bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2022–09–18
twenty-one papers selected by
Dylan Ryan, University of Cambridge
  1. Metabolic plasticity and regulation of T cell exhaustion.
  2. mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity.
  3. Physiological Convergence and Antagonism Between GR and PPARγ in Inflammation and Metabolism.
  4. Enhancing arginase 2 expression using target site blockers as a strategy to modulate macrophage phenotype.
  5. Tumor-associated macrophages are shaped by intratumoral high potassium via Kir2.1.
  6. Metabolic reprogramming and alteration of the redox state in hyper-productive MDCK cells for influenza a virus production.
  7. Effect of mycobacterial proteins that target mitochondria on the alveolar macrophages activation during Mycobacterium tuberculosis infection.
  8. Adipose tissue macrophages in remote modulation of hepatic glucose production.
  9. Identify metabolism-related genes IDO1, ALDH2, NCOA2, SLC7A5, SLC3A2, LDHB, and HPRT1 as potential prognostic markers and correlate with immune infiltrates in head and neck squamous cell carcinoma.
  10. NK cell immunometabolism as target for liver cancer therapy.
  11. Systemic consequences of abnormal cholesterol handling: Interdependent pathways of inflammation and dyslipidemia.
  12. The Amino Acid Homoarginine Inhibits Atherogenesis by Modulating T-Cell Function.
  13. Optimized protocol to isolate primary mouse peritoneal macrophage metabolites.
  14. Evaluation of Glutaminolysis in T Cells.
  15. Down-regulating Interleukin-22/Interleukin-22 binding protein axis promotes inflammation and aggravates diet-induced metabolic disorders.
  16. Inhibition of glutaminolysis ameliorates lupus by regulating T and B cell subsets and downregulating the mTOR/P70S6K/4EBP1 and NLRP3/caspase-1/IL-1β pathways in MRL/lpr mice.
  17. Glucose promotes regulatory T cell differentiation to maintain intestinal homeostasis.
  18. Skip the buffet, for SPARC's sake.
  19. Kinetic compartmentalization by unnatural reaction for itaconate production.
  20. SREBP2-dependent lipid gene transcription enhances the infection of human dendritic cells by Zika virus.
  21. Metabolic regulation of Cathepsin B in tumor macrophages drives their pro-metastatic function.
  1. Immunology. 2022 Sep 11.
    Metabolic plasticity and regulation of T cell exhaustion.
    Fei Li, Huiling Liu, Dan Zhang, Yanlin Ma, Bingdong Zhu.
      The metabolic reprogramming during T cell activation and differentiation affects T cell fate and immune responses. Cell metabolism may serve as the driving force that induces epigenetic modifications, contributing to regulating T cell differentiation. Persistent pathogen infection leads to T cell exhaustion, which is composed of two main subsets and with distinct metabolic characteristics. The progenitor exhausted T cells utilize mitochondrial fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) for energy, while terminally exhausted T cells mainly rely on glycolytic metabolism with impaired glycolysis and OXPHOS. Here, we compiled the latest research on how T cell metabolism defines differentiation, focusing on T cell exhaustion during chronic infections. In addition, metabolic-related factors including antigen stimulation signals strength, cytokines and epigenetics affecting T cell exhaustion were also reviewed. Furthermore, the intervention strategies on metabolism and epigenetics to reverse T cell exhaustion were discussed in detail, which may contribute to achieving the goal of prevention and treatment of T cell exhaustion.
    Keywords:  Chronic infection; Epigenetics; Glycolysis; T cell exhaustion; T cell metabolism
    DOI:  https://doi.org/10.1111/imm.13575
  2. Cell. 2022 Sep 08. pii: S0092-8674(22)01112-6. [Epub ahead of print]
    mTOR-regulated mitochondrial metabolism limits mycobacterium-induced cytotoxicity.
    Antonio J Pagán, Lauren J Lee, Joy Edwards-Hicks, Cecilia B Moens, David M Tobin, Elisabeth M Busch-Nentwich, Erika L Pearce, Lalita Ramakrishnan.
      Necrosis of macrophages in the granuloma, the hallmark immunological structure of tuberculosis, is a major pathogenic event that increases host susceptibility. Through a zebrafish forward genetic screen, we identified the mTOR kinase, a master regulator of metabolism, as an early host resistance factor in tuberculosis. We found that mTOR complex 1 protects macrophages from mycobacterium-induced death by enabling infection-induced increases in mitochondrial energy metabolism fueled by glycolysis. These metabolic adaptations are required to prevent mitochondrial damage and death caused by the secreted mycobacterial virulence determinant ESAT-6. Thus, the host can effectively counter this early critical mycobacterial virulence mechanism simply by regulating energy metabolism, thereby allowing pathogen-specific immune mechanisms time to develop. Our findings may explain why Mycobacterium tuberculosis, albeit humanity's most lethal pathogen, is successful in only a minority of infected individuals.
    Keywords:  ESAT-6 mitotoxicity; Mycobacterium marinum; Mycobacterium tuberculosis; granuloma necrosis; mTOR; macrophage death; mitochondrial metabolism; oxidative phosphorylation; tuberculosis; zebrafish TB model
    DOI:  https://doi.org/10.1016/j.cell.2022.08.018
  3. Adv Exp Med Biol. 2022 ;1390 123-141
    Physiological Convergence and Antagonism Between GR and PPARγ in Inflammation and Metabolism.
    Marija Dacic, Gayathri Shibu, Inez Rogatsky.
      Nuclear receptors (NRs) are transcription factors that modulate gene expression in a ligand-dependent manner. The ubiquitously expressed glucocorticoid receptor (GR) and peroxisome proliferator-activated receptor gamma (PPARγ) represent steroid (type I) and non-steroid (type II) classes of NRs, respectively. The diverse transcriptional and physiological outcomes of their activation are highly tissue-specific. For example, in subsets of immune cells, such as macrophages, the signaling of GR and PPARγ converges to elicit an anti-inflammatory phenotype; in contrast, in the adipose tissue, their signaling can lead to reciprocal metabolic outcomes. This review explores the cooperative and divergent outcomes of GR and PPARγ functions in different cell types and tissues, including immune cells, adipose tissue and the liver. Understanding the coordinated control of these NR pathways should advance studies in the field and potentially pave the way for developing new therapeutic approaches to exploit the GR:PPARγ crosstalk.
    Keywords:  Glucocorticoid receptor (GR); Immune cells; Inflammation; Metabolic tissues; Peroxisome proliferator-activated receptor gamma (PPARγ); Transcription
    DOI:  https://doi.org/10.1007/978-3-031-11836-4_7
  4. Mol Ther Nucleic Acids. 2022 Sep 13. 29 643-655
    Enhancing arginase 2 expression using target site blockers as a strategy to modulate macrophage phenotype.
    Chiara De Santi, Frances K Nally, Remsha Afzal, Conor P Duffy, Stephen Fitzsimons, Stephanie L Annett, Tracy Robson, Jennifer K Dowling, Sally-Ann Cryan, Claire E McCoy.
      Macrophages are plastic cells playing a crucial role in innate immunity. While fundamental in responding to infections, when persistently maintained in a pro-inflammatory state they can initiate and sustain inflammatory diseases. Therefore, a strategy that reprograms pro-inflammatory macrophages toward an anti-inflammatory phenotype could hold therapeutic potential in that context. We have recently shown that arginase 2 (Arg2), a mitochondrial enzyme involved in arginine metabolism, promotes the resolution of inflammation in macrophages and it is targeted by miR-155. Here, we designed and tested a target site blocker (TSB) that specifically interferes and blocks the interaction between miR-155 and Arg2 mRNA, leading to Arg2 increased expression and activity. In bone marrow-derived macrophages transfected with Arg2 TSB (in the presence or absence of the pro-inflammatory stimulus LPS), we observed an overall shift of the polarization status of macrophages toward an anti-inflammatory phenotype, as shown by significant changes in surface markers (CD80 and CD71), metabolic parameters (mitochondrial oxidative phosphorylation) and cytokines secretion (IL-1β, IL-6, and TNF). Moreover, in an in vivo model of LPS-induced acute inflammation, intraperitoneal administration of Arg2 TSB led to an overall decrease in systemic levels of pro-inflammatory cytokines. Overall, this proof-of-concept strategy represent a promising approach to modulating macrophage phenotype.
    Keywords:  MT: non-coding RNAs; PLGA; arginase 2; macrophages; miR-155; microRNAs; target site blocker; transfection
    DOI:  https://doi.org/10.1016/j.omtn.2022.08.004
  5. Cell Metab. 2022 Sep 07. pii: S1550-4131(22)00359-X. [Epub ahead of print]
    Tumor-associated macrophages are shaped by intratumoral high potassium via Kir2.1.
    Sheng Chen, Wenyu Cui, Zhexu Chi, Qian Xiao, Tianyi Hu, Qizhen Ye, Kaixiang Zhu, Weiwei Yu, Zhen Wang, Chengxuan Yu, Xiang Pan, Siqi Dai, Qi Yang, Jiacheng Jin, Jian Zhang, Mobai Li, Dehang Yang, Qianzhou Yu, Quanquan Wang, Xiafei Yu, Wei Yang, Xue Zhang, Junbin Qian, Kefeng Ding, Di Wang.
      The tumor microenvironment (TME) is a unique niche governed by constant crosstalk within and across all intratumoral cellular compartments. In particular, intratumoral high potassium (K+) has shown immune-suppressive potency on T cells. However, as a pan-cancer characteristic associated with local necrosis, the impact of this ionic disturbance on innate immunity is unknown. Here, we reveal that intratumoral high K+ suppresses the anti-tumor capacity of tumor-associated macrophages (TAMs). We identify the inwardly rectifying K+ channel Kir2.1 as a central modulator of TAM functional polarization in high K+ TME, and its conditional depletion repolarizes TAMs toward an anti-tumor state, sequentially boosting local anti-tumor immunity. Kir2.1 deficiency disturbs the electrochemically dependent glutamine uptake, engendering TAM metabolic reprogramming from oxidative phosphorylation toward glycolysis. Kir2.1 blockade attenuates both murine tumor- and patient-derived xenograft growth. Collectively, our findings reveal Kir2.1 as a determinant and potential therapeutic target for regaining the anti-tumor capacity of TAMs within ionic-imbalanced TME.
    Keywords:  Kir2.1; immunometabolism; potassium; tumor microenvironment; tumor-associated macrophage
    DOI:  https://doi.org/10.1016/j.cmet.2022.08.016
  6. Biologicals. 2022 Sep 13. pii: S1045-1056(22)00048-3. [Epub ahead of print]
    Metabolic reprogramming and alteration of the redox state in hyper-productive MDCK cells for influenza a virus production.
    Qian Ye, Xuping Liu, Yuxiang Wan, Wen-Song Tan, Liang Zhao.
      Influenza is a global public health issue leading to widespread morbidity and mortality with devastating economic loss annually. Madin-Darby Canine Kidney (MDCK) cell line has been a major cell line for influenza vaccine applications. Though many details of the host metabolic responses upon influenza A virus (IAV) infection have been documented, little is known about the metabolic reprogramming features of a hyper-productive host for IAV vaccine production. In this study, a MDCK cell clone H1 was shown to have a particular high productivity of 30 × 103 virions/cell. The glucose and amino acid metabolism of H1 were evaluated, indicating that the high producer had a particular metabolic reprogramming phenotype compared to its parental cell line (P): elevated glucose uptake, superior tricarboxylic acid cycle flux, moderate amino acid consumption, and better regulation of reactive oxygen species. Combined with the stronger mitochondrial function and mild antiviral and inflammatory responses characterized previously, our results indicated that the high producer had a sufficient intracellular energy supply, and balanced substrate distribution for IAV and host protein synthesis as well as the intracellular redox status. Understanding of these metabolic alterations paves the way for the rational cell line development and reasonable process optimization for high-yield influenza vaccine production.
    Keywords:  Influenza a virus; MDCK cells; Metabolic reprogramming; Productive cell line; Reactive oxygen species
    DOI:  https://doi.org/10.1016/j.biologicals.2022.08.004
  7. Exp Lung Res. 2022 Sep 14. 1-15
    Effect of mycobacterial proteins that target mitochondria on the alveolar macrophages activation during Mycobacterium tuberculosis infection.
    Iris Selene Paredes-González, Omar Emiliano Aparicio-Trejo, Octavio Ramos-Espinosa, Manuel Othoniel López-Torres, Milena Maya-Hoyos, Monserrat Mendoza-Trujillo, Alejandra Barrera-Rosales, Dulce Mata-Espinosa, Juan Carlos León-Contreras, José Pedraza-Chaverri, Clara Espitia, Rogelio Hernández-Pando.
      Purpose of the study: During the early and progressive (late) stages of murine experimental pulmonary tuberculosis, the differential activation of macrophages contributes to disease development by controlling bacterial growth and immune regulation. Mycobacterial proteins P27 and PE_PGRS33 can target the mitochondria of macrophages. This study aims to evaluate the effect of both proteins on macrophage activation during mycobacterial infection. Materials and methods: We assess both proteins for mitochondrial oxygen consumption, and morphological changes, as well as bactericide activity, production of metabolites, cytokines, and activation markers in infected MQs. The cell line MH-S was used for all the experiments. Results: We show that P27 and PE_PGRS33 proteins modified mitochondrial dynamics, oxygen consumption, bacilli growth, cytokine production, and some genes that contribute to macrophage alternative activation and mycobacterial intracellular survival. Conclusions: Our findings showed that these bacterial proteins partially contribute to promoting M2 differentiation by altering mitochondrial metabolic activity.
    Keywords:  Macrophage activation; mitochondria; mycobacterial protein; tuberculosis
    DOI:  https://doi.org/10.1080/01902148.2022.2120649
  8. Front Immunol. 2022 ;13 998947
    Adipose tissue macrophages in remote modulation of hepatic glucose production.
    Yan Tao, Quanhong Jiang, Qun Wang.
      Hepatic glucose production (HGP) is fine-regulated via glycogenolysis or gluconeogenesis to maintain physiological concentration of blood glucose during fasting-feeding cycle. Aberrant HGP leads to hyperglycemia in obesity-associated diabetes. Adipose tissue cooperates with the liver to regulate glycolipid metabolism. During these processes, adipose tissue macrophages (ATMs) change their profiles with various physio-pathological settings, producing diverse effects on HGP. Here, we briefly review the distinct phenotypes of ATMs under different nutrition states including feeding, fasting or overnutrition, and detail their effects on HGP. We discuss several pathways by which ATMs regulate hepatic gluconeogenesis or glycogenolysis, leading to favorable or unfavorable metabolic consequences. Furthermore, we summarize emerging therapeutic targets to correct metabolic disorders in morbid obesity or diabetes based on ATM-HGP axis. This review puts forward the importance and flexibility of ATMs in regulating HGP, proposing ATM-based HGP modulation as a potential therapeutic approach for obesity-associated metabolic dysfunction.
    Keywords:  adipose tissue; gluconeogenesis; hepatic glucose production; liver; macrophage
    DOI:  https://doi.org/10.3389/fimmu.2022.998947
  9. Front Immunol. 2022 ;13 955614
    Identify metabolism-related genes IDO1, ALDH2, NCOA2, SLC7A5, SLC3A2, LDHB, and HPRT1 as potential prognostic markers and correlate with immune infiltrates in head and neck squamous cell carcinoma.
    Ce Li, Shuai Chen, Wenming Jia, Wenming Li, Dongmin Wei, Shengda Cao, Ye Qian, Rui Guan, Heng Liu, Dapeng Lei.
      Hypopharyngeal squamous cell carcinoma (HSCC) is a kind of head and neck squamous cell carcinoma (HNSCC) with poor prognosis. Metabolic reprogramming may regulate the tumor microenvironment (TME) by adapting quickly to cellular stress and regulating immune response, but its role in HSCC has not been reported. We used the nCounter® Metabolic Pathways Panel to investigate metabolic reprogramming, cellular stress, and their relationship in HSCC tissues and adjacent normal tissues. Metabolism-related pathways nucleotide synthesis and glycolysis pathways were significantly upregulated, while amino acid synthesis and fatty acid oxidation pathways were significantly downregulated in HSCC tissues compared to adjacent normal tissues. There is a significant correlation between metabolism-related pathways and cellular stress pathways. Enrichment of immune cell and tumor infiltrating lymphocyte (TIL) analysis showed changes in immune responses between HSCC tissues and adjacent normal tissues. Overall survival analysis showed that upregulated genes CD276, LDHB, SLC3A2, EGFR, SLC7A5, and HPRT1 are potential unfavorable prognostic markers in HNSCC, while downregulated genes EEA1, IDO1, NCOA2, REST, CCL19, and ALDH2 are potential favorable prognostic markers in HNSCC. Moreover, metabolism-related genes IDO1, ALDH2, NCOA2, SLC7A5, SLC3A2, LDHB, and HPRT1 are correlated with immune infiltrates in HNSCC. These results suggest that metabolic reprogramming occurs and correlates with cellular stress and immune response in HSCC, which may help researchers understand mechanisms of metabolic reprogramming and develop effective immunotherapeutic strategies in HNSCC.
    Keywords:  cellular stress; hypopharyngeal squamous cell carcinoma; immune response; metabolic reprogramming; tumor infiltrating lymphocytes
    DOI:  https://doi.org/10.3389/fimmu.2022.955614
  10. Int Immunopharmacol. 2022 Sep 07. pii: S1567-5769(22)00677-4. [Epub ahead of print]112 109193
    NK cell immunometabolism as target for liver cancer therapy.
    Junqi Wang, Xiaolin Liu, Tianqiang Jin, Yuqing Cao, Yu Tian, Feng Xu.
      Natural killer (NK) cells are being used effectively as a potential candidate in tumor immunotherapy. However, the migration and transport of NK cells to solid tumors is inadequate. NK cell dysfunction, tumor invasiveness, and metastasis are associated with altered metabolism of NK cells in the liver cancer microenvironment. However, in liver cancers, metabolic impairment of NK cells is still not understood fully. Evidence from various sources has shown that the interaction of NK cell's immune checkpoints with its metabolic checkpoints is responsible for the regulation of the development and function of these cells. How immune checkpoints contribute to metabolic programming is still not fully understood, and how this can be beneficial needs a better understanding, but they are emerging to be incredibly compelling to rebuilding the function of NK cells in the tumor. It is expected to represent a potential aim that focuses on improving the efficacy of therapies based on NK cells for treating liver cancer. Here, the recent advancements made to understand the NK cell's metabolic reprogramming in liver cancer have been summarized, along with the possible interplay between the immune and the metabolic checkpoints in NK cell function. Finally, an overview of some potential metabolic-related targets that can be used for liver cancer therapy treatment has been presented.
    Keywords:  Immune checkpoints; Immunometabolism; Liver cancer; Natural killer cells
    DOI:  https://doi.org/10.1016/j.intimp.2022.109193
  11. Front Immunol. 2022 ;13 972140
    Systemic consequences of abnormal cholesterol handling: Interdependent pathways of inflammation and dyslipidemia.
    Ross O'Hagan, Alex R Berg, Christin G Hong, Philip M Parel, Nehal N Mehta, Heather L Teague.
      Metabolic conditions such as obesity and associated comorbidities are increasing in prevalence worldwide. In chronically inflamed pathologies, metabolic conditions are linked to early onset cardiovascular disease, which remains the leading cause of death despite decades of research. In recent years, studies focused on the interdependent pathways connecting metabolism and the immune response have highlighted that dysregulated cholesterol trafficking instigates an overactive, systemic inflammatory response, thereby perpetuating early development of cardiovascular disease. In this review, we will discuss the overlapping pathways connecting cholesterol trafficking with innate immunity and present evidence that cholesterol accumulation in the bone marrow may drive systemic inflammation in chronically inflamed pathologies. Lastly, we will review the current therapeutic strategies that target both inflammation and cholesterol transport, and how biologic therapy restores lipoprotein function and mitigates the immune response.
    Keywords:  cholesterol handling; dyslipidemia; immunometabolism; inflammation; psoriasis
    DOI:  https://doi.org/10.3389/fimmu.2022.972140
  12. Circ Res. 2022 Sep 14. 101161CIRCRESAHA122321094
    The Amino Acid Homoarginine Inhibits Atherogenesis by Modulating T-Cell Function.
    Katrin Nitz, Michael Lacy, Mariaelvy Bianchini, Kanin Wichapong, Irem Avcilar Kücükgöze, Cecilia A Bonfiglio, Roberta Migheli, Yuting Wu, Carina Burger, Yuanfang Li, Ignasi Forné, Constantin Ammar, Aleksandar Janjic, Sarajo Mohanta, Johan Duchene, Johan W M Heemskerk, Remco T A Megens, Edzard Schwedhelm, Stephan Huveneers, Craig A Lygate, Donato Santovito, Ralf Zimmer, Axel Imhof, Christian Weber, Esther Lutgens, Dorothee Atzler.
       BACKGROUND: Amino acid metabolism is crucial for inflammatory processes during atherogenesis. The endogenous amino acid homoarginine is a robust biomarker for cardiovascular outcome and mortality with high levels being protective. However, the underlying mechanisms remain elusive. We investigated the effect of homoarginine supplementation on atherosclerotic plaque development with a particular focus on inflammation.
    METHODS: Female ApoE-deficient mice were supplemented with homoarginine (14 mg/L) in drinking water starting 2 weeks before and continuing throughout a 6-week period of Western-type diet feeding. Control mice received normal drinking water. Immunohistochemistry and flow cytometry were used for plaque- and immunological phenotyping. T cells were characterized using mass spectrometry-based proteomics, by functional in vitro approaches, for example, proliferation and migration/chemotaxis assays as well as by super-resolution microscopy.
    RESULTS: Homoarginine supplementation led to a 2-fold increase in circulating homoarginine concentrations. Homoarginine-treated mice exhibited reduced atherosclerosis in the aortic root and brachiocephalic trunk. A substantial decrease in CD3+ T cells in the atherosclerotic lesions suggested a T-cell-related effect of homoarginine supplementation, which was mainly attributed to CD4+ T cells. Macrophages, dendritic cells, and B cells were not affected. CD4+ T-cell proteomics and subsequent pathway analysis together with in vitro studies demonstrated that homoarginine profoundly modulated the spatial organization of the T-cell actin cytoskeleton and increased filopodia formation via inhibition of Myh9 (myosin heavy chain 9). Further mechanistic studies revealed an inhibition of T-cell proliferation as well as a striking impairment of the migratory capacities of T cells in response to relevant chemokines by homoarginine, all of which likely contribute to its atheroprotective effects.
    CONCLUSIONS: Our study unravels a novel mechanism by which the amino acid homoarginine reduces atherosclerosis, establishing that homoarginine modulates the T-cell cytoskeleton and thereby mitigates T-cell functions important during atherogenesis. These findings provide a molecular explanation for the beneficial effects of homoarginine in atherosclerotic cardiovascular disease.
    Keywords:  amino acid; atherosclerosis; biomarker; cardiovascular disease; homoarginine
    DOI:  https://doi.org/10.1161/CIRCRESAHA.122.321094
  13. STAR Protoc. 2022 Sep 13. pii: S2666-1667(22)00548-2. [Epub ahead of print]3(4): 101668
    Optimized protocol to isolate primary mouse peritoneal macrophage metabolites.
    Adam De Jesus, Carolina M Pusec, Tivoli Nguyen, Farnaz Keyhani-Nejad, Peng Gao, Samuel E Weinberg, Hossein Ardehali.
      Peritoneal macrophages (PMs) have been shown to have higher stability compared to other macrophage subtypes. However, obtaining enough PMs from a single mouse is often a limitation for metabolomics analysis. Here, we describe a protocol to isolate metabolites from a small number of mouse primary PMs for 13C-stable glucose tracing and metabolomics. Our protocol uses X for metabolite extraction instead of methanol. Our protocol can consistently extract metabolites from low cell number samples with fewer steps than methanol-based approaches. For complete details on the use and execution of this protocol, please refer to De Jesus et al., (2022).
    Keywords:  Cell isolation; Immunology; Mass spectrometry; Metabolism; Metabolomics
    DOI:  https://doi.org/10.1016/j.xpro.2022.101668
  14. Curr Protoc. 2022 Sep;2(9): e540
    Evaluation of Glutaminolysis in T Cells.
    Masaki Tajima, Warren Strober.
      The activity of living cells is necessarily dependent on the amount of available bioenergy. In T cells, the latter is mainly derived from ATP, a molecular energy "coin" generated by one of several metabolic processes that differ in their ability to satisfy energy demand. Thus, whereas naïve or quiescent T cells efficiently utilize oxidative phosphorylation to generate ATP, T cells subjected to antigenic stimulation followed by clonal expansion and cytokine production meet their increased need for energy by supplementing ATP generation by oxidative phosphorylation with ATP generation by glycolysis. Yet additional need for ATP can be met by other basic biologic sources of energy such as glutamine, an amino acid that is metabolized through a process called glutaminolysis to result in end products that flows into the TCA cycle and augment ATP generation by oxidative phosphorylation. It is now possible to track the dominant energy supplying processes (i.e., the ATP generation process) in differentiating or activated T cells in a real-time manner. Here, we provide one element of such tracking by describing protocols for the assessment of the contribution of glutaminolysis to overall ATP production within different T cell subsets. © 2022 Wiley Periodicals LLC. This article has been contributed to by US Government employees and their work is in the public domain in the USA. Basic Protocol 1: Evaluation of the role of glutaminolysis during T cell activation/differentiation Basic Protocol 2: Evaluation of the role of glutaminolysis in T cell responses utilizing glutaminolysis inhibitors Basic Protocol 3: Evaluation of the effect of glutaminolysis on cellular oxidative phosphorylation/glycolysis.
    Keywords:  T cell; glutaminolysis; glycolysis; oxidative phosphorylation
    DOI:  https://doi.org/10.1002/cpz1.540
  15. Mol Cell Endocrinol. 2022 Sep 12. pii: S0303-7207(22)00224-6. [Epub ahead of print] 111776
    Down-regulating Interleukin-22/Interleukin-22 binding protein axis promotes inflammation and aggravates diet-induced metabolic disorders.
    Jiayi Gu, Ping Zhou, Ying Liu, Qiao Xu, Xi Chen, Mengqi Chen, Chen Lu, Chen Qu, Yanli Tong, Qinghua Yu, Xiang Lu, Chunzhao Yu, Zhengxia Liu.
      The prevalence of metabolic diseases has become a severe public health problem. Previously, we reported that Interleukin-22 (IL-22) was independently associated with type 2 diabetes mellitus and cardiovascular disease, and could protect endothelial cells from glucose- and lysophosphatidylcholine-induced injury. The activity of IL-22 is strongly regulated by IL-22-binding protein (IL-22BP). The aim of this investigation was to determine the effect of IL-22/IL-22BP axis on glucolipid metabolism. Serum IL-22 and IL-22BP expression in metabolic syndrome (MetS) patients and healthy controls was examined. IL-22BP-knockout (IL-22ra2-/-) and wild-type (WT) mice were fed with control diet (CTD) and high-fat diet (HFD) for 12 weeks. The IL-22 related pathway expression, the glucolipid metabolism, and inflammatory markers in mice were examined. Serum IL-22 and IL-22BP levels were found significantly increased in MetS patients (p < 0.001). IL-22BP deficiency down-regulated IL-22-related pathway, aggravated glucolipid metabolism disorder, and promoted inflammation in mice. Collectively, this work deepens the understanding of the relationship between IL-22/IL-22BP axis and metabolism disorders, and identified that down-regulation of IL-22/IL-22BP axis promotes metabolic disorders in mice.
    Keywords:  Glucolipid metabolism; IL-22/IL-22BP axis; Inflammation; Metabolic syndrome
    DOI:  https://doi.org/10.1016/j.mce.2022.111776
  16. Int Immunopharmacol. 2022 Sep 13. pii: S1567-5769(22)00617-8. [Epub ahead of print]112 109133
    Inhibition of glutaminolysis ameliorates lupus by regulating T and B cell subsets and downregulating the mTOR/P70S6K/4EBP1 and NLRP3/caspase-1/IL-1β pathways in MRL/lpr mice.
    Xiaomei Zhang, Gang Wang, Ying Bi, Zhihang Jiang, Xiaofei Wang.
       BACKGROUND AND AIM OF THE STUDY: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by lymphocyte imbalance. The differentiation and function of T and B cells receive regulation from intracellular energy metabolism. Herein, we aimed to investigate glutamine metabolism levels in SLE and explore the effects of modulating glutamine metabolism on T and B cell subsets and related signaling pathways in MRL/lpr lupus mice.
    METHODS: We assessed intracellular glutamine metabolism in SLE patients and MRL/lpr mice by measuring intracellular glutamate and Glutaminase 1 (GLS1) protein levels. Intraperitoneal injection of the GLS1 inhibitor CB839 was performed to reduce glutamine metabolism and lupus-like manifestations in MRL/lpr mice were evaluated. The proportions and numbers of T and B cell subsets were determinedvia flow cytometry. Pathway-related proteins were detected using western blotting.
    RESULTS: In this study, we reported that glutamine metabolism levels were aberrantly elevated in splenic mononuclear cells from MRL/lpr lupus mice, as well as in peripheral blood mononuclear cells (PBMCs) of SLE patients. Inhibition of glutamine metabolism by CB839 treatment for 8 weeks alleviated the lupus-like manifestations in MRL/lpr mice, including the kidney lesions, urinary protein/creatinine ratio, spleen index, and serum IgG1. Meanwhile, CB839 treatment ameliorated the depletion of IL-10 producing B cells (B10) and adjusted the Th1/TH2 and TH17/Treg imbalance. The inhibition of GLS1 by CB839 reduced the numbers of follicular helper T (TfH) cells and activated B cells in lupus mice. The proportions of mature B cells and plasma cells were not affected. Furthermore, the hyperactivated mTOR/P70S6K/4EBP1 and NLRP3/caspase-1/IL-1β pathways in MRL/lpr mice were reversed by CB839 treatment.
    CONCLUSION: Our study confirmed the presence of abnormal intracellular glutamine metabolism in SLE and revealed potential therapeutic targets for this disease.
    Keywords:  B cell subsets; CB839; Glutamine metabolism; Lupus nephritis; NLRP3 pathway; Systemic lupus erythematosus; T cell subsets; mTOR pathway
    DOI:  https://doi.org/10.1016/j.intimp.2022.109133
  17. iScience. 2022 Sep 16. 25(9): 105004
    Glucose promotes regulatory T cell differentiation to maintain intestinal homeostasis.
    Yu Yu, Wenjing Yang, Tianming Yu, Xiaojing Zhao, Zheng Zhou, Yanbo Yu, Lifeng Xiong, Hui Yang, Anthony J Bilotta, Suxia Yao, George Golovko, Agustin Plasencia, Francisco J Quintana, Liang Zhou, Yanqing Li, Yingzi Cong.
      Glucose, the critical energy source in the human body, is considered a potential risk factor in various autoimmune diseases when consumed in high amounts. However, the roles of glucose at moderate doses in the regulation of autoimmune inflammatory diseases and CD4+ T cell responses are controversial. Here, we show that while glucose at a high concentration (20% w/v) promotes intestinal inflammation, it suppresses colitis at a moderate dose (6% w/v), which increases the proportion of intestinal regulatory T (Treg) cells but does not affect effector CD4+ T cells. Glucose treatment promotes Treg cell differentiation but it does not affect Treg stability. Feeding glucose alters gut microbiota compositions, which are not involved in the glucose induction of Treg cells. Glucose promotes aryl hydrocarbon receptor (AhR) activation to induce Treg polarization. These findings reveal the different effects of glucose at different doses on the intestinal immune response.
    Keywords:  Biological sciences; Cell biology; Components of the immune system; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2022.105004
  18. Immunity. 2022 Sep 13. pii: S1074-7613(22)00405-8. [Epub ahead of print]55(9): 1583-1585
    Skip the buffet, for SPARC's sake.
    Lukai Zhai, Connie M Krawczyk.
      Caloric restriction (CR) reduces inflammation and the incidence of chronic diseases, thereby extending healthspan and lifespan. In this issue of Immunity, Ryu et al. (2022) propose that reduction of SPARC, a matricellular protein, during CR offers beneficial effects by reducing SPARC-driven inflammatory phenotypes in macrophages.
    DOI:  https://doi.org/10.1016/j.immuni.2022.08.012
  19. Nat Commun. 2022 Sep 12. 13(1): 5353
    Kinetic compartmentalization by unnatural reaction for itaconate production.
    Dae-Yeol Ye, Myung Hyun Noh, Jo Hyun Moon, Alfonsina Milito, Minsun Kim, Jeong Wook Lee, Jae-Seong Yang, Gyoo Yeol Jung.
      Physical compartmentalization of metabolism using membranous organelles in eukaryotes is helpful for chemical biosynthesis to ensure the availability of substrates from competitive metabolic reactions. Bacterial hosts lack such a membranous system, which is one of the major limitations for efficient metabolic engineering. Here, we employ kinetic compartmentalization with the introduction of an unnatural enzymatic reaction by an engineered enzyme as an alternative strategy to enable substrate availability from competitive reactions through kinetic isolation of metabolic pathways. As a proof of concept, we kinetically isolate the itaconate synthetic pathway from the tricarboxylic acid cycle in Escherichia coli, which is natively separated by mitochondrial membranes in Aspergillus terreus. Specifically, 2-methylcitrate dehydratase is engineered to alternatively catalyze citrate and kinetically secure cis-aconitate for efficient production using a high-throughput screening system. Itaconate production can be significantly improved with kinetic compartmentalization and its strategy has the potential to be widely applicable.
    DOI:  https://doi.org/10.1038/s41467-022-33033-1
  20. Nat Commun. 2022 Sep 12. 13(1): 5341
    SREBP2-dependent lipid gene transcription enhances the infection of human dendritic cells by Zika virus.
    Emilie Branche, Ying-Ting Wang, Karla M Viramontes, Joan M Valls Cuevas, Jialei Xie, Fernanda Ana-Sosa-Batiz, Norazizah Shafee, Sascha H Duttke, Rachel E McMillan, Alex E Clark, Michael N Nguyen, Aaron F Garretson, Jan J Crames, Nathan J Spann, Zhe Zhu, Jeremy N Rich, Deborah H Spector, Christopher Benner, Sujan Shresta, Aaron F Carlin.
      The emergence of Zika virus (ZIKV) as a global health threat has highlighted the unmet need for ZIKV-specific vaccines and antiviral treatments. ZIKV infects dendritic cells (DC), which have pivotal functions in activating innate and adaptive antiviral responses; however, the mechanisms by which DC function is subverted to establish ZIKV infection are unclear. Here we develop a genomics profiling method that enables discrete analysis of ZIKV-infected versus neighboring, uninfected primary human DCs to increase the sensitivity and specificity with which ZIKV-modulated pathways can be identified. The results show that ZIKV infection specifically increases the expression of genes enriched for lipid metabolism-related functions. ZIKV infection also increases the recruitment of sterol regulatory element-binding protein (SREBP) transcription factors to lipid gene promoters, while pharmacologic inhibition or genetic silencing of SREBP2 suppresses ZIKV infection of DCs. Our data thus identify SREBP2-activated transcription as a mechanism for promoting ZIKV infection amenable to therapeutic targeting.
    DOI:  https://doi.org/10.1038/s41467-022-33041-1
  21. Cancer Cell. 2022 Sep 02. pii: S1535-6108(22)00391-9. [Epub ahead of print]
    Metabolic regulation of Cathepsin B in tumor macrophages drives their pro-metastatic function.
    Romana Vidergar, Subhra K Biswas.
      Tumor macrophages possess tumor-promoting functions, but the mechanism regulating such functions is poorly understood. Providing new insight into such mechanism, Shi et al. in this issue of Cancer Cell identify how metabolic regulation of Cathepsin B and its O-GlcNAcylation by lysosomal O-GlcNAc transferase (OGT) in macrophages drives pro-metastatic function.
    DOI:  https://doi.org/10.1016/j.ccell.2022.08.023
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