bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2021‒12‒05
ten papers selected by
Dylan Ryan
University of Cambridge

  1. Front Immunol. 2021 ;12 700431
      The transcription factor BMAL1 is a clock protein that generates daily or circadian rhythms in physiological functions including the inflammatory response of macrophages. Intracellular metabolic pathways direct the macrophage inflammatory response, however whether the clock is impacting intracellular metabolism to direct this response is unclear. Specific metabolic reprogramming of macrophages controls the production of the potent pro-inflammatory cytokine IL-1β. We now describe that the macrophage molecular clock, through Bmal1, regulates the uptake of glucose, its flux through glycolysis and the Krebs cycle, including the production of the metabolite succinate to drive Il-1β production. We further demonstrate that BMAL1 modulates the level and localisation of the glycolytic enzyme PKM2, which in turn activates STAT3 to further drive Il-1β mRNA expression. Overall, this work demonstrates that BMAL1 is a key metabolic sensor in macrophages, and its deficiency leads to a metabolic shift of enhanced glycolysis and mitochondrial respiration, leading to a heightened pro-inflammatory state. These data provide insight into the control of macrophage driven inflammation by the molecular clock, and the potential for time-based therapeutics against a range of chronic inflammatory diseases.
    Keywords:  IL-1β; macrophage inflammation; metabolism; molecular clock; pSTAT3
  2. Cell Metab. 2021 Nov 24. pii: S1550-4131(21)00531-3. [Epub ahead of print]
      Uncoupling protein 1 (UCP1) is a major regulator of brown and beige adipocyte energy expenditure and metabolic homeostasis. However, the widely employed UCP1 loss-of-function model has recently been shown to have a severe deficiency in the entire electron transport chain of thermogenic fat. As such, the role of UCP1 in metabolic regulation in vivo remains unclear. We recently identified cysteine-253 as a regulatory site on UCP1 that elevates protein activity upon covalent modification. Here, we examine the physiological importance of this site through the generation of a UCP1 cysteine-253-null (UCP1 C253A) mouse, a precise genetic model for selective disruption of UCP1 in vivo. UCP1 C253A mice exhibit significantly compromised thermogenic responses in both males and females but display no measurable effect on fat accumulation in an obesogenic environment. Unexpectedly, we find that a lack of C253 results in adipose tissue redox stress, which drives substantial immune cell infiltration and systemic inflammatory pathology in adipose tissues and liver of male, but not female, mice. Elevation of systemic estrogen reverses this male-specific pathology, providing a basis for protection from inflammation due to loss of UCP1 C253 in females. Together, our results establish the UCP1 C253 activation site as a regulator of acute thermogenesis and sex-dependent tissue inflammation.
    Keywords:  UCP1; cysteine; inflammation; metabolism; reactive oxygen species; sex differences
  3. Naunyn Schmiedebergs Arch Pharmacol. 2021 Dec 01.
      Macrophages are myeloid immune cells, present in virtually all tissues which exhibit considerable functional plasticity and diversity. Macrophages are often subdivided into two distinct subsets described as classically activated (M1) and alternatively activated (M2) macrophages. It has recently emerged that metabolites regulate the polarization and function of macrophages by altering metabolic pathways. These metabolites often cannot freely pass the cell membrane and are therefore transported by the corresponding metabolite transporters. Here, we reviewed how glucose, glutamate, lactate, fatty acid, and amino acid transporters are involved in the regulation of macrophage polarization. Understanding the interactions among metabolites, metabolite transporters, and macrophage function under physiological and pathological conditions may provide further insights for novel drug targets for the treatment of macrophage-associated diseases. In Brief Recent studies have shown that the polarization and function of macrophages are regulated by metabolites, most of which cannot pass freely through biofilms. Therefore, metabolite transporters required for the uptake of metabolites have emerged seen as important regulators of macrophage polarization and may represent novel drug targets for the treatment of macrophage-associated diseases. Here, we summarize the role of metabolite transporters as regulators of macrophage polarization.
    Keywords:  Macrophage polarization; Metabolite transporters; Metabolites; Solute carriers
  4. Front Oncol. 2021 ;11 759015
      Immune checkpoint inhibitors (ICIs), Ipilimumab, Nivolumab, Pembrolizumab and Atezolizumab, have been applied in anti-tumor therapy and demonstrated exciting performance compared to conventional treatments. However, the unsatisfactory response rates, high recurrence and adaptive resistance limit their benefits. Metabolic reprogramming appears to be one of the crucial barriers to immunotherapy. The deprivation of required nutrients and altered metabolites not only promote tumor progression but also confer dysfunction on immune cells in the tumor microenvironment (TME). Glycolysis plays a central role in metabolic reprogramming and immunoregulation in the TME, and many therapies targeting glycolysis have been developed, and their combinations with ICIs are in preclinical and clinical trials. Additional attention has been paid to the role of amino acids, lipids, nucleotides and mitochondrial biogenesis in metabolic reprogramming and clinical anti-tumor therapy. This review attempts to describe reprogramming metabolisms within tumor cells and immune cells, from the aspects of glycolysis, amino acid metabolism, lipid metabolism, nucleotide metabolism and mitochondrial biogenesis and their impact on immunity in the TME, as well as the significance of targeting metabolism in anti-tumor therapy, especially in combination with ICIs. In particular, we highlight the expression mechanism of programmed cell death (ligand) 1 [PD-(L)1] in tumor cells and immune cells under reprogramming metabolism, and discuss in detail the potential of targeting key metabolic pathways to break resistance and improve the efficacy of ICIs based on results from current preclinical and clinical trials. Besides, we draw out biomarkers of potential predictive value in ICIs treatment from a metabolic perspective.
    Keywords:  PD-1; amino acid metabolism; glycolysis; immune checkpoints; lipid metabolism; mitochondrial biogenesis; nucleotide metabolism; the tumor microenvironment
  5. Elife. 2021 Dec 02. pii: e70978. [Epub ahead of print]10
      After antigenic activation, quiescent naive CD4+ T cells alter their metabolism to proliferate. This metabolic shift increases production of nucleotides, amino acids, fatty acids, and sterols. Here, we show that histone deacetylase 3 (HDAC3) is critical for activation of murine peripheral CD4+ T cells. HDAC3-deficient CD4+ T cells failed to proliferate and blast after in vitro TCR/CD28 stimulation. Upon T-cell activation, genes involved in cholesterol biosynthesis are upregulated while genes that promote cholesterol efflux are repressed. HDAC3-deficient CD4+ T cells had reduced levels of cellular cholesterol both before and after activation. HDAC3-deficient cells upregulate cholesterol synthesis appropriately after activation, but fail to repress cholesterol efflux; notably, they overexpress cholesterol efflux transporters ABCA1 and ABCG1. Repression of these genes is the primary function for HDAC3 in peripheral CD4+ T cells, as addition of exogenous cholesterol restored proliferative capacity. Collectively, these findings demonstrate HDAC3 is essential during CD4+ T-cell activation to repress cholesterol efflux.
    Keywords:  HDAC3; T cell activation; cholesterol regulation; immunology; inflammation; mouse
  6. Front Immunol. 2021 ;12 733921
      A hallmark of COVID-19 is a hyperinflammatory state associated with severity. Monocytes undergo metabolic reprogramming and produce inflammatory cytokines when stimulated with SARS-CoV-2. We hypothesized that binding by the viral spike protein mediates this effect, and that drugs which regulate immunometabolism could inhibit the inflammatory response. Monocytes stimulated with recombinant SARS-CoV-2 spike protein subunit 1 showed a dose-dependent increase in glycolytic metabolism associated with production of pro-inflammatory cytokines. This response was dependent on hypoxia-inducible factor-1α, as chetomin inhibited glycolysis and cytokine production. Inhibition of glycolytic metabolism by 2-deoxyglucose (2-DG) or glucose deprivation also inhibited the glycolytic response, and 2-DG strongly suppressed cytokine production. Glucose-deprived monocytes rescued cytokine production by upregulating oxidative phosphorylation, an effect which was not present in 2-DG-treated monocytes due to the known effect of 2-DG on suppressing mitochondrial metabolism. Finally, pre-treatment of monocytes with metformin strongly suppressed spike protein-mediated cytokine production and metabolic reprogramming. Likewise, metformin pre-treatment blocked cytokine induction by SARS-CoV-2 strain WA1/2020 in direct infection experiments. In summary, the SARS-CoV-2 spike protein induces a pro-inflammatory immunometabolic response in monocytes that can be suppressed by metformin, and metformin likewise suppresses inflammatory responses to live SARS-CoV-2. This has potential implications for the treatment of hyperinflammation during COVID-19.
    Keywords:  COVID-19; SARS-CoV-2; immunometabolism; inflammation; monocyte
  7. Brain. 2021 Nov 29. 144(10): 3126-3141
      Dimethyl fumarate, an approved treatment for relapsing-remitting multiple sclerosis, exerts pleiotropic effects on immune cells as well as CNS resident cells. Here, we show that dimethyl fumarate exerts a profound alteration of the metabolic profile of human CD4+ as well as CD8+ T cells and restricts their antioxidative capacities by decreasing intracellular levels of the reactive oxygen species scavenger glutathione. This causes an increase in mitochondrial reactive oxygen species levels accompanied by an enhanced mitochondrial stress response, ultimately leading to impaired mitochondrial function. Enhanced mitochondrial reactive oxygen species levels not only result in enhanced T-cell apoptosis in vitro as well as in dimethyl fumarate-treated patients, but are key for the well-known immunomodulatory effects of dimethyl fumarate both in vitro and in an animal model of multiple sclerosis, i.e. experimental autoimmune encephalomyelitis. Indeed, dimethyl fumarate immune-modulatory effects on T cells were completely abrogated by pharmacological interference of mitochondrial reactive oxygen species production. These data shed new light on dimethyl fumarate as bona fide immune-metabolic drug that targets the intracellular stress response in activated T cells, thereby restricting mitochondrial function and energetic capacity, providing novel insight into the role of oxidative stress in modulating cellular immune responses and T cell-mediated autoimmunity.
    Keywords:  T-cell; antioxidative T-cell capacities; autoimmunity; dimethyl fumarate; multiple sclerosis;  metabolism
  8. Nature. 2021 Dec;600(7887): 116-120
      The Toll/interleukin-1 receptor (TIR) domain is a canonical component of animal and plant immune systems1,2. In plants, intracellular pathogen sensing by immune receptors triggers their TIR domains to generate a molecule that is a variant of cyclic ADP-ribose3,4. This molecule is hypothesized to mediate plant cell death through a pathway that has yet to be resolved5. TIR domains have also been shown to be involved in a bacterial anti-phage defence system called Thoeris6, but the mechanism of Thoeris defence remained unknown. Here we show that phage infection triggers Thoeris TIR-domain proteins to produce an isomer of cyclic ADP-ribose. This molecular signal activates a second protein, ThsA, which then depletes the cell of the essential molecule nicotinamide adenine dinucleotide (NAD) and leads to abortive infection and cell death. We also show that, similar to eukaryotic innate immune systems, bacterial TIR-domain proteins determine the immunological specificity to the invading pathogen. Our results describe an antiviral signalling pathway in bacteria, and suggest that the generation of intracellular signalling molecules is an ancient immunological function of TIR domains that is conserved in both plant and bacterial immunity.
  9. Leukemia. 2021 Dec 02.
      Mutations in isocitrate dehydrogenase 2 (IDH2) have been noted to impact cellular differentiation in addition to DNA and histone methylation. However, little is known about the impact of IDH2 mutations on intracellular signaling. Using an isogenic cell line model, we investigated both differentiation and signaling responses in IDH2 mutant cells and show augmented responses to inflammatory immune ligands. Using phospho-specific flow and mass cytometry, we demonstrate IDH2 mutant cells were significantly more sensitive to IL-1β at multiple downstream readouts. Further, bulk RNA sequencing confirmed increases in cytokine-related signaling pathways and NF-κB target genes. Single-cell RNA sequencing of unstimulated and stimulated cells confirmed altered IL-1β transcriptional responses in the IDH2 mutant cells. Targeted inhibition of the IKK complex reduced IL-1β responses and induced cell death in primary IDH-mutated leukemia samples. Together, these results confirm altered IL-1β signaling in IDH2 mutant cells and identify this pathway as a potential therapeutic target.
  10. Mol Ther Nucleic Acids. 2021 Dec 03. 26 1303-1317
      MiR-30a-5p plays an important role in various cardiovascular diseases, but its effect in atherosclerosis has not been reported. Apolipoprotein E-deficient (Apo E-/-) mice were used to investigate the role of miR-30a-5p in atherosclerosis, and the underlying mechanism was investigated in vivo and in vitro. The fluorescence in situ hybridization test revealed that miR-30a-5p was expressed in Apo E-/- mice lesions. Nevertheless, in RAW264.7 macrophages, the expression of miR-30a-5p was reduced by lipopolysaccharide (LPS) or oxidized low-density lipoprotein. MiR-30a-5p-ago-treated Apo E-/- mice significantly reduced lesion areas in the aorta and aortic root, reduced levels of lipoprotein and pro-inflammatory cytokines, and increased levels of anti-inflammatory cytokines. The ratio of M1/M2 macrophages was decreased in miR-30a-5p-ago-treated Apo E-/- mice and LPS-treated RAW264.7 macrophages by the regulation of Smad-1/2 phosphorylation. MiR-30a-5p reduced lipid uptake in oxidized low-density lipoprotein-treated macrophages by regulating the expression of PPAR-γ, ABCA1, ABCG1, LDLR, and PCSK9. Ubiquitinated ligase NEDD4L was identified as a target of miR-30a-5p. Interestingly, knockdown of NEDD4L decreased the M1/M2 ratio and oxidized low-density lipoprotein uptake in macrophages by inhibiting the ubiquitination of PPAR-γ and phosphorylation of Smad-1/2 and regulating ABCA1, ABCG1, LDLR, and PCSK9. We demonstrated a novel effect and mechanism of miR-30a-5p in atherosclerosis.
    Keywords:  ABCA1; ABCG1; LDLR; M1/M2 polarization; NEDD4L; PCSK9; Smad-1/2/3; macrophage; miR-30a-5p; ubiquitin