bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2022‒10‒23
29 papers selected by
Dylan Ryan
University of Cambridge
  1. An evolutionary trade-off between host immunity and metabolism drives fatty liver in male mice.
  2. Complement membrane attack complex is an immunometabolic regulator of NLRP3 activation and IL-18 secretion in human macrophages.
  3. Nitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases.
  4. Taking mitochondria to heart.
  5. Metabolic guidance and stress in tumors modulate antigen-presenting cells.
  6. Metabolic regulation of immune responses to cancer.
  7. Immunometabolism in Livestock.
  8. Metabolic modeling of single bronchoalveolar macrophages reveals regulators of hyperinflammation in COVID-19.
  9. Innate metabolic responses against viral infections.
  10. Associations of microbial and indoleamine-2,3-dioxygenase-derived tryptophan metabolites with immune activation in healthy adults.
  11. Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection.
  12. MPYS Modulates Fatty Acid Metabolism and Immune Tolerance at Homeostasis Independent of Type I IFNs.
  13. Non-invasive classification of macrophage polarisation by 2P-FLIM and machine learning.
  14. The metabolite-controlled ubiquitin conjugase Ubc8 promotes mitochondrial protein import.
  15. Lipids reroute mitochondria.
  16. Methionine uptake via the SLC43A2 transporter is essential for regulatory T-cell survival.
  17. Activation of Nrf2 signaling by 4-octyl itaconate attenuates the cartilaginous endplate degeneration by inhibiting E3 ubiquitin ligase ZNF598.
  18. Immunometabolism and inflammation: a perspective on animal productivity.
  19. Rewiring the altered tryptophan metabolism as a novel therapeutic strategy in inflammatory bowel diseases.
  20. Immunometabolic considerations with regard to the domestic chicken, Gallus gallus.
  21. ANGPTL3 deficiency associates with the expansion of regulatory T cells with reduced lipid content.
  22. Modulating immunometabolism in transition dairy cows: the role of inflammatory lipid mediators.
  23. Nitrosylation rewires metabolism.
  24. Metabolomics-based investigation of SARS-CoV-2 vaccination (Sinovac) reveals an immune-dependent metabolite biomarker.
  25. Cross talk between glucose metabolism and immunosuppression in IFN-γ-primed mesenchymal stem cells.
  26. Prohibitin 1 regulates mtDNA release and downstream inflammatory responses.
  27. Sodium butyrate attenuated diet-induced obesity, insulin resistance and inflammation partly by promoting fat thermogenesis via intro-adipose sympathetic innervation.
  28. cGAS/STING and innate brain inflammation following acute high-fat feeding.
  29. Dysfunctional purinergic signaling correlates with disease severity in COVID-19 patients.
  1. Science. 2022 Oct 21. 378(6617): 290-295
    An evolutionary trade-off between host immunity and metabolism drives fatty liver in male mice.
    Joni Nikkanen, Yew Ann Leong, William C Krause, Denis Dermadi, J Alan Maschek, Tyler Van Ry, James E Cox, Ethan J Weiss, Omer Gokcumen, Ajay Chawla, Holly A Ingraham.
      Adaptations to infectious and dietary pressures shape mammalian physiology and disease risk. How such adaptations affect sex-biased diseases remains insufficiently studied. In this study, we show that sex-dependent hepatic gene programs confer a robust (~300%) survival advantage for male mice during lethal bacterial infection. The transcription factor B cell lymphoma 6 (BCL6), which masculinizes hepatic gene expression at puberty, is essential for this advantage. However, protection by BCL6 protein comes at a cost during conditions of dietary excess, which result in overt fatty liver and glucose intolerance in males. Deleting hepatic BCL6 reverses these phenotypes but markedly lowers male survival during infection, thus establishing a sex-dependent trade-off between host defense and metabolic systems. Our findings offer strong evidence that some current sex-biased diseases are rooted in ancient evolutionary trade-offs between immunity and metabolism.
    DOI:  https://doi.org/10.1126/science.abn9886
  2. Front Immunol. 2022 ;13 918551
    Complement membrane attack complex is an immunometabolic regulator of NLRP3 activation and IL-18 secretion in human macrophages.
    Gisela Jimenez-Duran, Joseph Kozole, Rachel Peltier-Heap, Eleanor R Dickinson, Christopher R Kwiatkowski, Francesca Zappacosta, Roland S Annan, Nicholas W Galwey, Eva-Maria Nichols, Louise K Modis, Martha Triantafilou, Kathy Triantafilou, Lee M Booty.
      The complement system is an ancient and critical part of innate immunity. Recent studies have highlighted novel roles of complement beyond lysis of invading pathogens with implications in regulating the innate immune response, as well as contributing to metabolic reprogramming of T-cells, synoviocytes as well as cells in the CNS. These findings hint that complement can be an immunometabolic regulator, but whether this is also the case for the terminal step of the complement pathway, the membrane attack complex (MAC) is not clear. In this study we focused on determining whether MAC is an immunometabolic regulator of the innate immune response in human monocyte-derived macrophages. Here, we uncover previously uncharacterized metabolic changes and mitochondrial dysfunction occurring downstream of MAC deposition. These alterations in glycolytic flux and mitochondrial morphology and function mediate NLRP3 inflammasome activation, pro-inflammatory cytokine release and gasdermin D formation. Together, these data elucidate a novel signalling cascade, with metabolic alterations at its center, in MAC-stimulated human macrophages that drives an inflammatory consequence in an immunologically relevant cell type.
    Keywords:  NLRP3 inflammasome; complement; immunometabolism; macrophage; mitochondrial dysfunction; reactive oxygen species
    DOI:  https://doi.org/10.3389/fimmu.2022.918551
  3. Nat Chem Biol. 2022 Oct 20.
    Nitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases.
    Gretchen L Seim, Steven V John, Nicholas L Arp, Zixiang Fang, David J Pagliarini, Jing Fan.
      Pyruvate dehydrogenase complex (PDHC) and oxoglutarate dehydrogenase complex (OGDC), which belong to the mitochondrial α-ketoacid dehydrogenase family, play crucial roles in cellular metabolism. These multi-subunit enzyme complexes use lipoic arms covalently attached to their E2 subunits to transfer an acyl group to coenzyme A (CoA). Here, we report a novel mechanism capable of substantially inhibiting PDHC and OGDC: reactive nitrogen species (RNS) can covalently modify the thiols on their lipoic arms, generating a series of adducts that block catalytic activity. S-Nitroso-CoA, a product between RNS and the E2 subunit's natural substrate, CoA, can efficiently deliver these modifications onto the lipoic arm. We found RNS-mediated inhibition of PDHC and OGDC occurs during classical macrophage activation, driving significant rewiring of cellular metabolism over time. This work provides a new mechanistic link between RNS and mitochondrial metabolism with potential relevance for numerous physiological and pathological conditions in which RNS accumulate.
    DOI:  https://doi.org/10.1038/s41589-022-01153-w
  4. Sci Signal. 2022 Oct 18. 15(756): eadf2995
    Taking mitochondria to heart.
    Wei Wong.
      Long-chain fatty acids redirect the uptake of mitochondria released from adipocytes from macrophages to the heart.
    DOI:  https://doi.org/10.1126/scisignal.adf2995
  5. Oncogenesis. 2022 Oct 16. 11(1): 62
    Metabolic guidance and stress in tumors modulate antigen-presenting cells.
    Jaeoh Park, Limei Wang, Ping-Chih Ho.
      Successful antitumor immunity largely relies on efficient T cell priming by antigen-presenting cells (APCs); however, the capacity of APCs is found to be defective in many cancers. Metabolically reprogrammed cancer cells support the energetic and biosynthetic demands of their high proliferation rates by exploiting nutrients available in the tumor microenvironment (TME), which in turn limits proper metabolic reprogramming of APCs during recruitment, differentiation, activation and antigen presentation. Furthermore, some metabolites generated by the TME are unfavorable to antitumor immunity. This review summarizes recent studies on the metabolic features of APCs and their functionality in the TME. Particularly, we will describe how APCs respond to altered TME and how metabolic byproducts from cancer and immunomodulatory cells affect APCs. Finally, we introduce the current status of APC-oriented research and clinical trials targeting metabolic features to boost efficient immunotherapy.
    DOI:  https://doi.org/10.1038/s41389-022-00438-y
  6. Cancer Biol Med. 2022 Oct 24. pii: j.issn.2095-3941.2022.0381. [Epub ahead of print]
    Metabolic regulation of immune responses to cancer.
    Jannis Wißfeld, Anke Werner, Xin Yan, Nora Ten Bosch, Guoliang Cui.
      The tumor microenvironment is an ecosystem composed of multiple types of cells, such as tumor cells, immune cells, and cancer-associated fibroblasts. Cancer cells grow faster than non-cancerous cells and consume larger amounts of nutrients. The rapid growth characteristic of cancer cells fundamentally alters nutrient availability in the tumor microenvironment and results in reprogramming of immune cell metabolic pathways. Accumulating evidence suggests that cellular metabolism of nutrients, such as lipids and amino acids, beyond being essential to meet the bioenergetic and biosynthetic demands of immune cells, also regulates a broad spectrum of cellular signal transduction, and influences immune cell survival, differentiation, and anti-tumor effector function. The cancer immunometabolism research field is rapidly evolving, and exciting new discoveries are reported in high-profile journals nearly weekly. Therefore, all new findings in this field cannot be summarized within this short review. Instead, this review is intended to provide a brief introduction to this rapidly developing research field, with a focus on the metabolism of two classes of important nutrients-lipids and amino acids-in immune cells. We highlight recent research on the roles of lipids and amino acids in regulating the metabolic fitness and immunological functions of T cells, macrophages, and natural killer cells in the tumor microenvironment. Furthermore, we discuss the possibility of "editing" metabolic pathways in immune cells to act synergistically with currently available immunotherapies in enhancing anti-tumor immune responses.
    Keywords:  Lipids; NK cells; T cells; amino acids; anti-tumor immunity; cancer; immunometabolism; metabolism
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2022.0381
  7. Anim Front. 2022 Oct;12(5): 11-12
    Immunometabolism in Livestock.
      
    DOI:  https://doi.org/10.1093/af/vfac066
  8. iScience. 2022 Oct 10. 105319
    Metabolic modeling of single bronchoalveolar macrophages reveals regulators of hyperinflammation in COVID-19.
    Qiuchen Zhao, Zhenyang Yu, Shengyuan Zhang, Xu-Rui Shen, Hao Yang, Yangyang Xu, Yang Liu, Lin Yang, Qing Zhang, Jiaqi Chen, Mengmeng Lu, Fei Luo, Mingming Hu, Yan Gong, Conghua Xie, Peng Zhou, Li Wang, Lishan Su, Zheng Zhang, Liang Cheng.
      SARS-CoV-2 infection induces imbalanced immune response such as hyperinflammation in patients with severe COVID-19. Here we studied the immunometabolic regulatory mechanisms for the pathogenesis of COVID-19. We depicted the metabolic landscape of immune cells, especially macrophages, from bronchoalveolar lavage fluid of COVID-19 patients at single-cell level. We found that most metabolic processes were upregulated in macrophages from lungs of mild COVID-19 patients compared to cells from heathy controls, whereas macrophages from severe COVID-19 showed downregulation of most of the core metabolic pathways including glutamate metabolism, fatty acid oxidation, citrate cycle and oxidative phosphorylation, and upregulation of a few pathways such as glycolysis. Rewiring cellular metabolism by amino acid supplementation, glycolysis inhibition or PPARγ stimulation reduces inflammation in macrophages stimulated with SARS-CoV-2. Altogether, this study demonstrates that metabolic imbalance of bronchoalveolar macrophages may contribute to hyperinflammation in patients with severe COVID-19, and provides insights into treating COVID-19 by immunometabolic modulation.
    DOI:  https://doi.org/10.1016/j.isci.2022.105319
  9. Nat Metab. 2022 Oct;4(10): 1245-1259
    Innate metabolic responses against viral infections.
    Clovis S Palmer.
      Metabolic adaptation to viral infections critically determines the course and manifestations of disease. At the systemic level, a significant feature of viral infection and inflammation that ensues is the metabolic shift from anabolic towards catabolic metabolism. Systemic metabolic sequelae such as insulin resistance and dyslipidaemia represent long-term health consequences of many infections such as human immunodeficiency virus, hepatitis C virus and severe acute respiratory syndrome coronavirus 2. The long-held presumption that peripheral and tissue-specific 'immune responses' are the chief line of defence and thus regulate viral control is incomplete. This Review focuses on the emerging paradigm shift proposing that metabolic engagements and metabolic reconfiguration of immune and non-immune cells following virus recognition modulate the natural course of viral infections. Early metabolic footprints are likely to influence longer-term disease manifestations of infection. A greater appreciation and understanding of how local biochemical adjustments in the periphery and tissues influence immunity will ultimately lead to interventions that curtail disease progression and identify new and improved prognostic biomarkers.
    DOI:  https://doi.org/10.1038/s42255-022-00652-3
  10. Front Immunol. 2022 ;13 917966
    Associations of microbial and indoleamine-2,3-dioxygenase-derived tryptophan metabolites with immune activation in healthy adults.
    Niknaz Riazati, Mary E Kable, John W Newman, Yuriko Adkins, Tammy Freytag, Xiaowen Jiang, Charles B Stephensen.
      Background: Tryptophan (Trp) metabolites from intestinal bacteria (indole, indole acetic acid [IAA] and indole propionic acid [IPA]), and the Trp metabolite kynurenine (Kyn) from the indoleamine 2,3-dioxygenase (IDO) pathway, are aryl hydrocarbon receptor (AhR) agonists and thus, can regulate immune activity via the AhR pathway. We hypothesized that plasma concentrations of these metabolites would be associated with markers of immune activation in a cohort of healthy adults in a manner consistent with AhR-mediated immune-regulation. We also hypothesized that the plasma Kyn/Trp ratio, a marker of IDO activity, would be associated with immune markers reflecting IDO activation in innate immune cells. Finally, we hypothesized that some intestinal bacteria would be associated with plasma indole, IPA and IAA, and that these bacteria themselves would be associated with immune markers.Methods: A novel set of 88 immune markers, and plasma Trp metabolites, were measured in 362 healthy adults. Bacterial taxa from stool were identified by 16S rRNA gene analysis. Multiple linear regression analysis was used to identify significant associations with immune markers.
    Results: The sum of indole and IAA was positively associated with natural killer T-cells levels. Kyn and Kyn/Trp were positively associated with neopterin and IP-10, markers of type 1 immunity, and TNF-α and C-reactive protein (CRP), markers of the acute phase response, and the regulatory cytokine IL-10. Three bacteria negatively associated with Trp metabolites were associated with markers of immune activation: the family Lachnospiraceae with higher lymphocyte counts but lower level of activated CD4 T-cells, the genus Dorea with higher production of IFN-γ by T-cells in PBMC cultures, and the genus Ruminococcus with higher production IL-6 in PBMC cultures stimulated with bacterial lipopolysaccharide (LPS).
    Conclusions: In this cohort of healthy adults bacterial Trp metabolites were not strongly associated with immune markers. Conversely, the Kyn/Trp ratio was strongly associated with markers of systemic inflammation and the acute phase response, consistent with IDO activation in innate immune cells. Finally, commensal bacteria associated with lower plasma (and perhaps intestinal) levels of bacterial Trp metabolites were associated with greater immune activation, possibly reflecting decreased regulatory immune activity related to lower intestinal levels of bacterial indole metabolites.
    Keywords:  immunity; indole; indole acetic acid (IAA); indole producing bacteria; indole propionic acid (IPA); inflammation; kynurenine; tryptophan
    DOI:  https://doi.org/10.3389/fimmu.2022.917966
  11. Elife. 2022 Oct 20. pii: e76744. [Epub ahead of print]11
    Enriched dietary saturated fatty acids induce trained immunity via ceramide production that enhances severity of endotoxemia and clearance of infection.
    Amy L Seufert, James W Hickman, Ste K Traxler, Rachael M Peterson, Trent A Waugh, Sydney J Lashley, Natalia Shulzhenko, Ruth J Napier, Brooke A Napier.
      Trained immunity is an innate immune memory response that is induced by primary microbial or sterile stimuli that sensitizes monocytes and macrophages to a secondary pathogenic challenge, reprogramming the host response to infection and inflammatory disease. Nutritional components, such as dietary fatty acids, can act as inflammatory stimuli, but it is unknown if they can act as the primary stimuli in the context of innate immune memory. Here we find mice fed a diet enriched exclusively in saturated fatty acids (SFAs; ketogenic diet; KD) confer a hyper-inflammatory response to systemic lipopolysaccharide (LPS) and increased mortality, independent of diet-induced microbiome and glycemic modulation. We find KD mediates the composition of the hematopoietic stem cell (HSC) compartment, and macrophages derived from the bone marrow of mice fed KD do not have altered baseline inflammation, but enhanced responses to a secondary inflammatory challenge. Lipidomics identified enhanced free palmitic acid (PA) and PA-associated lipids in KD-fed mice serum. We found pre-treatment with physiologically relevant concentrations of PA alone reprograms macrophages to induce a hyper-inflammatory response to secondary challenge with LPS. This response was found to be dependent on the synthesis of ceramide, and reversible when treated with a ceramide synthase inhibitor. In vivo, we found systemic PA confers enhanced inflammation and mortality during an acute inflammatory response to systemic LPS, and this phenotype was not reversible for up to 7 days post-PA-exposure. While PA-treatment is harmful for endotoxemia outcome, we find PA exposure enhanced clearance of Candida albicans in Rag1-/- mice. Further, we show that oleic acid (OA), a mono-unsaturated FA that depletes intracellular ceramide, reverses the PA-induced hyper-inflammatory response shown in macrophages treated with LPS, and reduces severity and mortality of LPS endotoxin stimulation, highlighting the plasticity of SFA-dependent enhanced endotoxemia severity in vivo. These are the first data to implicate enriched dietary SFAs, and specifically PA, in the induction of long-lived innate immune memory that is detrimental during an acute inflammatory response, but beneficial for clearance of pathogens.
    Keywords:  immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.76744
  12. J Immunol. 2022 Oct 19. pii: ji2200158. [Epub ahead of print]
    MPYS Modulates Fatty Acid Metabolism and Immune Tolerance at Homeostasis Independent of Type I IFNs.
    Samira Mansouri, Himanshu Gogoi, Seema Patel, Divya S Katikaneni, Arashdeep Singh, Alexandra Aybar-Torres, Guillaume de Lartigue, Lei Jin.
      MPYS/STING (stimulator of IFN genes) senses cyclic dinucleotides (CDNs), generates type I IFNs, and plays a critical role in infection, inflammation, and cancer. In this study, analyzing genotype and haplotype data from the 1000 Genomes Project, we found that the R71H-G230A-R293Q (HAQ) MPYS allele frequency increased 57-fold in East Asians compared with sub-Saharan Africans. Meanwhile, the G230A-R293Q (AQ) allele frequency decreased by 98% in East Asians compared with sub-Saharan Africans. We propose that the HAQ and AQ alleles underwent a natural selection during the out-of-Africa migration. We used mouse models of HAQ and AQ to investigate the underlying mechanism. We found that the mice carrying the AQ allele, which disappeared in East Asians, had normal CDN-type I IFN responses. Adult AQ mice, however, had less fat mass than did HAQ or wild-type mice on a chow diet. AQ epididymal adipose tissue had increased regulatory T cells and M2 macrophages with protein expression associated with enhanced fatty acid oxidation. Conditional knockout mice and adoptive cell transfer indicate a macrophage and regulatory T cell-intrinsic role of MPYS in fatty acid metabolism. Mechanistically, AQ/IFNAR1-/- mice had a similar lean phenotype as for the AQ mice. MPYS intrinsic tryptophan fluorescence revealed that the R71H change increased MPYS hydrophilicity. Lastly, we found that the second transmembrane (TM) and the TM2-TM3 linker region of MPYS interact with activated fatty acid, fatty acyl-CoA. In summary, studying the evolution of the human MPYS gene revealed an MPYS function in modulating fatty acid metabolism that may be critical during the out-of-Africa migration.
    DOI:  https://doi.org/10.4049/jimmunol.2200158
  13. Elife. 2022 10 18. pii: e77373. [Epub ahead of print]11
    Non-invasive classification of macrophage polarisation by 2P-FLIM and machine learning.
    Nuno G B Neto, Sinead A O'Rourke, Mimi Zhang, Hannah K Fitzgerald, Aisling Dunne, Michael G Monaghan.
      In this study, we utilise fluorescence lifetime imaging of NAD(P)H-based cellular autofluorescence as a non-invasive modality to classify two contrasting states of human macrophages by proxy of their governing metabolic state. Macrophages derived from human blood-circulating monocytes were polarised using established protocols and metabolically challenged using small molecules to validate their responding metabolic actions in extracellular acidification and oxygen consumption. Large field-of-view images of individual polarised macrophages were obtained using fluorescence lifetime imaging microscopy (FLIM). These were challenged in real time with small-molecule perturbations of metabolism during imaging. We uncovered FLIM parameters that are pronounced under the action of carbonyl cyanide-p-trifluoromethoxyphenylhydrazone (FCCP), which strongly stratifies the phenotype of polarised human macrophages; however, this performance is impacted by donor variability when analysing the data at a single-cell level. The stratification and parameters emanating from a full field-of-view and single-cell FLIM approach serve as the basis for machine learning models. Applying a random forests model, we identify three strongly governing FLIM parameters, achieving an area under the receiver operating characteristics curve (ROC-AUC) value of 0.944 and out-of-bag (OBB) error rate of 16.67% when classifying human macrophages in a full field-of-view image. To conclude, 2P-FLIM with the integration of machine learning models is showed to be a powerful technique for analysis of both human macrophage metabolism and polarisation at full FoV and single-cell level.
    Keywords:  FLIM; cell biology; cellular metabolism; human; immunology; inflammation; machine learning; macrophages; multiphoton
    DOI:  https://doi.org/10.7554/eLife.77373
  14. Life Sci Alliance. 2023 Jan;pii: e202201526. [Epub ahead of print]6(1):
    The metabolite-controlled ubiquitin conjugase Ubc8 promotes mitochondrial protein import.
    Saskia Rödl, Fabian den Brave, Markus Räschle, Büsra Kizmaz, Svenja Lenhard, Carina Groh, Hanna Becker, Jannik Zimmermann, Bruce Morgan, Elke Richling, Thomas Becker, Johannes M Herrmann.
      Mitochondria play a key role in cellular energy metabolism. Transitions between glycolytic and respiratory conditions induce considerable adaptations of the cellular proteome. These metabolism-dependent changes are particularly pronounced for the protein composition of mitochondria. Here, we show that the yeast cytosolic ubiquitin conjugase Ubc8 plays a crucial role in the remodeling process when cells transition from respiratory to fermentative conditions. Ubc8 is a conserved and well-studied component of the catabolite control system that is known to regulate the stability of gluconeogenic enzymes. Unexpectedly, we found that Ubc8 also promotes the assembly of the translocase of the outer membrane of mitochondria (TOM) and increases the levels of its cytosol-exposed receptor subunit Tom22. Ubc8 deficiency results in compromised protein import into mitochondria and reduced steady-state levels of mitochondrial proteins. Our observations show that Ubc8, which is controlled by the prevailing metabolic conditions, promotes the switch from glucose synthesis to glucose usage in the cytosol and induces the biogenesis of the mitochondrial TOM machinery to improve mitochondrial protein import during phases of metabolic transition.
    DOI:  https://doi.org/10.26508/lsa.202201526
  15. Nat Metab. 2022 Oct;4(10): 1218
    Lipids reroute mitochondria.
    Michael Attwaters.
      
    DOI:  https://doi.org/10.1038/s42255-022-00662-1
  16. Life Sci Alliance. 2022 Dec;pii: e202201663. [Epub ahead of print]5(12):
    Methionine uptake via the SLC43A2 transporter is essential for regulatory T-cell survival.
    Neetu Saini, Afsana Naaz, Shree Padma Metur, Pinki Gahlot, Adhish Walvekar, Anupam Dutta, Umamaheswari Davathamizhan, Apurva Sarin, Sunil Laxman.
      Cell death, survival, or growth decisions in T-cell subsets depend on interplay between cytokine-dependent and metabolic processes. The metabolic requirements of T-regulatory cells (Tregs) for their survival and how these are satisfied remain unclear. Herein, we identified a necessary requirement of methionine uptake and usage for Tregs survival upon IL-2 deprivation. Activated Tregs have high methionine uptake and usage to S-adenosyl methionine, and this uptake is essential for Tregs survival in conditions of IL-2 deprivation. We identify a solute carrier protein SLC43A2 transporter, regulated in a Notch1-dependent manner that is necessary for this methionine uptake and Tregs viability. Collectively, we uncover a specifically regulated mechanism of methionine import in Tregs that is required for cells to adapt to cytokine withdrawal. We highlight the need for methionine availability and metabolism in contextually regulating cell death in this immunosuppressive population of T cells.
    DOI:  https://doi.org/10.26508/lsa.202201663
  17. Osteoarthritis Cartilage. 2022 Oct 18. pii: S1063-4584(22)00887-1. [Epub ahead of print]
    Activation of Nrf2 signaling by 4-octyl itaconate attenuates the cartilaginous endplate degeneration by inhibiting E3 ubiquitin ligase ZNF598.
    Bao Huang, Haihao Wu, Lin Zheng, Xiaoan Wei, Zeyu Zheng, Hao Wu, Jian Chen, Zhi Shan, Junhui Liu, Fengdong Zhao.
      OBJECTIVE: Cartilaginous endplate (CEP) degeneration is the main early manifestations of intervertebral disc degeneration (IVDD), and is closely related to the oxidative stress. Nrf2 (nuclear factor E2-related factor 2, NFE2L2) is a vital transcriptional factor of cellular antioxidant and anti-inflammatory responses. We aimed to illustrate whether the Nrf2 which was increased in expression by 4-octyl itaconate (4OI) could attenuate intervertebral disc degeneration through suppressing macrophage associated inflammation and catabolism of cartilaginous endplate.METHODS: Firstly, we detected the expression of Nrf2 in human degenerative CEPs. Then, we performed in vitro, ex vivo and in vivo (a rat-tail puncture model) experiments to explore the role of 4OI in IVDD. Also, by cell co-culture experiments, we demonstrated 4OI restrained the macrophage-associated inflammatory responses. Finally, through western blotting and IP assay, we clarified the ZNF598-mediated ubiquitination of Nrf2.
    RESULTS: We found decreased expression of Nrf2 in human degenerative CEPs. Using a rat IVDD model(n=6), 4OI significantly ameliorated the progression of IVDD by MR images and histological analysis. Immunofluorescence results reveal that catabolism of CEPs and macrophage-associated inflammation are suppressed by 4OI treatment. Mechanistically, the 4OI increases Nrf2 expression and inhibits the secretion of inflammatory factors (IL-1β) by LPS-induced macrophages, thus preventing the inflammatory-related CEP degeneration. Meanwhile, 4OI suppresses the ROS production and catabolism of LPS-induced rat CEP cells. In addition, 4OI inhibits the ZNF598-dependent ubiquitination of Nrf2 in LPS-induced rat CEP cells.
    CONCLUSIONS: 4OI may alleviate IVDD by suppressing CEP degeneration and macrophage-associated inflammation. 4OI may be an alternative therapy for degenerative CEPs/IVDs.
    Keywords:  4-octyl itaconate; Cartilaginous endplate; Inflammation; Intervertebral disc degeneration; Nrf2
    DOI:  https://doi.org/10.1016/j.joca.2022.10.008
  18. Anim Front. 2022 Oct;12(5): 5-7
    Immunometabolism and inflammation: a perspective on animal productivity.
    Ellen Davis.
      
    Keywords:  homeostasis; immune development; proinflammatory
    DOI:  https://doi.org/10.1093/af/vfac060
  19. Gut. 2022 Oct 21. pii: gutjnl-2022-327337. [Epub ahead of print]
    Rewiring the altered tryptophan metabolism as a novel therapeutic strategy in inflammatory bowel diseases.
    Chloé Michaudel, Camille Danne, Allison Agus, Aurélie Magniez, Anne Aucouturier, Madeleine Spatz, Antoine Lefevre, Julien Kirchgesner, Nathalie Rolhion, Yazhou Wang, Aonghus Lavelle, Chloé Galbert, Gregory Da Costa, Maxime Poirier, Alexia Lapière, Julien Planchais, Petr Nádvorník, Peter Illes, Cyriane Oeuvray, Laura Creusot, Marie-Laure Michel, Nicolas Benech, Anne Bourrier, Isabelle Nion-Larmurier, Cecilia Landman, Mathias L Richard, Patrick Emond, Philippe Seksik, Laurent Beaugerie, Rafael Rose Arguello, David Moulin, Sridhar Mani, Zdenek Dvorák, Luis G Bermúdez-Humarán, Philippe Langella, Harry Sokol.
      OBJECTIVE: The extent to which tryptophan (Trp) metabolism alterations explain or influence the outcome of inflammatory bowel diseases (IBDs) is still unclear. However, several Trp metabolism end-products are essential to intestinal homeostasis. Here, we investigated the role of metabolites from the kynurenine pathway.DESIGN: Targeted quantitative metabolomics was performed in two large human IBD cohorts (1069 patients with IBD). Dextran sodium sulphate-induced colitis experiments in mice were used to evaluate effects of identified metabolites. In vitro, ex vivo and in vivo experiments were used to decipher mechanisms involved. Effects on energy metabolism were evaluated by different methods including Single Cell mEtabolism by profiling Translation inHibition.
    RESULTS: In mice and humans, intestinal inflammation severity negatively correlates with the amount of xanthurenic (XANA) and kynurenic (KYNA) acids. Supplementation with XANA or KYNA decreases colitis severity through effects on intestinal epithelial cells and T cells, involving Aryl hydrocarbon Receptor (AhR) activation and the rewiring of cellular energy metabolism. Furthermore, direct modulation of the endogenous tryptophan metabolism, using the recombinant enzyme aminoadipate aminotransferase (AADAT), responsible for the generation of XANA and KYNA, was protective in rodent colitis models.
    CONCLUSION: Our study identified a new mechanism linking Trp metabolism to intestinal inflammation and IBD. Bringing back XANA and KYNA has protective effects involving AhR and the rewiring of the energy metabolism in intestinal epithelial cells and CD4+ T cells. This study paves the way for new therapeutic strategies aiming at pharmacologically correcting its alterations in IBD by manipulating the endogenous metabolic pathway with AADAT.
    Keywords:  inflammatory bowel disease
    DOI:  https://doi.org/10.1136/gutjnl-2022-327337
  20. Anim Front. 2022 Oct;12(5): 8-10
    Immunometabolic considerations with regard to the domestic chicken, Gallus gallus.
    Ted H Elsasser.
      
    Keywords:  gut microbiome; immunometabolism; nutrient partitioning; nutrient sensing
    DOI:  https://doi.org/10.1093/af/vfac052
  21. Atherosclerosis. 2022 Oct 07. pii: S0021-9150(22)01454-X. [Epub ahead of print]
    ANGPTL3 deficiency associates with the expansion of regulatory T cells with reduced lipid content.
    Alessandra Pinzon Grimaldos, Ilenia Pacella, Simone Bini, Gloria Tucci, Ilenia Cammarata, Alessia Di Costanzo, Ilenia Minicocci, Laura D'Erasmo, Marcello Arca, Silvia Piconese.
      BACKGROUND AND AIMS: Angiopoietin-like 3 (ANGPTL3) regulates lipid and glucose metabolism. Loss-of-function mutations in its gene, leading to ANGPTL3 deficiency, cause in humans the familial combined hypolipidemia type 2 (FHBL2) phenotype, characterized by very low concentrations of circulating lipoproteins and reduced risk of atherosclerotic cardiovascular disease. Whether this condition is accompanied by immune dysfunctions is unknown. Regulatory T cells (Tregs) are CD4 T lymphocytes endowed with immune suppressive and atheroprotective functions and sensitive to metabolic signals. By investigating FHBL2, we explored the hypothesis that Tregs expand in response to extreme hypolipidemia, through a modulation of the Treg-intrinsic lipid metabolism.METHODS: Treg frequency, phenotype, and intracellular lipid content were assessed ex vivo from FHBL2 subjects and age- and sex-matched controls, through multiparameter flow cytometry. The response of CD4 T cells from healthy controls to marked hypolipidemia was tested in vitro in low-lipid culture conditions.
    RESULTS: The ex vivo analysis revealed that FHBL2 subjects showed higher percentages of Tregs with a phenotype undistinguishable from controls and with a lower lipid content, which directly correlated with the concentrations of circulating lipoproteins. In vitro, lipid restriction induced the upregulation of genes of the mevalonate pathway, including those involved in isoprenoid biosynthesis, and concurrently increased the expression of the Treg markers FOXP3 and Helios. The latter event was found to be prenylation-dependent, and likely related to increased IL-2 production and signaling.
    CONCLUSIONS: Our study demonstrates that FHBL2 is characterized by high Treg frequencies, a feature which may concur to the reduced atherosclerotic risk in this condition. Mechanistically, hypolipidemia may directly favor Treg expansion, through the induction of the mevalonate pathway and the prenylation of key signaling proteins.
    Keywords:  ANGPTL3; Genetic dyslipidemia; Lipid metabolism; Regulatory T cells
    DOI:  https://doi.org/10.1016/j.atherosclerosis.2022.09.014
  22. Anim Front. 2022 Oct;12(5): 37-45
    Modulating immunometabolism in transition dairy cows: the role of inflammatory lipid mediators.
    Maya Zachut, Joseph Tam, Genaro Andres Contreras.
      
    Keywords:  endocannabinoids; fatty acids; immune; niacin; oxylipid; transition dairy cow
    DOI:  https://doi.org/10.1093/af/vfac062
  23. Nat Chem Biol. 2022 Oct 20.
    Nitrosylation rewires metabolism.
    James A Nathan.
      
    DOI:  https://doi.org/10.1038/s41589-022-01169-2
  24. Front Immunol. 2022 ;13 954801
    Metabolomics-based investigation of SARS-CoV-2 vaccination (Sinovac) reveals an immune-dependent metabolite biomarker.
    Maozhang He, Yixuan Huang, Yun Wang, Jiling Liu, Maozhen Han, Yixuan Xiao, Na Zhang, Hongya Gui, Huan Qiu, Liqing Cao, Weihua Jia, Shenghai Huang.
      SARS-CoV-2 and its mutant strains continue to rapidly spread with high infection and fatality. Large-scale SARS-CoV-2 vaccination provides an important guarantee for effective resistance to existing or mutated SARS-CoV-2 virus infection. However, whether the host metabolite levels respond to SARS-CoV-2 vaccine-influenced host immunity remains unclear. To help delineate the serum metabolome profile of SARS-CoV-2 vaccinated volunteers and determine that the metabolites tightly respond to host immune antibodies and cytokines, in this study, a total of 59 sera samples were collected from 30 individuals before SARS-CoV-2 vaccination and from 29 COVID-19 vaccines 2 weeks after the two-dose vaccination. Next, untargeted metabolomics was performed and a distinct metabolic composition was revealed between the pre-vaccination (VB) group and two-dose vaccination (SV) group by partial least squares-discriminant and principal component analyses. Based on the criteria: FDR < 0.05, absolute log2 fold change greater than 0.25, and VIP >1, we found that L-glutamic acid, gamma-aminobutyric acid (GABA), succinic acid, and taurine showed increasing trends from SV to VB. Furthermore, SV-associated metabolites were mainly annotated to butanoate metabolism and glutamate metabolism pathways. Moreover, two metabolite biomarkers classified SV from VB individuals with an area under the curve (AUC) of 0.96. Correlation analysis identified a positive association between four metabolites enriched in glutamate metabolism and serum antibodies in relation to IgG, IgM, and IgA. These results suggest that the contents of gamma-aminobutyric acid and indole in serum could be applied as biomarkers in distinguishing vaccinated volunteers from the unvaccinated. What's more, metabolites such as GABA and taurine may serve as a metabolic target for adjuvant vaccines to boost the ability of the individuals to improve immunity.
    Keywords:  COVID-19; SARS-CoV-2 vaccination; antibodies and cytokines; metabolomic analysis; serum
    DOI:  https://doi.org/10.3389/fimmu.2022.954801
  25. Life Sci Alliance. 2022 Dec;pii: e202201493. [Epub ahead of print]5(12):
    Cross talk between glucose metabolism and immunosuppression in IFN-γ-primed mesenchymal stem cells.
    Mengwei Yao, Zhuo Chen, Xiao He, Jiaoyue Long, Xuewei Xia, Zhan Li, Yu Yang, Luoquan Ao, Wei Xing, Qizhou Lian, Huaping Liang, Xiang Xu.
      The immunosuppressive function "licensed" by IFN-γ is a vital attribute of mesenchymal stem cells (MSCs) widely used in the treatment of inflammatory diseases. However, the mechanism and impact of metabolic reprogramming on MSC immunomodulatory plasticity remain unclear. Here, we explored the mechanism by which glucose metabolism affects the immunomodulatory reprogramming of MSCs "licensed" by IFN-γ. Our data showed that glucose metabolism regulates the immunosuppressive function of human umbilical cord MSCs (hUC-MSCs) challenged by IFN-γ through the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Furthermore, ATP facilitated the cross talk between glucose metabolism and the JAK-STAT system, which stimulates the phosphorylation of JAK2 and STATs, as well as the expression of indoleamine 2, 3-dioxygenase and programmed cell death-1 ligand. Moreover, ATP synergistically enhanced the therapeutic efficacy of IFN-γ-primed hUC-MSCs against acute pneumonia in mice. These results indicate a novel cross talk between the immunosuppressive function, glucose metabolism, and mitochondrial oxidation and provide a novel targeting strategy to enhance the therapeutic efficacies of hUC-MSCs.
    DOI:  https://doi.org/10.26508/lsa.202201493
  26. EMBO J. 2022 Oct 17. e111173
    Prohibitin 1 regulates mtDNA release and downstream inflammatory responses.
    Hao Liu, Hualin Fan, Pengcheng He, Haixia Zhuang, Xiao Liu, Meiting Chen, Wenwei Zhong, Yi Zhang, Cien Zhen, Yanling Li, Huilin Jiang, Tian Meng, Yiming Xu, Guojun Zhao, Du Feng.
      Exposure of mitochondrial DNA (mtDNA) to the cytosol activates innate immune responses. But the mechanisms by which mtDNA crosses the inner mitochondrial membrane are unknown. Here, we found that the inner mitochondrial membrane protein prohibitin 1 (PHB1) plays a critical role in mtDNA release by regulating permeability across the mitochondrial inner membrane. Loss of PHB1 results in alterations in mitochondrial integrity and function. PHB1-deficient macrophages, serum from myeloid-specific PHB1 KO (Phb1MyeKO) mice, and peripheral blood mononuclear cells from neonatal sepsis patients show increased interleukin-1β (IL-1β) levels. PHB1 KO mice are also intolerant of lipopolysaccharide shock. Phb1-depleted macrophages show increased cytoplasmic release of mtDNA and inflammatory responses. This process is suppressed by cyclosporine A and VBIT-4, which inhibit the mitochondrial permeability transition pore (mPTP) and VDAC oligomerization. Inflammatory stresses downregulate PHB1 expression levels in macrophages. Under normal physiological conditions, the inner mitochondrial membrane proteins, AFG3L2 and SPG7, are tethered to PHB1 to inhibit mPTP opening. Downregulation of PHB1 results in enhanced interaction between AFG3L2 and SPG7, mPTP opening, mtDNA release, and downstream inflammatory responses.
    Keywords:  AFG3L2; MIMP; PHB; SPG7; mtDNA
    DOI:  https://doi.org/10.15252/embj.2022111173
  27. Front Pharmacol. 2022 ;13 938760
    Sodium butyrate attenuated diet-induced obesity, insulin resistance and inflammation partly by promoting fat thermogenesis via intro-adipose sympathetic innervation.
    Wanlong Zhu, Ke Peng, Yan Zhao, Changjing Xu, Xuemei Tao, Yuanzhi Liu, Yilan Huang, Xuping Yang.
      Emerging evidence suggests that butyrate, a short-chain fatty acid, may have beneficial effects on obesity and its associated metabolic comorbidities, but the related molecular mechanism is largely unknown. This study aims to investigate the role of butyrate in diet-induced obesity and metabolic disorders and the relevant regulatory mechanisms. Here, dietary supplementation with Sodium butyrate (NaB) was carried out in mice fed with a high-fat diet (HFD) or chow diet. At week 14, mice on HFD displayed an obese phenotype and down-regulated expression of thermogenic regulators including Ucp-1 and Pgc-1α in adipose tissue. Excitingly, NaB add-on treatment abolished these detrimental effects. Moreover, the obesity-induced insulin resistance, inflammation, fatty liver, and intestinal dysfunction were also attenuated by NaB administration. Mechanistically, NaB can promote fat thermogenesis via the increased local sympathetic innervation of adipose tissue, and blocking the β3-adrenergic signaling pathway by 6-hydroxydopamine abolished NaB-induced thermogenesis. Our study reveals a potential pharmacological target for NaB to combat obesity and metabolic disorders.
    Keywords:  adipose tissue; obesity; sodium butyrate; sympathetic innervation; thermogenesis
    DOI:  https://doi.org/10.3389/fphar.2022.938760
  28. Front Immunol. 2022 ;13 1012594
    cGAS/STING and innate brain inflammation following acute high-fat feeding.
    Sarah E Elzinga, Rosemary Henn, Benjamin J Murdock, Bhumsoo Kim, John M Hayes, Faye Mendelson, Ian Webber-Davis, Sam Teener, Crystal Pacut, Stephen I Lentz, Eva L Feldman.
      Obesity, prediabetes, and diabetes are growing in prevalence worldwide. These metabolic disorders are associated with neurodegenerative diseases, particularly Alzheimer's disease and Alzheimer's disease related dementias. Innate inflammatory signaling plays a critical role in this association, potentially via the early activation of the cGAS/STING pathway. To determine acute systemic metabolic and inflammatory responses and corresponding changes in the brain, we used a high fat diet fed obese mouse model of prediabetes and cognitive impairment. We observed acute systemic changes in metabolic and inflammatory responses, with impaired glucose tolerance, insulin resistance, and alterations in peripheral immune cell populations. Central inflammatory changes included microglial activation in a pro-inflammatory environment with cGAS/STING activation. Blocking gap junctions in neuron-microglial co-cultures significantly decreased cGAS/STING activation. Collectively these studies suggest a role for early activation of the innate immune system both peripherally and centrally with potential inflammatory crosstalk between neurons and glia.
    Keywords:  acute; cGAS/STING; high fat diet; innate inflammation; microglia
    DOI:  https://doi.org/10.3389/fimmu.2022.1012594
  29. Front Immunol. 2022 ;13 1012027
    Dysfunctional purinergic signaling correlates with disease severity in COVID-19 patients.
    Anna Julia Pietrobon, Roberta Andrejew, Ricardo Wesley Alberca Custódio, Luana de Mendonça Oliveira, Juliete Nathali Scholl, Franciane Mouradian Emidio Teixeira, Cyro Alves de Brito, Talita Glaser, Julia Kazmierski, Christine Goffinet, Anna Claudia Turdo, Tatiana Yendo, Valeria Aoki, Fabricio Figueiró, Ana Maria Battastini, Henning Ulrich, Gill Benard, Alberto Jose da Silva Duarte, Maria Notomi Sato.
      Ectonucleotidases modulate inflammatory responses by balancing extracellular ATP and adenosine (ADO) and might be involved in COVID-19 immunopathogenesis. Here, we explored the contribution of extracellular nucleotide metabolism to COVID-19 severity in mild and severe cases of the disease. We verified that the gene expression of ectonucleotidases is reduced in the whole blood of patients with COVID-19 and is negatively correlated to levels of CRP, an inflammatory marker of disease severity. In line with these findings, COVID-19 patients present higher ATP levels in plasma and reduced levels of ADO when compared to healthy controls. Cell type-specific analysis revealed higher frequencies of CD39+ T cells in severely ill patients, while CD4+ and CD8+ expressing CD73 are reduced in this same group. The frequency of B cells CD39+CD73+ is also decreased during acute COVID-19. Interestingly, B cells from COVID-19 patients showed a reduced capacity to hydrolyze ATP into ADP and ADO. Furthermore, impaired expression of ADO receptors and a compromised activation of its signaling pathway is observed in COVID-19 patients. The presence of ADO in vitro, however, suppressed inflammatory responses triggered in patients' cells. In summary, our findings support the idea that alterations in the metabolism of extracellular purines contribute to immune dysregulation during COVID-19, possibly favoring disease severity, and suggest that ADO may be a therapeutic approach for the disease.
    Keywords:  ATP; CD39; CD73; COVID-19; SARS-CoV-2; adenosine; purinergic signaling
    DOI:  https://doi.org/10.3389/fimmu.2022.1012027
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