bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2022‒01‒02
eighteen papers selected by
Dylan Ryan
University of Cambridge

  1. Mol Metab. 2021 Dec 22. pii: S2212-8778(21)00282-9. [Epub ahead of print] 101424
      Glucocorticoids (GCs) are one of the most widely prescribed anti-inflammatory drugs. By acting through their cognate receptor, the glucocorticoid receptor (GR), GCs down-regulate the expression of pro-inflammatory genes, and up-regulate anti-inflammatory genes. Metabolic pathways have recently been identified as key parts of both the inflammatory activation and anti-inflammatory polarization of macrophages, immune cells responsible for acute inflammation and tissue repair. It is currently unknown whether GCs control macrophage metabolism, and if so, to what extent metabolic regulation by GCs confers anti-inflammatory activity. Using transcriptomic and metabolomic profiling of macrophages, we identified GC controlled pathways involved in metabolism, especially in mitochondrial function. Metabolic analyses revealed that GCs repress glycolysis in inflammatory myeloid cells and promote tricarboxylic acid (TCA) cycle flux, promoting succinate metabolism and preventing intracellular accumulation of succinate. Inhibition of ATP synthase attenuated GC induced transcriptional changes, likely through stalling of TCA cycle anaplerosis. We further identified a glycolytic regulatory transcription factor, HIF1α, as regulated by GCs, and as a key regulator of GC responsiveness during inflammatory challenge, further linking metabolism to GC action in macrophages.
    Keywords:  Glucocorticoids; Succinate; TCA Cycle; immunometabolism; macrophage
  2. Eur J Immunol. 2021 Dec 27.
      Alterations in cell metabolism can shift the differentiation of immune cells towards a regulatory or inflammatory phenotype, thus opening up new therapeutic opportunities for immune-related diseases. Indeed, growing knowledge on T cell metabolism has revealed differences in the metabolic programs of suppressive regulatory T cells (Tregs) as compared to inflammatory Th1 and Th17 cells. In addition to Tregs, IL-10-producing regulatory B cells are crucial for maintaining tolerance, inhibiting inflammation and autoimmunity. Yet, the metabolic networks regulating diverse B lymphocyte responses are not well known. Here, we show that glutaminase blockade decreased downstream mTOR activation and attenuated IL-10 secretion. Direct suppression of mTOR activity by rapamycin selectively impaired IL-10 production by B cells whereas secretion was restored upon GSK3 inhibition. Mechanistically, we found mTORC1 activation leads to GSK3 inhibition, identifying a key signalling pathway regulating IL-10 secretion by B lymphocytes. Thus, our results identify glutaminolysis and the mTOR/GSK3 signalling axis, as critical regulators of the generation of IL-10 producing B cells with regulatory functions. This article is protected by copyright. All rights reserved.
    Keywords:  B10; GSK3; IL-10; glutamine; immunotherapy; mTOR; metabolism; regulatory B cells
  3. Semin Immunol. 2021 Dec 25. pii: S1044-5323(21)00114-7. [Epub ahead of print] 101583
      Neutrophils are critical innate immune cells for the host anti-bacterial defense. Throughout their lifecycle, neutrophils are exposed to different microenvironments and modulate their metabolism to survive and sustain their functions. Although tumor cell metabolism has been intensively investigated, how neutrophil metabolism is affected in cancer remains largely to be discovered. Neutrophils are described as mainly glycolytic cells. However, distinct tumor-associated neutrophil (TAN) states may co-exist in tumors and adapt their metabolism to exert different or even opposing activities ranging from tumor cell killing to tumor support. In this review, we gather evidence about the metabolic mechanisms that underly TANs' pro- or anti-tumoral functions in cancer. We first discuss how tumor-secreted factors and the heterogenous tumor microenvironment can have a strong impact on TAN metabolism. We then describe alternative metabolic pathways used by TANs to exert their functions in cancer, from basic glycolysis to more recently-recognized but less understood metabolic shifts toward mitochondrial oxidative metabolism, lipid and amino acid metabolism and even autophagy. Last, we discuss promising strategies targeting neutrophil metabolism to combat cancer.
    Keywords:  Cancer metabolism; Neutrophil metabolism; Tumor-associated neutrophils
  4. Cell Rep. 2021 Dec 28. pii: S2211-1247(21)01671-5. [Epub ahead of print]37(13): 110171
      Macrophages are often prominently present in the tumor microenvironment, where distinct macrophage populations can differentially affect tumor progression. Although metabolism influences macrophage function, studies on the metabolic characteristics of ex vivo tumor-associated macrophage (TAM) subsets are rather limited. Using transcriptomic and metabolic analyses, we now reveal that pro-inflammatory major histocompatibility complex (MHC)-IIhi TAMs display a hampered tricarboxylic acid (TCA) cycle, while reparative MHC-IIlo TAMs show higher oxidative and glycolytic metabolism. Although both TAM subsets rapidly exchange lactate in high-lactate conditions, only MHC-IIlo TAMs use lactate as an additional carbon source. Accordingly, lactate supports the oxidative metabolism in MHC-IIlo TAMs, while it decreases the metabolic activity of MHC-IIhi TAMs. Lactate subtly affects the transcriptome of MHC-IIlo TAMs, increases L-arginine metabolism, and enhances the T cell suppressive capacity of these TAMs. Overall, our data uncover the metabolic intricacies of distinct TAM subsets and identify lactate as a carbon source and metabolic and functional regulator of TAMs.
    Keywords:  TCA cycle break; immunometabolism; immunosuppression; lactate; macrophage metabolism; metabolomics; non-small-cell lung carcinoma; single-cell metabolic profiling; tumor microenvironment; tumor-associated macrophages
  5. Pharmacol Res. 2021 Dec 27. pii: S1043-6618(21)00631-9. [Epub ahead of print] 106047
      G protein-coupled receptors (GPCRs) are key regulatory proteins of immune cell function inducing signaling in response to extracellular (pathogenic) stimuli. Although unrelated, hydroxycarboxylic acid receptor 3 (HCA3) and GPR84 share signaling via Gαi/o proteins and the agonist 3-hydroxydecanoate (3HDec). Both receptors are abundantly expressed in monocytes, macrophages and neutrophils but have opposing functions in these innate immune cells. Detailed insights into the molecular mechanisms and signaling components involved in immune cell regulation by GPR84 and HCA3 are still lacking. Here, we report that GPR84-mediated pro-inflammatory signaling depends on coupling to the hematopoietic cell-specific Gα15 protein in human macrophages, while HCA3 exclusively couples to Gαi protein. We show that activated GPR84 induces Gα15-dependent ERK activation, increases intracellular Ca2+ and IP3 levels as well as ROS production. In contrast, HCA3 activation shifts macrophage metabolism to a less glycolytic phenotype, which is associated with anti-inflammatory responses. This is supported by an increased release of anti-inflammatory IL-10 and a decreased secretion of pro-inflammatory IL-1β. In primary human neutrophils, stimulation with HCA3 agonists counteracts the GPR84-induced neutrophil activation. Our analyses reveal that 3HDec acts solely through GPR84 but not HCA3 activation in macrophages. In summary, this study shows that HCA3 mediates hyporesponsiveness in response to metabolites derived from dietary lactic bacteria and uncovers that GPR84, which is already targeted in clinical trials, promotes pro-inflammatory signaling via Gα15 protein in macrophages.
    Keywords:  1-(1-Methylethyl)-1H-benzotriazole-5-carboxylic acid (PubChem CID: 2736690); 3-Hydroxydecanoic acid (PubChem CID: 26612); 3-Hydroxyoctanoic acid (PubChem CID: 26613); 6-n-Octylaminouracil (PubChem CID: 10354234); D-(+)-3-Phenyllactic acid (PubChem CID: 643327); D-phenyllactic acid; Decanoic acid (PubChem CID: 2969); GPR84; Lactic acid bacteria; hydroxycarboxylic acid receptor 3; macrophages; neutrophils
  6. Dokl Biol Sci. 2021 Nov;501(1): 206-209
      Immunological non-responders (INR) are HIV-infected subjects that fail to restore CD4+ T-cell counts despite undetectable HIV viral load, which is controlled by highly active antiretroviral therapy (HAART). In INR, impaired immune restoration is linked to low-productive proliferation of memory CD4+ T-lymphocytes. Taking into account that T-cell ability to divide depends on the activity of metabolic pathways, we aimed to determine rates of mitochondrial respiration and glycolysis in memory CD4+ T-cells of INR. Two groups of HIV-infected HAART-treated patients were studied: immunological non-responders and subjects with an adequate immunological response to therapy (immunological responders - IR). Control (C) group comprised uninfected volunteers. In both groups of HIV-infected patients glycolytic activity of memory CD4+ T-cells was lower than that in C. Mitochondrial respiration rate in memory CD4+ T-cells derived from IR was comparable to that of C at basal state, however, after stimulation IR failed to reach the values of uninfected subjects. INR had the lowest mitochondrial respiration rate both at basal state and after stimulation. Taken together, the data presented herein demonstrate that low regenerative potential of memory CD4+ T-cells derived from INR might be linked to diminished lymphocytes' metabolic activity.
    Keywords:  CD4+ T lymphocytes; HIV infection; glycolysis; highly active antiretroviral therapy; metabolism; mitochondria
  7. Front Cardiovasc Med. 2021 ;8 777098
      Macrophages play a central role in the pathogenesis of atherosclerosis. Our previous study demonstrated that solute carrier family 37 member 2 (SLC37A2), an endoplasmic reticulum-anchored phosphate-linked glucose-6-phosphate transporter, negatively regulates macrophage Toll-like receptor activation by fine-tuning glycolytic reprogramming in vitro. Whether macrophage SLC37A2 impacts in vivo macrophage inflammation and atherosclerosis under hyperlipidemic conditions is unknown. We generated hematopoietic cell-specific SLC37A2 knockout and control mice in C57Bl/6 Ldlr-/- background by bone marrow transplantation. Hematopoietic cell-specific SLC37A2 deletion in Ldlr-/- mice increased plasma lipid concentrations after 12-16 wks of Western diet induction, attenuated macrophage anti-inflammatory responses, and resulted in more atherosclerosis compared to Ldlr-/- mice transplanted with wild type bone marrow. Aortic root intimal area was inversely correlated with plasma IL-10 levels, but not total cholesterol concentrations, suggesting inflammation but not plasma cholesterol was responsible for increased atherosclerosis in bone marrow SLC37A2-deficient mice. Our in vitro study demonstrated that SLC37A2 deficiency impaired IL-4-induced macrophage activation, independently of glycolysis or mitochondrial respiration. Importantly, SLC37A2 deficiency impaired apoptotic cell-induced glycolysis, subsequently attenuating IL-10 production. Our study suggests that SLC37A2 expression is required to support alternative macrophage activation in vitro and in vivo. In vivo disruption of hematopoietic SLC37A2 accelerates atherosclerosis under hyperlipidemic pro-atherogenic conditions.
    Keywords:  IL-10; atherosclerosis; efferocytosis; glucose 6-phosphate transporter; macrophage inflammation
  8. Cancer Cell. 2021 Dec 16. pii: S1535-6108(21)00660-7. [Epub ahead of print]
      In a recent publication in Nature, Zhang et al. report that foreign antigen stimulation elicits bountiful changes in lymphatic metabolite production-changes that include B cells secreting GABA, which reprograms macrophages and limits T cell cytotoxicity. This signifies a new mechanism by which B cells regulate immune suppression and facilitate tumor progression.
  9. Int Immunopharmacol. 2021 Dec 23. pii: S1567-5769(21)01086-9. [Epub ahead of print]103 108450
      T helper 17 cells (Th17) have been associated with the pathogenesis of autoimmune and inflammatory diseases, which makes them become a sharp focus when the researchers are seeking therapeutic target for these diseases. A growing body of evidence has suggested that cellular metabolism dictates Th17 cell differentiation and effector function. Moreover, various studies have disclosed that metabolism is linked to the occurrence of autoimmune diseases. In this article, we reviewed the most recent findings regarding the importance of metabolism in Th17 cell differentiation and autoimmune diseases and also discussed the modulation mechanisms of glycolysis, fatty acid and cholesterol synthesis, and amino acids metabolism for Th17 cell differentiation. This review summarized the potential therapeutic or preventing strategies for Th17 cell-mediated autoimmune diseases.
    Keywords:  Amino acids; Autoimmune diseases; Fatty acid synthesis; Glutaminolysis; Glycolysis; Th17 cells
  10. Immunology. 2021 Dec 28.
      In the past few years, the evolution of immunotherapy has resulted in a shift in cancer treatment models. However, with immunosuppressive effects of the tumour microenvironment continue to limit advances in tumour immunotherapy. The tumour microenvironment induces metabolic reprogramming in cancer cells, which results in competition for nutrients between tumour cells and host immunocytes. Metabolic and waste products originating in tumour cells can influence the activation and effector properties of immunocytes in numerous ways and ultimately promote the survival and propagation of tumour cells. In this paper, we discuss metabolic reprogramming in tumour cells and the influence of metabolite byproducts on the immune microenvironment, providing novel insights into tumour immunotherapy.
    Keywords:  immunotherapy; metabolic disorder; tumour immunology
  11. Redox Biol. 2021 Dec 24. pii: S2213-2317(21)00385-2. [Epub ahead of print]49 102225
      BACKGROUND: Neutrophils play a role in innate immunity and are critical for clearance of Staphylococcus aureus. Current understanding of neutrophil bactericidal effects is that NADPH oxidase produces reactive oxygen species (ROS), mediating bacterial killing. Neutrophils also contain numerous mitochondria; since these organelles lack oxidative metabolism, their function is unclear. We hypothesize that mitochondria in human neutrophils contribute to the bactericidal capacity of S. aureus.METHODS: and Findings: Using human neutrophils isolated from healthy volunteers (n = 13; 7 females, 6 males), we show that mitochondria are critical in the immune response to S. aureus. Using live-cell and fixed confocal, and transmission electron microscopy, we show mitochondrial tagging of bacteria prior to ingestion and surrounding of phagocytosed bacteria immediately upon engulfment. Further, we demonstrate that mitochondria are ejected from intact neutrophils and engage bacteria during vital NETosis. Inhibition of the mitochondrial electron transport chain at Complex III, but not Complex I, attenuates S. aureus killing by 50 ± 7%, comparable to the NADPH oxidase inhibitor apocynin. Similarly, mitochondrial ROS scavenging using MitoTEMPO attenuates bacterial killing 112 ± 60% versus vehicle control. Antimycin A treatment also reduces mitochondrial ROS production by 50 ± 12% and NETosis by 53 ± 5%.
    CONCLUSIONS: We identify a previously unrecognized role for mitochondria in human neutrophils in the killing of S. aureus. Inhibition of electron transport chain Complex III significantly impairs antimicrobial activity. This is the first demonstration that vital NETosis, an early event in the antimicrobial response, occurring within 5 min of bacterial exposure, depends on the function of mitochondrial Complex III. Mitochondria join NADPH oxidase as bactericidal ROS generators that mediate the bactericidal activities of human neutrophils.
    Keywords:  Electron transport chain complex III; Immunity; Neutrophil extracellular trap (NET); Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases; Phagocytosis; Staphylococcus aureus
  12. Cell Rep. 2021 Dec 28. pii: S2211-1247(21)01651-X. [Epub ahead of print]37(13): 110155
      During somatic reprogramming, cellular energy metabolism fundamentally switches from predominantly mitochondrial oxidative phosphorylation toward glycolysis. This metabolic reprogramming, also called the Warburg effect, is critical for the induction of pluripotency, but its molecular mechanisms remain poorly defined. Notably, SIRT2 is consistently downregulated during the reprogramming process and regulates glycolytic switch. Here, we report that downregulation of SIRT2 increases acetylation of mitogen-activated protein kinase (MAPK) kinase-1 (MEK1) at Lys175, resulting in activation of extracellular signal-regulated kinases (ERKs) and subsequent activation of the pro-fission factor dynamin-related protein 1 (DRP1). In parallel, downregulation of SIRT2 hyperacetylates the serine/threonine protein kinase AKT1 at Lys20 in a non-canonical way, activating DRP1 and metabolic reprogramming. Together, our study identified two axes, SIRT2-MEK1-ERK-DRP1 and SIRT2-AKT1-DRP1, that critically link mitochondrial dynamics and oxidative phosphorylation to the somatic reprogramming process. These upstream signals, together with SIRT2's role in glycolytic switching, may underlie the Warburg effect observed in human somatic cell reprogramming.
    Keywords:  AKT1; DRP1; MEK1-ERK axis; OXPHOS; SIRT2; Warburg-like effect; human somatic cell reprogramming; induced pluripotent stem cells; metabolic reprogramming; mitochondrial remodeling
  13. Biochem Biophys Res Commun. 2021 Dec 20. pii: S0006-291X(21)01703-4. [Epub ahead of print]588 161-167
      Distinct macrophage populations exert highly heterogeneity and perform various functions, among which, a crucial function of lipid metabolism is highlighted. However, the role of histidine metabolism disorder in macrophage lipid metabolism remains elusive. Addressed this question, we sorted and cultured the bone marrow-derived macrophages (BMDMs) of histidine decarboxylase (Hdc) knockout (Hdc-/-) mice with an in vitro oxidized low-density lipoprotein (ox-LDL) model, and detected the intracellular lipids by Oil Red O staining as well as lipid probe staining. Astemizole, a canonical and long-acting histamine H1 receptor (H1R) antagonist, was applied to elucidate the impact of antagonizing the H1R-dependent signaling pathway on macrophage lipid metabolism. Subsequently, the differential expressed genes were screened and analyzed in the bone marrow-derived CD11b+ immature myeloid cells of Hdc-/- and Hdc+/+ mice with a high fat diet by the microarray study. The expression levels of cholesterol metabolism-related genes were examined by qRT-PCR to explore underlying mechanisms. Lastly, we used a high-sensitivity histidine probe to detect the intracellular histidine in the BMDMs after oxidative stress. The results revealed that histidine metabolism disorder and histamine deficiency aggravated lipid accumulation in the ox-LDL-treated BMDMs. The expression level of H1R gene in the BMDMs was down-regulated after ox-LDL stimulation. The disruption of the H1R-dependent signaling pathway by astemizole further exacerbated ox-LDL-induced lipid deposition in the BMDMs partly by up-regulating scavenger receptor class A (SR-A) for lipid intake, down-regulating neutral cholesteryl ester hydrolase (nCEH) for cholesterol esterification and down-regulating ATP-binding cassette transporters A1 (ABCA1) and ABCG1 for reverse cholesterol transport. The intracellular histidine increased under ox-LDL condition, which was further increased by Hdc knockout. Collectively, these results partially reveal the relationship between histidine metabolism and lipid metabolism in the BMDMs and offer a novel strategy for lipid metabolism disorder-associated diseases.
    Keywords:  Histamine H1 receptor; Histidine decarboxylase; Histidine metabolism; Lipid metabolism; Macrophage
  14. Cell Rep. 2021 Dec 28. pii: S2211-1247(21)01646-6. [Epub ahead of print]37(13): 110150
      Enteric pathogens overcome barrier immunity within the intestinal environment that includes the endogenous flora. The microbiota produces diverse ligands, and the full spectrum of microbial products that are sensed by the epithelium and prime protective immunity is unknown. Using Drosophila, we find that the gut presents a high barrier to infection, which is partially due to signals from the microbiota, as loss of the microbiota enhances oral viral infection. We report cyclic dinucleotide (CDN) feeding is sufficient to protect microbiota-deficient flies from enhanced oral infection, suggesting that bacterial-derived CDNs induce immunity. Mechanistically, we find CDN protection is dSTING- and dTBK1-dependent, leading to NF-kB-dependent gene expression. Furthermore, we identify the apical nucleoside transporter, CNT2, as required for oral CDN protection. Altogether, our studies define a role for bacterial products in priming immune defenses in the gut.
    Keywords:  Drosophila; NFkB; STING; antiviral; cGAMP; cyclic dinucleotides; immunity; intestine; virus
  15. Front Med (Lausanne). 2021 ;8 781567
      Metabolic (dysfunction)-associated fatty liver disease (MAFLD) is the definition recently proposed to better circumscribe the spectrum of conditions long known as non-alcoholic fatty liver disease (NAFLD) that range from simple steatosis without inflammation to more advanced liver diseases. The progression of MAFLD, as well as other chronic liver diseases, toward cirrhosis, is driven by hepatic inflammation and fibrogenesis. The latter, result of a "chronic wound healing reaction," is a dynamic process, and the understanding of its underlying pathophysiological events has increased in recent years. Fibrosis progresses in a microenvironment where it takes part an interplay between fibrogenic cells and many other elements, including some cells of the immune system with an underexplored or still unclear role in liver diseases. Some therapeutic approaches, also acting on the immune system, have been probed over time to evaluate their ability to improve inflammation and fibrosis in NAFLD, but to date no drug has been approved to treat this condition. In this review, we will focus on the contribution of the liver immune system in the progression of NAFLD, and on therapies under study that aim to counter the immune substrate of the disease.
    Keywords:  MAFLD; NAFLD; NAFLD therapies; immunometabolism; liver fibrogenesis; liver immunology
  16. J Lipid Res. 2021 Dec 21. pii: S0022-2275(21)00148-6. [Epub ahead of print] 100165
      Oxysterols, the oxidized forms of cholesterol or of its precursors, are formed in the first steps of cholesterol metabolism. Oxysterols have interested chemists, biologists, and physicians for many decades, but their exact biological relevance in vivo, other than as intermediates in bile acid biosynthesis, has long been debated. However, in first quarter of this century, a role for side-chain oxysterols and their C-7 oxidized metabolites has been convincingly established in the immune system. 25-Hydroxycholesterol has been shown to be synthesized by macrophages in response to the activation of Toll-like receptors and to offer protection against microbial pathogens, while 7α,25-dihydroxycholesterol has been shown to act as a chemoattractant to lymphocytes expressing the G protein-coupled receptor EBI2 and to be important in coordinating the action of B, T, and dendritic cells in secondary lymphoid tissue. There is a growing body of evidence that not only these two oxysterols but also many of their isomers are of importance to the proper function of the immune system. Here, we review recent findings related to the roles of oxysterols in immunology.
    Keywords:  B cell; T cell; accessible cholesterol; bacterial infection; dendritic cell; hydroxycholesterol; macrophage; membrane fusion; oxysterol; virus
  17. Nat Microbiol. 2021 Dec 31.
      Gene exchange between viruses and their hosts acts as a key facilitator of horizontal gene transfer and is hypothesized to be a major driver of evolutionary change. Our understanding of this process comes primarily from bacteria and phage co-evolution, but the mode and functional importance of gene transfers between eukaryotes and their viruses remain anecdotal. Here we systematically characterized viral-eukaryotic gene exchange across eukaryotic and viral diversity, identifying thousands of transfers and revealing their frequency, taxonomic distribution and projected functions. Eukaryote-derived viral genes, abundant in the Nucleocytoviricota, highlighted common strategies for viral host-manipulation, including metabolic reprogramming, proteolytic degradation and extracellular modification. Furthermore, viral-derived eukaryotic genes implicate genetic exchange in the early evolution and diversification of eukaryotes, particularly through viral-derived glycosyltransferases, which have impacted structures as diverse as algal cell walls, trypanosome mitochondria and animal tissues. These findings illuminate the nature of viral-eukaryotic gene exchange and its impact on the evolution of viruses and their eukaryotic hosts.
  18. Elife. 2021 Dec 30. pii: e72430. [Epub ahead of print]10
      Bisphosphonates drugs target the skeleton and are used globally for the treatment of common bone disorders. Nitrogen-containing bisphosphonates act by inhibiting the mevalonate pathway in bone-resorbing osteoclasts but, surprisingly, also appear to reduce the risk of death from pneumonia. We overturn the long-held belief that these drugs act only in the skeleton and show that a fluorescently labelled bisphosphonate is internalised by alveolar macrophages and large peritoneal macrophages in vivo. Furthermore, a single dose of a nitrogen-containing bisphosphonate (zoledronic acid) in mice was sufficient to inhibit the mevalonate pathway in tissue-resident macrophages, causing the build-up of a mevalonate metabolite and preventing protein prenylation. Importantly, one dose of bisphosphonate enhanced the immune response to bacterial endotoxin in the lung and increased the level of cytokines and chemokines in bronchoalveolar fluid. These studies suggest that bisphosphonates, as well as preventing bone loss, may boost immune responses to infection in the lung and provide a mechanistic basis to fully examine the potential of bisphosphonates to help combat respiratory infections that cause pneumonia.
    Keywords:  alveolar macrophage; bisphosphonate; inflammasome; medicine; mouse; osteoporosis; pneumonia; prenylation