conditions and after exposure to oxidized LDL, as well as increased HDL-mediated cholesterol efflux. CETP knockdown in human THP1 cells increased unesterified cholesterol and abolished the effects on mitofusin-2 and TNFα. In summary, the expression of CETP in macrophages modulates mitochondrial structure and function to promote an intracellular antioxidant state and oxidative metabolism, attenuation of pro-inflammatory gene expression, reduced cholesterol accumulation, and phagocytosis. These localized functions of CETP may be relevant for the prevention of atherosclerosis and other inflammatory diseases.

Keywords:  CETP; cholesterol; inflammation; macrophage; mitochondria; oxidants

DOI:  https://doi.org/10.3390/antiox11091734
Chin Herb Med. 2021 Oct;13(4): 451-460

Targeting immunometabolism by active ingredients derived from traditional Chinese medicines for treatment of rheumatoid arthritis.

Yu-Fei He, Chu-Tian Mai, Hu-Dan Pan, Liang Liu, Hua Zhou, Ying Xie.

  Rheumatoid arthritis (RA), the most common inflammatory arthropathy word wild, is a systemic autoimmune disease that mainly affects the synovium of joints with a high disability rate. Metabolic mis-regulation has emerged as a fundamental pathogenesis of RA linked to immune cell dysfunction, while targeting immunometabolism provides a new and effective approach to regulate the immune responses and thus alleviate the symptom of RA. Recently, natural active compounds from traditional Chinese medicines (TCMs) have potential therapeutic effects on RA and regulating immunometabolism. In this review, in addition to updating the connection between cellular metabolism and cell function in immune cells of RA, we summarized that the anti-inflammatory mechanisms of the potential natural compounds from TCM by targeting metabolic reprogramming of immune cells, and discusses them as a rich resource for providing the new potential paradigm for the treatment of RA.

Keywords:  immune cells; immunometabolism; natural compounds; rheumatoid arthritis; traditional Chinese medicines

DOI:  https://doi.org/10.1016/j.chmed.2021.09.005
Nature. 2022 Sep 23.

How do humans resist tuberculosis? With a metabolic protein's help.



Keywords:  Infection

DOI:  https://doi.org/10.1038/d41586-022-02987-z
FEBS J. 2022 Sep 24.

Importance of temperature on immuno-metabolic regulation and cancer progression.

Haiping Wang, Melis Ülgen, Mirko Trajkovski.

  Cancer immunotherapies emerge as promising strategies for restricting tumor growth. The tumor microenvironment (TME) has a major impact on the anti-tumor immune response and on the efficacy of the immunotherapies. Environmental factors play critical roles in affecting overall energy metabolism and can also impact the TME. Recent studies have linked changes in the ambient temperature with particular immunometabolic reprogramming and anti-cancer immune response in laboratory animals. Here, we describe the energetic balance of the organism during change in temperature, and link this to the immune alterations that could be of relevance for cancer, as well as for other human diseases. We highlight the contribution of the gut microbiota in modifying this interaction. We describe the overall metabolic response and underlying mechanisms of tumorigenesis in mouse models at varying ambient temperatures and shed light on their potential importance in developing therapeutics against cancer.

Keywords:  Temperature; cancer immunometabolism; energy balance; fat metabolism; gut microbiota

DOI:  https://doi.org/10.1111/febs.16632
Metabolites. 2022 Sep 03. pii: 834. [Epub ahead of print]12(9):

Microbial Tryptophan Metabolism Tunes Host Immunity, Metabolism, and Extraintestinal Disorders.

Moyan Liu, Max Nieuwdorp, Willem M de Vos, Elena Rampanelli.

  The trillions of commensal microorganisms comprising the gut microbiota have received growing attention owing to their impact on host physiology. Recent advances in our understandings of the host-microbiota crosstalk support a pivotal role of microbiota-derived metabolites in various physiological processes, as they serve as messengers in the complex dialogue between commensals and host immune and endocrine cells. In this review, we highlight the importance of tryptophan-derived metabolites in host physiology, and summarize the recent findings on the role of tryptophan catabolites in preserving intestinal homeostasis and fine-tuning immune and metabolic responses. Furthermore, we discuss the latest evidence on the effects of microbial tryptophan catabolites, describe their mechanisms of action, and discuss how perturbations of microbial tryptophan metabolism may affect the course of intestinal and extraintestinal disorders, including inflammatory bowel diseases, metabolic disorders, chronic kidney diseases, and cardiovascular diseases.

Keywords:  cardiovascular diseases (CVD); chronic kidney diseases (CKD); inflammation; metabolic syndrome; microbiota; tryptophan

DOI:  https://doi.org/10.3390/metabo12090834
Micromachines (Basel). 2022 Sep 01. pii: 1442. [Epub ahead of print]13(9):

Droplet Microfluidic Technology for the Early and Label-Free Isolation of Highly-Glycolytic, Activated T-Cells.

Claudia Zielke, Adriana J Gutierrez Ramirez, Kelsey Voss, Maya S Ryan, Azam Gholizadeh, Jeffrey C Rathmell, Paul Abbyad.

  A label-free, fixation-free and passive sorting method is presented to isolate activated T-cells shortly after activation and prior to the display of activation surface markers. It uses a recently developed sorting platform dubbed "Sorting by Interfacial Tension" (SIFT) that sorts droplets based on pH. After polyclonal (anti-CD3/CD28 bead) activation and a brief incubation on chip, droplets containing activated T-cells display a lower pH than those containing naive cells due to increased glycolysis. Under specific surfactant conditions, a change in pH can lead to a concurrent increase in droplet interfacial tension. The isolation of activated T-cells on chip is hence achieved as flattened droplets are displaced as they encounter a micro-fabricated trench oriented diagonally with respect to the direction of flow. This technique leads to an enrichment of activated primary CD4+ T-cells to over 95% from an initial mixed population of naive cells and cells activated for as little as 15 min. Moreover, since the pH change is correlated to successful activation, the technique allows the isolation of T-cells with the earliest activation and highest glycolysis, an important feature for the testing of T-cell activation modulators and to determine regulators and predictors of differentiation outcomes.

Keywords:  T-cells; cytometry; droplet microfluidics; glycolysis; metabolism; microfluidics; passive sorting; sorting

DOI:  https://doi.org/10.3390/mi13091442
STAR Protoc. 2022 Sep 22. pii: S2666-1667(22)00595-0. [Epub ahead of print]3(4): 101715

Isotopic tracing of glucose metabolites in human monocytes to assess changes in inflammatory conditions.

Ginevra Giacomello, Chotima Böttcher, Maria Kristina Parr.

  Differences in metabolic profiles can link to functional changes of immune cells in disease conditions. Here, we detail a protocol for the detection and quantitation of 19 metabolites in one analytical run. We provide the parameters for chromatographic separation and mass spectrometric analysis of isotopically labeled and unlabeled metabolites. We include steps for incubation and sample preparation of PBMCs and monocytes. This protocol overcomes the chromatographic challenges caused by the chelating properties of some metabolites.

Keywords:  Chemistry; Immunology; Mass spectrometry; Metabolism; Metabolomics

DOI:  https://doi.org/10.1016/j.xpro.2022.101715
Front Immunol. 2022 ;13 953115

Targeting immunometabolism mediated by the IDO1 Pathway: A new mechanism of immune resistance in endometrial cancer.

Anna Passarelli, Carmela Pisano, Sabrina Chiara Cecere, Marilena Di Napoli, Sabrina Rossetti, Rosa Tambaro, Jole Ventriglia, Federica Gherardi, Eva Iannacone, Sergio Setola Venanzio, Francesco Fiore, Michele Bartoletti, Giosuè Scognamiglio, Daniela Califano, Sandro Pignata.

  Immunotherapy is acquiring a primary role in treating endometrial cancer (EC) with a relevant benefit for many patients. Regardless, patients progressing during immunotherapy or those who are resistant represent an unmet need. The mechanisms of immune resistance and escape need to be better investigated. Here, we review the major mechanisms of immune escape activated by the indolamine 2,3-dioxygenase 1 (IDO1) pathway in EC and focus on potential therapeutic strategies based on IDO1 signaling pathway control. IDO1 catalyzes the first rate-limiting step of the so-called "kynurenine (Kyn) pathway", which converts the essential amino acid l-tryptophan into the immunosuppressive metabolite l-kynurenine. Functionally, IDO1 has played a pivotal role in cancer immune escape by catalyzing the initial step of the Kyn pathway. The overexpression of IDO1 is also associated with poor prognosis in EC. These findings can lead to advantages in immunotherapy-based approaches as a rationale for overcoming the immune escape. Indeed, besides immune checkpoints, other mechanisms, including the IDO enzymes, contribute to the EC progression due to the immunosuppression induced by the tumor milieu. On the other hand, the IDO1 enzyme has recently emerged as both a promising therapeutic target and an unfavorable prognostic biomarker. This evidence provides the basis for translational strategies of immune combination, whereas IDO1 expression would serve as a potential prognostic biomarker in metastatic EC.

Keywords:  3-dioxygenase (IDO); endometrial cancer; immune metabolism; immune suppression; immunotherapy; indolamine 2; kynurenine; tryptophan

DOI:  https://doi.org/10.3389/fimmu.2022.953115
Front Immunol. 2022 ;13 926304

A novel gene signature unveils three distinct immune-metabolic rewiring patterns conserved across diverse tumor types and associated with outcomes.

Leire Pedrosa, Carles Foguet, Helena Oliveres, Iván Archilla, Marta García de Herreros, Adela Rodríguez, Antonio Postigo, Daniel Benítez-Ribas, Jordi Camps, Miriam Cuatrecasas, Antoni Castells, Aleix Prat, Timothy M Thomson, Joan Maurel, Marta Cascante.

  Existing immune signatures and tumor mutational burden have only modest predictive capacity for the efficacy of immune check point inhibitors. In this study, we developed an immune-metabolic signature suitable for personalized ICI therapies. A classifier using an immune-metabolic signature (IMMETCOLS) was developed on a training set of 77 metastatic colorectal cancer (mCRC) samples and validated on 4,200 tumors from the TCGA database belonging to 11 types. Here, we reveal that the IMMETCOLS signature classifies tumors into three distinct immune-metabolic clusters. Cluster 1 displays markers of enhanced glycolisis, hexosamine byosinthesis and epithelial-to-mesenchymal transition. On multivariate analysis, cluster 1 tumors were enriched in pro-immune signature but not in immunophenoscore and were associated with the poorest median survival. Its predicted tumor metabolic features suggest an acidic-lactate-rich tumor microenvironment (TME) geared to an immunosuppressive setting, enriched in fibroblasts. Cluster 2 displays features of gluconeogenesis ability, which is needed for glucose-independent survival and preferential use of alternative carbon sources, including glutamine and lipid uptake/β-oxidation. Its metabolic features suggest a hypoxic and hypoglycemic TME, associated with poor tumor-associated antigen presentation. Finally, cluster 3 is highly glycolytic but also has a solid mitochondrial function, with concomitant upregulation of glutamine and essential amino acid transporters and the pentose phosphate pathway leading to glucose exhaustion in the TME and immunosuppression. Together, these findings suggest that the IMMETCOLS signature provides a classifier of tumors from diverse origins, yielding three clusters with distinct immune-metabolic profiles, representing a new predictive tool for patient selection for specific immune-metabolic therapeutic approaches.

Keywords:  biomarker; immune checkpoint-based therapy; immunotherapy; metabolism; precision medicine

DOI:  https://doi.org/10.3389/fimmu.2022.926304
Commun Biol. 2022 Sep 21. 5(1): 994

Blockade of PGK1 and ALDOA enhances bilirubin control of Th17 cells in Crohn's disease.

Marta Vuerich, Na Wang, Jonathon J Graham, Li Gao, Wei Zhang, Ahmadreza Kalbasi, Lina Zhang, Eva Csizmadia, Jason Hristopoulos, Yun Ma, Efi Kokkotou, Adam S Cheifetz, Simon C Robson, Maria Serena Longhi.

Unconjugated bilirubin (UCB) confers Th17-cells immunosuppressive features by activating aryl-hydrocarbon-receptor, a modulator of toxin and adaptive immune responses. In Crohn's disease, Th17-cells fail to acquire regulatory properties in response to UCB, remaining at an inflammatory/pathogenic state. Here we show that UCB modulates Th17-cell metabolism by limiting glycolysis and through downregulation of glycolysis-related genes, namely phosphoglycerate-kinase-1 (PGK1) and aldolase-A (ALDOA). Th17-cells of Crohn's disease patients display heightened PGK1 and ALDOA and defective response to UCB. Silencing of PGK1 or ALDOA restores Th17-cell response to UCB, as reflected by increase in immunoregulatory markers like FOXP3, IL-10 and CD39. In vivo, PGK1 and ALDOA silencing enhances UCB salutary effects in trinitro-benzene-sulfonic-acid-induced colitis in NOD/scid/gamma humanized mice where control over disease activity and enhanced immunoregulatory phenotypes are achieved. PGK1 and/or ALDOA blockade might have therapeutic effects in Crohn's disease by favoring acquisition of regulatory properties by Th17-cells along with control over their pathogenic potential.

DOI: https://doi.org/10.1038/s42003-022-03913-9
J Immunol. 2022 Sep 23. pii: ji2200178. [Epub ahead of print]

Polarization and β-Glucan Reprogram Immunomodulatory Metabolism in Human Macrophages and Ex Vivo in Human Lung Cancer Tissues.

Teresa W-M Fan, Saeed Daneshmandi, Teresa A Cassel, Mohammad B Uddin, James Sledziona, Patrick T Thompson, Penghui Lin, Richard M Higashi, Andrew N Lane.

Immunomodulatory (IM) metabolic reprogramming in macrophages (Mϕs) is fundamental to immune function. However, limited information is available for human Mϕs, particularly in response plasticity, which is critical to understanding the variable efficacy of immunotherapies in cancer patients. We carried out an in-depth analysis by combining multiplex stable isotope-resolved metabolomics with reversed phase protein array to map the dynamic changes of the IM metabolic network and key protein regulators in four human donors' Mϕs in response to differential polarization and M1 repolarizer β-glucan (whole glucan particles [WGPs]). These responses were compared with those of WGP-treated ex vivo organotypic tissue cultures (OTCs) of human non-small cell lung cancer. We found consistently enhanced tryptophan catabolism with blocked NAD+ and UTP synthesis in M1-type Mϕs (M1-Mϕs), which was associated with immune activation evidenced by increased release of IL-1β/CXCL10/IFN-γ/TNF-α and reduced phagocytosis. In M2a-Mϕs, WGP treatment of M2a-Mϕs robustly increased glucose utilization via the glycolysis/oxidative branch of the pentose phosphate pathway while enhancing UDP-N-acetyl-glucosamine turnover and glutamine-fueled gluconeogenesis, which was accompanied by the release of proinflammatory IL-1β/TNF-α to above M1-Mϕ's levels, anti-inflammatory IL-10 to above M2a-Mϕ's levels, and attenuated phagocytosis. These IM metabolic responses could underlie the opposing effects of WGP, i.e., reverting M2- to M1-type immune functions but also boosting anti-inflammation. Variable reprogrammed Krebs cycle and glutamine-fueled synthesis of UTP in WGP-treated OTCs of human non-small cell lung cancer were observed, reflecting variable M1 repolarization of tumor-associated Mϕs. This was supported by correlation with IL-1β/TNF-α release and compromised tumor status, making patient-derived OTCs unique models for studying variable immunotherapeutic efficacy in cancer patients.

DOI: https://doi.org/10.4049/jimmunol.2200178
Nat Immunol. 2022 Sep 22.

tRNA-m1A modification promotes T cell expansion via efficient MYC protein synthesis.

Yongbo Liu, Jing Zhou, Xiaoyu Li, Xiaoting Zhang, Jintong Shi, Xuefei Wang, Hao Li, Shan Miao, Huifang Chen, Xiaoxiao He, Liting Dong, Gap Ryol Lee, Junke Zheng, Ru-Juan Liu, Bing Su, Youqiong Ye, Richard A Flavell, Chengqi Yi, Yuzhang Wu, Hua-Bing Li.

Naive T cells undergo radical changes during the transition from dormant to hyperactive states upon activation, which necessitates de novo protein production via transcription and translation. However, the mechanism whereby T cells globally promote translation remains largely unknown. Here, we show that on exit from quiescence, T cells upregulate transfer RNA (tRNA) m1A58 'writer' proteins TRMT61A and TRMT6, which confer m1A58 RNA modification on a specific subset of early expressed tRNAs. These m1A-modified early tRNAs enhance translation efficiency, enabling rapid and necessary synthesis of MYC and of a specific group of key functional proteins. The MYC protein then guides the exit of naive T cells from a quiescent state into a proliferative state and promotes rapid T cell expansion after activation. Conditional deletion of the Trmt61a gene in mouse CD4+ T cells causes MYC protein deficiency and cell cycle arrest, disrupts T cell expansion upon cognate antigen stimulation and alleviates colitis in a mouse adoptive transfer colitis model. Our study elucidates for the first time, to our knowledge, the in vivo physiological roles of tRNA-m1A58 modification in T cell-mediated pathogenesis and reveals a new mechanism of tRNA-m1A58-controlled T cell homeostasis and signal-dependent translational control of specific key proteins.

DOI: https://doi.org/10.1038/s41590-022-01301-3
PLoS One. 2022 ;17(9): e0274910

Metabolomics analysis identifies glutamic acid and cystine imbalances in COVID-19 patients without comorbid conditions. Implications on redox homeostasis and COVID-19 pathophysiology.

José C Páez-Franco, José L Maravillas-Montero, Nancy R Mejía-Domínguez, Jiram Torres-Ruiz, Karla M Tamez-Torres, Alfredo Pérez-Fragoso, Juan Manuel Germán-Acacio, Alfredo Ponce-de-León, Diana Gómez-Martín, Alfredo Ulloa-Aguirre.

It is well known that the presence of comorbidities and age-related health issues may hide biochemical and metabolic features triggered by SARS-CoV-2 infection and other diseases associated to hypoxia, as they are by themselves chronic inflammatory conditions that may potentially disturb metabolic homeostasis and thereby negatively impact on COVID-19 progression. To unveil the metabolic abnormalities inherent to hypoxemia caused by COVID-19, we here applied gas chromatography coupled to mass spectrometry to analyze the main metabolic changes exhibited by a population of male patients less than 50 years of age with mild/moderate and severe COVID-19 without pre-existing comorbidities known to predispose to life-threatening complications from this infection. Several differences in serum levels of particular metabolites between normal controls and patients with COVID-19 as well as between mild/moderate and severe COVID-19 were identified. These included increased glutamic acid and reduced glutamine, cystine, threonic acid, and proline levels. In particular, using the entire metabolomic fingerprint obtained, we observed that glutamine/glutamate metabolism was associated with disease severity as patients in the severe COVID-19 group presented the lowest and higher serum levels of these amino acids, respectively. These data highlight the hypoxia-derived metabolic alterations provoked by SARS-CoV-2 infection in the absence of pre-existing co-morbidities as well as the value of amino acid metabolism in determining reactive oxygen species recycling pathways, which when impaired may lead to increased oxidation of proteins and cell damage. They also provide insights on new supportive therapies for COVID-19 and other disorders that involve altered redox homeostasis and lower oxygen levels that may lead to better outcomes of disease severity.

DOI: https://doi.org/10.1371/journal.pone.0274910
Clin Rheumatol. 2022 Sep 20.

Serum metabolite differences detected by HILIC UHPLC-Q-TOF MS in systemic sclerosis.

Chen Sun, Huimin Zhu, Yun Wang, Yichen Han, Dongdong Zhang, Xi Cao, Mihribangvl Alip, Min Nie, Xue Xu, Liangjing Lv, Xuebing Feng, Lingyun Sun, Dandan Wang.

   BACKGROUND: Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by extensive fibrosis and vascular damage. Vasculopathy, activation of the immune system, and diffuse fibrosis are all involved in the fatal pathogenesis of SSc. However, little metabolomic research has been conducted in SSc.
METHODS: This study included 30 SSc patients and 30 healthy individuals. The metabolite differences in serum samples were analyzed using ultra-high-pressure liquid chromatography and quadrupole-time-of-flight mass spectrometry. Meanwhile, serum metabolites were analyzed in patients with systemic involvement (lung or skin fibrosis).
RESULTS: A total of 2360 ion peaks were detected, all of which were attributable to 38 metabolites. These metabolites primarily consisted of fatty acids, amino acids, and glycerophospholipids, which were the major metabolic pathways altered in SSc patients. Glutamine metabolism was the main pathway altered in SSc patients with lung involvement, whereas amino acid metabolism and steroid hormone biosynthesis were the main pathways altered in SSc patients with skin involvement.
CONCLUSION: These findings suggested that metabolic profiles and pathways differed between SSc patients and healthy people, potentially providing new targets for SSc-directed therapeutics and diagnostics. Key Points • Metabolic profiles and pathways differed between SSc patients and healthy people. • The levels of trans-dehydroandrosterone are substantially lower in lcSSc than in dcSSc, potentially providing new targets for SSc patients with skin involvement. • L-glutamine could be used as a serum metabolic marker and a therapeutic target for SSc patients with lung involvement.

Keywords:  Amino acids; Fatty acids; Liquid chromatography-mass spectrometry; Metabolomics; Systemic sclerosis

DOI:  https://doi.org/10.1007/s10067-022-06372-z
Biomolecules. 2022 Sep 01. pii: 1216. [Epub ahead of print]12(9):

Mitochondrial Dysfunction in Rheumatoid Arthritis.

Chen Ma, Jie Wang, Fenfang Hong, Shulong Yang.

  Rheumatoid arthritis, a chronic autoimmune disease with complex etiology, is characterized by excessive proliferation of synovial cells, massive production of inflammatory cells and cartilage destruction. Studies have shown that mitochondrial dysfunction plays an important role in promoting the occurrence of RA. Mitochondria with normal structure and function are essential for the normal survival of chondrocytes and synovial cells. Once mitochondrial function is destroyed, it will affect the survival, activation and differentiation of immune cells and non-immune cells involved in the pathogenesis of RA, thus leading to the occurrence of RA. However, the mechanism of mitochondrial dysfunction in RA remains unclear. This article reviews the method of mitochondrial dysfunction leading to RA, the effects of mitochondrial dysfunction on immune cells, the etiology of mitochondrial dysfunction in RA, and the pathology of mitochondrial dysfunction in RA. We also outline some drugs that can exert therapeutic effects on RA which are associated with modulating mitochondrial activity. The understanding and summary of mitochondrial dysfunction in RA may provide new research directions for pathological intervention and prevention of RA.

Keywords:  mitochondria; rheumatoid arthritis

DOI:  https://doi.org/10.3390/biom12091216