bims-aditis Biomed News
on Adipose tissue, inflammation, immunometabolism
Issue of 2022–03–27
seven papers selected by
Matthew C. Sinton, University of Glasgow
  1. Peripheral γδ T cells regulate neutrophil expansion and recruitment in experimental psoriatic arthritis.
  2. Adipose tissue: a neglected organ in the response to severe trauma?
  3. Browning Epicardial Adipose Tissue: Friend or Foe?
  4. Mucosal-associated invariant T cells are associated with insulin resistance in childhood obesity, and disrupt insulin signalling via IL-17.
  5. The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming.
  6. Mitochondrial adaptations throughout the Trypanosoma brucei life cycle.
  7. Acute intermittent hypoxia drives hepatic de novo lipogenesis in humans and rodents.
  1. Arthritis Rheumatol. 2022 Mar 23.
    Peripheral γδ T cells regulate neutrophil expansion and recruitment in experimental psoriatic arthritis.
    Cuong Thach Nguyen, Hiroki Furuya, Dayasagar Das, Alina I Marusina, Alexander A Merleev, Resmi Ravindran, Zahra Jalali, Imran H Khan, Emanual Maverakis, Iannis E Adamopoulos.
       OBJECTIVE: This study was undertaken to identify the mechanistic role of γδ T cells in the pathogenesis of experimental psoriatic arthritis (PsA).
    METHODS: In this study, we perform IL-23 gene transfer in WT and TCR δ deficient mice and perform tissue phenotyping in the joint, skin, and nails to characterize the inflammatory infiltrate. We further perform detailed flow cytometry, immunofluorescence, RNAseq, T cell repertoire analysis and in vitro T -cell polarization assays to identify regulatory mechanisms of γδ T cells.
    RESULTS: We demonstrate that γδ T cells support systemic granulopoiesis which is critical for murine PsA-like pathology. Briefly, γδ T cell ablation inhibited the expression of neutrophil chemokines CXCL-1, CXCL-2 and neutrophil CD11b+ Ly6G+ accumulation in the aforementioned PsA-related tissues. Although a significantly reduced expression of GM-CSF and IL-17A was detected systemically in TCRδ-/- mice, no GM-CSF+ /IL-17A+ γδ T cells were detected locally in the inflamed skin and/or bone marrow in WT mice. Our data demonstrate that non-resident γδ T cells regulate the expansion of an CD11b+ Ly6G+ neutrophil population and their recruitment to joint and skin tissues, where they develop hallmark pathologic features of human PsA.
    CONCLUSION: Our findings do not support that tissue-resident γδ T cells are initiating the disease but demonstrate a novel role of γδ T cells in neutrophil regulation that can be exploited therapeutically in PsA patients.
    DOI:  https://doi.org/10.1002/art.42124
  2. Cell Mol Life Sci. 2022 Mar 26. 79(4): 207
    Adipose tissue: a neglected organ in the response to severe trauma?
    Lisa Wrba, Rebecca Halbgebauer, Julian Roos, Markus Huber-Lang, Pamela Fischer-Posovszky.
      Despite the manifold recent efforts to improve patient outcomes, trauma still is a clinical and socioeconomical issue of major relevance especially in younger people. The systemic immune reaction after severe injury is characterized by a strong pro- and anti-inflammatory response. Besides its functions as energy storage depot and organ-protective cushion, adipose tissue regulates vital processes via its secretion products. However, there is little awareness of the important role of adipose tissue in regulating the posttraumatic inflammatory response. In this review, we delineate the local and systemic role of adipose tissue in trauma and outline different aspects of adipose tissue as an immunologically active modifier of inflammation and as an immune target of injured remote organs after severe trauma.
    Keywords:  Adipokine; Adipose tissue; Immune response; Trauma
    DOI:  https://doi.org/10.1007/s00018-022-04234-0
  3. Cells. 2022 Mar 14. pii: 991. [Epub ahead of print]11(6):
    Browning Epicardial Adipose Tissue: Friend or Foe?
    Elisa Doukbi, Astrid Soghomonian, Coralie Sengenès, Shaista Ahmed, Patricia Ancel, Anne Dutour, Bénédicte Gaborit.
      The epicardial adipose tissue (EAT) is the visceral fat depot of the heart which is highly plastic and in direct contact with myocardium and coronary arteries. Because of its singular proximity with the myocardium, the adipokines and pro-inflammatory molecules secreted by this tissue may directly affect the metabolism of the heart and coronary arteries. Its accumulation, measured by recent new non-invasive imaging modalities, has been prospectively associated with the onset and progression of coronary artery disease (CAD) and atrial fibrillation in humans. Recent studies have shown that EAT exhibits beige fat-like features, and express uncoupling protein 1 (UCP-1) at both mRNA and protein levels. However, this thermogenic potential could be lost with age, obesity and CAD. Here we provide an overview of the physiological and pathophysiological relevance of EAT and further discuss whether its thermogenic properties may serve as a target for obesity therapeutic management with a specific focus on the role of immune cells in this beiging phenomenon.
    Keywords:  adipose tissue; beiging; browning; coronary artery disease; ectopic fat; epicardial adipose tissue; heart; immune cells; innate lymphoid cells
    DOI:  https://doi.org/10.3390/cells11060991
  4. Diabetologia. 2022 Mar 19.
    Mucosal-associated invariant T cells are associated with insulin resistance in childhood obesity, and disrupt insulin signalling via IL-17.
    Ronan Bergin, David Kinlen, Nidhi Kedia-Mehta, Eadaoin Hayes, Féaron C Cassidy, Declan Cody, Donal O'Shea, Andrew E Hogan.
       AIMS/HYPOTHESIS: Mucosal-associated invariant T cells (MAIT cells) are an abundant population of innate T cells. When activated, MAIT cells rapidly produce a range of cytokines, including IFNγ, TNF-α and IL-17. Several studies have implicated MAIT cells in the development of metabolic dysfunction, but the mechanisms through which this occurs are not fully understood. We hypothesised that MAIT cells are associated with insulin resistance in children with obesity, and affect insulin signalling through their production of IL-17.
    METHODS: In a cross-sectional observational study, we investigated MAIT cell cytokine profiles in a cohort of 30 children with obesity and 30 healthy control participants, of similar age, using flow cytometry. We then used a cell-based model to determine the direct effect of MAIT cells and IL-17 on insulin signalling and glucose uptake.
    RESULTS: Children with obesity display increased MAIT cell frequencies (2.2% vs 2.8%, p=0.047), and, once activated, these produced elevated levels of both TNF-α (39% vs 28%, p=0.03) and IL-17 (1.25% vs 0.5%, p=0.008). The IL-17-producing MAIT cells were associated with an elevated HOMA-IR (r=0.65, p=0.001). The MAIT cell secretome from adults with obesity resulted in reduced glucose uptake when compared with the secretome from healthy adult control (1.31 vs 0.96, p=0.0002), a defect that could be blocked by neutralising IL-17. Finally, we demonstrated that recombinant IL-17 blocked insulin-mediated glucose uptake via inhibition of phosphorylated Akt and extracellular signal-regulated kinase.
    CONCLUSIONS/INTERPRETATIONS: Collectively, these studies provide further support for the role of MAIT cells in the development of metabolic dysfunction, and suggest that an IL-17-mediated effect on intracellular insulin signalling is responsible.
    Keywords:  Insulin resistance; Interleukin-17; Mucosal-associated invariant T cells; Obesity
    DOI:  https://doi.org/10.1007/s00125-022-05682-w
  5. Cell Metab. 2022 Mar 15. pii: S1550-4131(22)00087-0. [Epub ahead of print]
    The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming.
    Sophia M Hochrein, Hao Wu, Miriam Eckstein, Laura Arrigoni, Josip S Herman, Fabian Schumacher, Christian Gerecke, Mathias Rosenfeldt, Dominic Grün, Burkhard Kleuser, Georg Gasteiger, Wolfgang Kastenmüller, Bart Ghesquière, Jan Van den Bossche, E Dale Abel, Martin Vaeth.
      Metabolic reprogramming is a hallmark of activated T cells. The switch from oxidative phosphorylation to aerobic glycolysis provides energy and intermediary metabolites for the biosynthesis of macromolecules to support clonal expansion and effector function. Here, we show that glycolytic reprogramming additionally controls inflammatory gene expression via epigenetic remodeling. We found that the glucose transporter GLUT3 is essential for the effector functions of Th17 cells in models of autoimmune colitis and encephalomyelitis. At the molecular level, we show that GLUT3-dependent glucose uptake controls a metabolic-transcriptional circuit that regulates the pathogenicity of Th17 cells. Metabolomic, epigenetic, and transcriptomic analyses linked GLUT3 to mitochondrial glucose oxidation and ACLY-dependent acetyl-CoA generation as a rate-limiting step in the epigenetic regulation of inflammatory gene expression. Our findings are also important from a translational perspective because inhibiting GLUT3-dependent acetyl-CoA generation is a promising metabolic checkpoint to mitigate Th17-cell-mediated inflammatory diseases.
    Keywords:  ACLY; ATP-citrate lyase; GLUT1; GLUT3; Th17 cells; acetyl-CoA; glucose metabolism; glycolysis; histone acetylation; immunometabolism
    DOI:  https://doi.org/10.1016/j.cmet.2022.02.015
  6. J Eukaryot Microbiol. 2022 Mar 24. e12911
    Mitochondrial adaptations throughout the Trypanosoma brucei life cycle.
    Alena Zíková.
      The unicellular parasite Trypanosoma brucei has a digenetic life cycle that alternates between a mammalian host and an insect vector. During programmed development, this extracellular parasite encounters strikingly different environments that determine its energy metabolism. Functioning as a bioenergetic, biosynthetic, and signaling center, the single mitochondrion of T. brucei is drastically remodeled to support the dynamic cellular demands of the parasite. This manuscript will provide an up-to-date overview of how the distinct T. brucei developmental stages differ in their mitochondrial metabolic and bioenergetic pathways, with a focus on the electron transport chain, proline oxidation, TCA cycle, acetate production, and ATP generation. Although mitochondrial metabolic rewiring has always been simply viewed as a consequence of the differentiation process, the possibility that certain mitochondrial activities reinforce parasite differentiation will be explored.
    DOI:  https://doi.org/10.1111/jeu.12911
  7. Metabol Open. 2022 Jun;14 100177
    Acute intermittent hypoxia drives hepatic de novo lipogenesis in humans and rodents.
    Jonathan M Hazlehurst, Teegan Reina Lim, Catriona Charlton, Jack J Miller, Laura L Gathercole, Thomas Cornfield, Nikolaos Nikolaou, Shelley E Harris, Ahmad Moolla, Nantia Othonos, Lisa C Heather, Thomas Marjot, Damian J Tyler, Carolyn Carr, Leanne Hodson, Jane McKeating, Jeremy W Tomlinson.
       Background and aims: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition. It is tightly associated with an adverse metabolic phenotype (including obesity and type 2 diabetes) as well as with obstructive sleep apnoea (OSA) of which intermittent hypoxia is a critical component. Hepatic de novo lipogenesis (DNL) is a significant contributor to hepatic lipid content and the pathogenesis of NAFLD and has been proposed as a key pathway to target in the development of pharmacotherapies to treat NAFLD. Our aim is to use experimental models to investigate the impact of hypoxia on hepatic lipid metabolism independent of obesity and metabolic disease.
    Methods: Human and rodent studies incorporating stable isotopes and hyperinsulinaemic euglycaemic clamp studies were performed to assess the regulation of DNL and broader metabolic phenotype by intermittent hypoxia. Cell-based studies, including pharmacological and genetic manipulation of hypoxia-inducible factors (HIF), were used to examine the underlying mechanisms.
    Results: Hepatic DNL increased in response to acute intermittent hypoxia in humans, without alteration in glucose production or disposal. These observations were endorsed in a prolonged model of intermittent hypoxia in rodents using stable isotopic assessment of lipid metabolism. Changes in DNL were paralleled by increases in hepatic gene expression of acetyl CoA carboxylase 1 and fatty acid synthase. In human hepatoma cell lines, hypoxia increased both DNL and fatty acid uptake through HIF-1α and -2α dependent mechanisms.
    Conclusions: These studies provide robust evidence linking intermittent hypoxia and the regulation of DNL in both acute and sustained in vivo models of intermittent hypoxia, providing an important mechanistic link between hypoxia and NAFLD.
    Keywords:  HIF; Hypoxia; Lipid metabolism; NAFLD
    DOI:  https://doi.org/10.1016/j.metop.2022.100177
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