bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2022‒07‒24
34 papers selected by
Dylan Ryan
University of Cambridge
  1. TREM2 macrophages induced by human lipids drive inflammation in acne lesions.
  2. Leptin receptor signaling sustains metabolic fitness of alveolar macrophages to attenuate pulmonary inflammation.
  3. T-bet+ B cells accumulate in adipose tissue and exacerbate metabolic disorder during obesity.
  4. TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages.
  5. Obesity-Mediated Immune Modulation: One Step Forward, (Th)2 Steps Back.
  6. Editorial: T Cell Metabolism in Infection.
  7. Glycolysis in Innate Immune Cells Contributes to Autoimmunity.
  8. ISG15 deficiency features a complex cellular phenotype that responds to treatment with itaconate and derivatives.
  9. TNFR2 Costimulation Differentially Impacts Regulatory and Conventional CD4+ T-Cell Metabolism.
  10. SARS-CoV-2 Achieves Immune Escape by Destroying Mitochondrial Quality: Comprehensive Analysis of the Cellular Landscapes of Lung and Blood Specimens From Patients With COVID-19.
  11. Role of succinic acid in the regulation of sepsis.
  12. Trained immunity of alveolar macrophages requires metabolic rewiring and type 1 interferon signaling.
  13. Interplay between Cellular Metabolism and DNA viruses.
  14. Altered adipose tissue macrophage populations in people with HIV on integrase inhibitor-containing ART.
  15. EBV Infection and Its Regulated Metabolic Reprogramming in Nasopharyngeal Tumorigenesis.
  16. T Cell-Intrinsic Vitamin A Metabolism and Its Signaling Are Targets for Memory T Cell-Based Cancer Immunotherapy.
  17. Biology of macrophage fate decision: Implication in inflammatory disorders.
  18. Dimethyl itaconate reprograms neurotoxic to neuroprotective primary astrocytes through the regulation of NLRP3 inflammasome and Nrf-2/HO-1 pathways.
  19. Reprogramming Macrophage Metabolism and its Effect on NLRP3 Inflammasome Activation in Sepsis.
  20. Transgenic expression of IL-7 regulates CAR-T cell metabolism and enhances in vivo persistence against tumor cells.
  21. Sepsis, pyruvate, and mitochondria energy supply chain shortage.
  22. Functional Restoration of Exhausted CD8 T Cells in Chronic HIV-1 Infection by Targeting Mitochondrial Dysfunction.
  23. Mucolytic bacteria license pathobionts to acquire host-derived nutrients during dietary nutrient restriction.
  24. Controlling Herpes Simplex Virus-Induced Immunoinflammatory Lesions Using Metabolic Therapy: a Comparison of 2-Deoxy-d-Glucose with Metformin.
  25. Mitochondrial Function and Microbial Metabolites as Central Regulators of Intestinal Immune Responses and Cancer.
  26. Inhibition of NLRP3-mediated crosstalk between hepatocytes and liver macrophages by geniposidic acid alleviates cholestatic liver inflammatory injury.
  27. The inhibition of GLUT1-induced glycolysis in macrophage by phloretin participates in the protection during acute lung injury.
  28. microRNA-103a-3p promotes inflammation and fibrosis in nonalcoholic fatty liver disease by targeting HBP1.
  29. Identification and receptor mechanism of TIR-catalyzed small molecules in plant immunity.
  30. Accumulation of Intracellular Ferrous Iron in Inflammatory-Activated Macrophages.
  31. TIR-catalyzed ADP-ribosylation reactions produce signaling molecules for plant immunity.
  32. Nutrient Condition in the Microenvironment Determines Essential Metabolisms of CD8+ T Cells for Enhanced IFNγ Production by Metformin.
  33. EBNA2-EBF1 complexes promote MYC expression and metabolic processes driving S-phase progression of Epstein-Barr virus-infected B cells.
  34. Resistance exercise with different workloads have distinct effects on cellular respiration of peripheral blood mononuclear cells.
  1. Sci Immunol. 2022 Jul 22. 7(73): eabo2787
    TREM2 macrophages induced by human lipids drive inflammation in acne lesions.
    Tran H Do, Feiyang Ma, Priscila R Andrade, Rosane Teles, Bruno J de Andrade Silva, Chanyue Hu, Alejandro Espinoza, Jer-En Hsu, Chun-Seok Cho, Myungjin Kim, Jingyue Xi, Xianying Xing, Olesya Plazyo, Lam C Tsoi, Carol Cheng, Jenny Kim, Bryan D Bryson, Alan M O'Neill, Marco Colonna, Johann E Gudjonsson, Eynav Klechevsky, Jun Hee Lee, Richard L Gallo, Barry R Bloom, Matteo Pellegrini, Robert L Modlin.
      Acne affects 1 in 10 people globally, often resulting in disfigurement. The disease involves excess production of lipids, particularly squalene, increased growth of Cutibacterium acnes, and a host inflammatory response with foamy macrophages. By combining single-cell and spatial RNA sequencing as well as ultrahigh-resolution Seq-Scope analyses of early acne lesions on back skin, we identified TREM2 macrophages expressing lipid metabolism and proinflammatory gene programs in proximity to hair follicle epithelium expressing squalene epoxidase. We established that the addition of squalene induced differentiation of TREM2 macrophages in vitro, which were unable to kill C. acnes. The addition of squalene to macrophages inhibited induction of oxidative enzymes and scavenged oxygen free radicals, providing an explanation for the efficacy of topical benzoyl peroxide in the clinical treatment of acne. The present work has elucidated the mechanisms by which TREM2 macrophages and unsaturated lipids, similar to their involvement in atherosclerosis, may contribute to the pathogenesis of acne.
    DOI:  https://doi.org/10.1126/sciimmunol.abo2787
  2. Sci Adv. 2022 Jul 15. 8(28): eabo3064
    Leptin receptor signaling sustains metabolic fitness of alveolar macrophages to attenuate pulmonary inflammation.
    Ziyi Guo, Haoqi Yang, Jing-Ren Zhang, Wenwen Zeng, Xiaoyu Hu.
      Alveolar macrophages (AMs) are critical mediators of pulmonary inflammation. Given the unique lung tissue environment, whether there exist AM-specific mechanisms that control inflammation is not known. Here, we found that among various tissue-resident macrophage populations, AMs specifically expressed Lepr, encoding receptor for a key metabolic hormone leptin. AM-intrinsic Lepr signaling attenuated pulmonary inflammation in vivo, manifested as subdued acute lung injury yet compromised host defense against Streptococcus pneumoniae infection. Lepr signaling protected AMs from necroptosis and thus constrained neutrophil recruitment and tissue damage secondary to release of proinflammatory cytokine interleukin-1α. Mechanistically, Lepr signaling sustained activation of adenosine monophosphate-activated protein kinase in a Ca2+ influx-dependent manner and rewired cellular metabolism, thus preventing excessive lipid droplet formation and overloaded metabolic stress in a lipid-rich alveolar microenvironment. In conclusion, our results defined AM-expressed Lepr as a metabolic checkpoint of pulmonary inflammation and exemplified a macrophage tissue adaptation strategy for maintenance of immune homeostasis.
    DOI:  https://doi.org/10.1126/sciadv.abo3064
  3. Cell Metab. 2022 Jul 18. pii: S1550-4131(22)00301-1. [Epub ahead of print]
    T-bet+ B cells accumulate in adipose tissue and exacerbate metabolic disorder during obesity.
    Thomas Hägglöf, Carlo Vanz, Abigail Kumagai, Elizabeth Dudley, Vanessa Ortega, McKenzie Siller, Raksha Parthasarathy, Josh Keegan, Abigail Koenigs, Travis Shute, Elizabeth A Leadbetter.
      Obesity is accompanied by inflammation in adipose tissue, impaired glucose tolerance, and changes in adipose leukocyte populations. These studies of adipose tissue from humans and mice revealed that increased frequencies of T-bet+ B cells in adipose tissue depend on invariant NKT cells and correlate with weight gain during obesity. Transfer of B cells enriched for T-bet+ cells exacerbates metabolic disorder in obesity, while ablation of Tbx21 specifically in B cells reduces serum IgG2c levels, inflammatory cytokines, and inflammatory macrophages in adipose tissue, ameliorating metabolic symptoms. Furthermore, transfer of serum or purified IgG from HFD mice restores metabolic disease in T-bet+ B cell-deficient mice, confirming T-bet+ B cell-derived IgG as a key mediator of inflammation during obesity. Together, these findings reveal an important pathological role for T-bet+ B cells that should inform future immunotherapy design in type 2 diabetes and other inflammatory conditions.
    Keywords:  B cells; CD11c(+) T-bet(+) B cells; IgG2c; adipose tissue; glucose intolerance; iNKT cells; inflammation; metabolic disorder; obesity; type 2 diabetes
    DOI:  https://doi.org/10.1016/j.cmet.2022.07.002
  4. Nat Metab. 2022 Jul 21.
    TFEB induces mitochondrial itaconate synthesis to suppress bacterial growth in macrophages.
    Ev-Marie Schuster, Maximilian W Epple, Katharina M Glaser, Michael Mihlan, Kerstin Lucht, Julia A Zimmermann, Anna Bremser, Aikaterini Polyzou, Nadine Obier, Nina Cabezas-Wallscheid, Eirini Trompouki, Andrea Ballabio, Jörg Vogel, Joerg M Buescher, Alexander J Westermann, Angelika S Rambold.
      Successful elimination of bacteria in phagocytes occurs in the phago-lysosomal system, but also depends on mitochondrial pathways. Yet, how these two organelle systems communicate is largely unknown. Here we identify the lysosomal biogenesis factor transcription factor EB (TFEB) as regulator for phago-lysosome-mitochondria crosstalk in macrophages. By combining cellular imaging and metabolic profiling, we find that TFEB activation, in response to bacterial stimuli, promotes the transcription of aconitate decarboxylase (Acod1, Irg1) and synthesis of its product itaconate, a mitochondrial metabolite with antimicrobial activity. Activation of the TFEB-Irg1-itaconate signalling axis reduces the survival of the intravacuolar pathogen Salmonella enterica serovar Typhimurium. TFEB-driven itaconate is subsequently transferred via the Irg1-Rab32-BLOC3 system into the Salmonella-containing vacuole, thereby exposing the pathogen to elevated itaconate levels. By activating itaconate production, TFEB selectively restricts proliferating Salmonella, a bacterial subpopulation that normally escapes macrophage control, which contrasts TFEB's role in autophagy-mediated pathogen degradation. Together, our data define a TFEB-driven metabolic pathway between phago-lysosomes and mitochondria that restrains Salmonella Typhimurium burden in macrophages in vitro and in vivo.
    DOI:  https://doi.org/10.1038/s42255-022-00605-w
  5. Front Immunol. 2022 ;13 932893
    Obesity-Mediated Immune Modulation: One Step Forward, (Th)2 Steps Back.
    Viviane Schmidt, Andrew E Hogan, Padraic G Fallon, Christian Schwartz.
      Over the past decades, the relationship between the immune system and metabolism has become a major research focus. In this arena of immunometabolism the capacity of adipose tissue to secrete immunomodulatory molecules, including adipokines, within the underlying low-grade inflammation during obesity brought attention to the impact obesity has on the immune system. Adipokines, such as leptin and adiponectin, influence T cell differentiation into different T helper subsets and their activation during immune responses. Furthermore, within the cellular milieu of adipose tissue nutrient availability regulates differentiation and activation of T cells and changes in cellular metabolic pathways. Upon activation, T cells shift from oxidative phosphorylation to oxidative glycolysis, while the differential signaling of the kinase mammalian target of rapamycin (mTOR) and the nuclear receptor PPARγ, amongst others, drive the subsequent T cell differentiation. While the mechanisms leading to a shift from the typical type 2-dominated milieu in lean people to a Th1-biased pro-inflammatory environment during obesity are the subject of extensive research, insights on its impact on peripheral Th2-dominated immune responses become more evident. In this review, we will summarize recent findings of how Th2 cells are metabolically regulated during obesity and malnutrition, and how these states affect local and systemic Th2-biased immune responses.
    Keywords:  T helper cell 2; Th2 (type-2) immune responses; adipokine cytokines; helminth; malnutrition; metabolism; obesity
    DOI:  https://doi.org/10.3389/fimmu.2022.932893
  6. Front Immunol. 2022 ;13 958276
    Editorial: T Cell Metabolism in Infection.
    Duojiao Wu, Jin-Fu Xu.
      
    Keywords:  Immune function; Infection; Metabolism; T cell; pathogen
    DOI:  https://doi.org/10.3389/fimmu.2022.958276
  7. Front Immunol. 2022 ;13 920029
    Glycolysis in Innate Immune Cells Contributes to Autoimmunity.
    Yue Xu, Yongkang Chen, Xuan Zhang, Jie Ma, Yudong Liu, Liyan Cui, Fang Wang.
      Autoimmune diseases (AIDs) refer to connective tissue inflammation caused by aberrant autoantibodies resulting from dysfunctional immune surveillance. Most of the current treatments for AIDs use non-selective immunosuppressive agents. Although these therapies successfully control the disease process, patients experience significant side effects, particularly an increased risk of infection. There is a great need to study the pathogenesis of AIDs to facilitate the development of selective inhibitors for inflammatory signaling to overcome the limitations of traditional therapies. Immune cells alter their predominant metabolic profile from mitochondrial respiration to glycolysis in AIDs. This metabolic reprogramming, known to occur in adaptive immune cells, i.e., B and T lymphocytes, is critical to the pathogenesis of connective tissue inflammation. At the cellular level, this metabolic switch involves multiple signaling molecules, including serine-threonine protein kinase, mammalian target of rapamycin, and phosphoinositide 3-kinase. Although glycolysis is less efficient than mitochondrial respiration in terms of ATP production, immune cells can promote disease progression by enhancing glycolysis to satisfy cellular functions. Recent studies have shown that active glycolytic metabolism may also account for the cellular physiology of innate immune cells in AIDs. However, the mechanism by which glycolysis affects innate immunity and participates in the pathogenesis of AIDs remains to be elucidated. Therefore, we reviewed the molecular mechanisms, including key enzymes, signaling pathways, and inflammatory factors, that could explain the relationship between glycolysis and the pro-inflammatory phenotype of innate immune cells such as neutrophils, macrophages, and dendritic cells. Additionally, we summarize the impact of glycolysis on the pathophysiological processes of AIDs, including systemic lupus erythematosus, rheumatoid arthritis, vasculitis, and ankylosing spondylitis, and discuss potential therapeutic targets. The discovery that immune cell metabolism characterized by glycolysis may regulate inflammation broadens the avenues for treating AIDs by modulating immune cell metabolism.
    Keywords:  autoimmune diseases; glycolysis; immunometabolism; innate immune cells; therapeutic target
    DOI:  https://doi.org/10.3389/fimmu.2022.920029
  8. Clin Transl Med. 2022 Jul;12(7): e931
    ISG15 deficiency features a complex cellular phenotype that responds to treatment with itaconate and derivatives.
    Syed Fakhar-Ul-Hassnain Waqas, Aaqib Sohail, Ariane Hai Ha Nguyen, Abdulai Usman, Tobias Ludwig, Andre Wegner, Muhammad Nasir Hayat Malik, Sven Schuchardt, Robert Geffers, Moritz Winterhoff, Sylvia Merkert, Ulrich Martin, Ruth Olmer, Nico Lachmann, Frank Pessler.
      BACKGROUND: Congenital ISG15 deficiency is a rare autoinflammatory disorder that is driven by chronically elevated systemic interferon levels and predominantly affects central nervous system and skin.METHODS AND RESULTS: We have developed induced pluripotent stem cell-derived macrophages and endothelial cells as a model to study the cellular phenotype of ISG15 deficiency and identify novel treatments. ISG15-/- macrophages exhibited the expected hyperinflammatory responses, but normal phagocytic function. In addition, they displayed a multifaceted pathological phenotype featuring increased apoptosis/pyroptosis, oxidative stress, glycolysis, and acylcarnitine levels, but decreased glutamine uptake, BCAT1 expression, branched chain amino acid catabolism, oxidative phosphorylation, β-oxidation, and NAD(P)H-dependent oxidoreductase activity. Furthermore, expression of genes involved in mitochondrial biogenesis and respiratory chain complexes II-V was diminished in ISG15-/- cells. Defective mitochondrial respiration was restored by transduction with wild-type ISG15, but only partially by a conjugation-deficient variant, suggesting that some ISG15 functions in mitochondrial respiration require ISGylation to cellular targets. Treatment with itaconate, dimethyl-itaconate, 4-octyl-itaconate, and the JAK1/2 inhibitor ruxolitinib ameliorated increased inflammation, propensity for cell death, and oxidative stress. Furthermore, the treatments greatly improved mitochondria-related gene expression, BCAT1 levels, redox balance, and intracellular and extracellular ATP levels. However, efficacy differed among the compounds according to read-out and cell type, suggesting that their effects on cellular targets are not identical. Indeed, only itaconates increased expression of anti-oxidant genes NFE2L2, HMOX1, and GPX7, and dimethyl-itaconate improved redox balance the most. Even though itaconate treatments normalized the elevated expression of interferon-stimulated genes, ISG15-/- macrophages maintained their reduced susceptibility to influenza virus infection.
    CONCLUSIONS: These findings expand the cellular phenotype of human ISG15 deficiency and reveal the importance of ISG15 for regulating oxidative stress, branched chain amino acid metabolism, and mitochondrial function in humans. The results validate ruxolitinib as treatment for ISG15 deficiency and suggest itaconate-based medications as additional therapeutics for this rare disorder.
    Keywords:  4-octyl itaconic acid; ATP; ISG15; NRF2; apoptosis; branched chain amino acid amino transferase 1; dimethyl itaconic acid; induced pluripotent stem cells; inflammation; itaconate; itaconic acid; mitochondrial biogenesis; oxidative stress; pyroptosis; reactive oxygen species; ruxolitinib
    DOI:  https://doi.org/10.1002/ctm2.931
  9. Front Immunol. 2022 ;13 881166
    TNFR2 Costimulation Differentially Impacts Regulatory and Conventional CD4+ T-Cell Metabolism.
    Mark Mensink, Thi Ngoc Minh Tran, Esther A Zaal, Ellen Schrama, Celia R Berkers, Jannie Borst, Sander de Kivit.
      CD4+ conventional T cells (Tconvs) mediate adaptive immune responses, whereas regulatory T cells (Tregs) suppress those responses to safeguard the body from autoimmunity and inflammatory diseases. The opposing activities of Tconvs and Tregs depend on the stage of the immune response and their environment, with an orchestrating role for cytokine- and costimulatory receptors. Nutrient availability also impacts T-cell functionality via metabolic and biosynthetic processes that are largely unexplored. Many data argue that costimulation by Tumor Necrosis Factor Receptor 2 (TNFR2) favors support of Treg over Tconv responses and therefore TNFR2 is a key clinical target. Here, we review the pertinent literature on this topic and highlight the newly identified role of TNFR2 as a metabolic regulator for thymus-derived (t)Tregs. We present novel transcriptomic and metabolomic data that show the differential impact of TNFR2 on Tconv and tTreg gene expression and reveal distinct metabolic impact on both cell types.
    Keywords:  TNFR2; conventional T cell; metabolism; regulatory T cell; therapy; transcriptomics
    DOI:  https://doi.org/10.3389/fimmu.2022.881166
  10. Front Immunol. 2022 ;13 946731
    SARS-CoV-2 Achieves Immune Escape by Destroying Mitochondrial Quality: Comprehensive Analysis of the Cellular Landscapes of Lung and Blood Specimens From Patients With COVID-19.
    Chenyang Duan, Ruiyan Ma, Xue Zeng, Bing Chen, Dongyao Hou, Ruixue Liu, Xuehan Li, Liangming Liu, Tao Li, He Huang.
      Mitochondria get caught in the crossfire of coronavirus disease 2019 (COVID-19) and antiviral immunity. The mitochondria-mediated antiviral immunity represents the host's first line of defense against viral infection, and the mitochondria are important targets of COVID-19. However, the specific manifestations of mitochondrial damage in patients with COVID-19 have not been systematically clarified. This study comprehensively analyzed one single-cell RNA-sequencing dataset of lung tissue and two bulk RNA-sequencing datasets of blood from COVID-19 patients. We found significant changes in mitochondrion-related gene expression, mitochondrial functions, and related metabolic pathways in patients with COVID-19. SARS-CoV-2 first infected the host alveolar epithelial cells, which may have induced excessive mitochondrial fission, inhibited mitochondrial degradation, and destroyed the mitochondrial calcium uniporter (MCU). The type II alveolar epithelial cell count decreased and the transformation from type II to type I alveolar epithelial cells was blocked, which exacerbated viral immune escape and replication in COVID-19 patients. Subsequently, alveolar macrophages phagocytized the infected alveolar epithelial cells, which decreased mitochondrial respiratory capacity and activated the ROS-HIF1A pathway in macrophages, thereby aggravating the pro-inflammatory reaction in the lungs. Infected macrophages released large amounts of interferon into the blood, activating mitochondrial IFI27 expression and destroying energy metabolism in immune cells. The plasma differentiation of B cells and lung-blood interaction of regulatory T cells (Tregs) was exacerbated, resulting in a cytokine storm and excessive inflammation. Thus, our findings systematically explain immune escape and excessive inflammation seen during COVID-19 from the perspective of mitochondrial quality imbalance.
    Keywords:  COVID-19; cytokine storm; immune escape; inflammation; mitochondrial quality
    DOI:  https://doi.org/10.3389/fimmu.2022.946731
  11. Int Immunopharmacol. 2022 Jul 16. pii: S1567-5769(22)00549-5. [Epub ahead of print]110 109065
    Role of succinic acid in the regulation of sepsis.
    Hao Liu, Hairong Zhang, Xiaoyu Zhang, Qian Chen, Lei Xia.
      Sepsis is a life-threatening disease characterized by a defensive response to damage. The immune response in patients with sepsis is overenhanced in the early stages and suppressed in the later stages, leading to poor prognosis. Metabolic reprogramming and epigenetic changes play a role in sepsis. Metabolic intermediates such as elevated succinic acid levels are significantly altered in patients with sepsis. Succinic acid, a metabolic intermediate of the tricarboxylic acid cycle, participates in energy supply and plays a role in metabolic reprogramming. Simultaneously, as an epigenetic regulator, it participates in gene transcription, translation, and post-translational modifications. It also participates in the inflammatory response, hypoxia, and the production of reactive oxygen species via endocrine and paracrine pathways. In this review, we have discussed the effects of succinic acid on sepsis and its therapeutic potential.
    Keywords:  Epigenetic change; Metabolic reprogramming; Pathophysiology; SUCNR1; Sepsis; Succinic acid
    DOI:  https://doi.org/10.1016/j.intimp.2022.109065
  12. Mucosal Immunol. 2022 Jul 18.
    Trained immunity of alveolar macrophages requires metabolic rewiring and type 1 interferon signaling.
    Sophie Zahalka, Philipp Starkl, Martin L Watzenboeck, Asma Farhat, Mariem Radhouani, Florian Deckert, Anastasiya Hladik, Karin Lakovits, Felicitas Oberndorfer, Caroline Lassnig, Birgit Strobl, Kristaps Klavins, Mai Matsushita, David E Sanin, Katarzyna M Grzes, Edward J Pearce, Anna-Dorothea Gorki, Sylvia Knapp.
      Environmental microbial triggers shape the development and functionality of the immune system. Alveolar macrophages (AMs), tissue-resident macrophages of the lungs, are in constant and direct contact with inhaled particles and microbes. Such exposures likely impact AM reactivity to subsequent challenges by immunological imprinting mechanisms referred to as trained immunity. Here, we investigated whether a ubiquitous microbial compound has the potential to induce AM training in vivo. We discovered that intranasal exposure to ambient amounts of lipopolysaccharide (LPS) induced a pronounced AM memory response, characterized by enhanced reactivity upon pneumococcal challenge. Exploring the mechanistic basis of AM training, we identified a critical role of type 1 interferon signaling and found that inhibition of fatty acid oxidation and glutaminolysis significantly attenuated the training effect. Notably, adoptive transfer of trained AMs resulted in increased bacterial loads and tissue damage upon subsequent pneumococcal infection. In contrast, intranasal pre-exposure to LPS promoted bacterial clearance, highlighting the complexity of stimulus-induced immune responses, which likely involve multiple cell types and may depend on the local immunological and metabolic environment. Collectively, our findings demonstrate the profound impact of ambient microbial exposure on pulmonary immune memory and reveal tissue-specific features of trained immunity.
    DOI:  https://doi.org/10.1038/s41385-022-00528-5
  13. J Med Virol. 2022 Jul 22.
    Interplay between Cellular Metabolism and DNA viruses.
    Milad Zandi, Somayeh Shokri, Shahab Mahmoudvand, Ahmad Hosseinzadeh Adli, Ramin Mohammadi, Azita Haddadi.
      Viruses as intracellular pathogens hijack the host metabolism and reprogram to facilitate optimal virus production. DNA viruses can cause alterations in several metabolic pathways, including aerobic glycolysis also known as the Warburg effect, pentose phosphate pathway (PPP) activation, and amino acid catabolism such as glutaminolysis, nucleotide biosynthesis, lipid metabolism, and amino acid biosynthesis. The available energy for productive infection can be increased in infected cells via modification of different carbon source utilization. This review discusses the metabolic alterations of the DNA viruses that will be the basis for future novel therapeutic approaches. This article is protected by copyright. All rights reserved.
    Keywords:  glutaminolysis; glycolysis; host metabolism; lipid metabolism; viruses
    DOI:  https://doi.org/10.1002/jmv.28018
  14. AIDS. 2022 Jul 08.
    Altered adipose tissue macrophage populations in people with HIV on integrase inhibitor-containing ART.
    Sarah Vakili, Bam Paneru, Cleandre M Guerrier, Jessica Miller, Emily Baumrin, Amy Forrestel, Kenneth Lynn, Ian Frank, Vincent Lo Re, Ronald G Collman, David A Hill.
      OBJECTIVE: Antiretroviral therapy (ART) extends the life of people with HIV (PWH), but these individuals are at increased risk for obesity, dyslipidemia, diabetes, and cardiovascular disease. These comorbidities may be a consequence of HIV-related chronic inflammation and/or adverse effects of ART on tissue regulatory adipose tissue macrophages (ATMs). We sought to determine the effects of HIV/ART on metabolically beneficial ATM populations and functions.DESIGN: We examined subcutaneous ATMs from PWH on integrase inhibitor-containing ART (n = 5) and uninfected persons (n = 9). We complemented these studies with ex vivo and in vitro analyses of peripheral blood mononuclear cell (PBMC) and murine macrophage lipid metabolism and fatty acid oxidation gene expression.
    METHODS: ATM populations were examined by flow cytometry. Macrophage lipid metabolism and fatty acid oxidation gene expression were examined by Seahorse assay and quantitative PCR.
    RESULTS: Adipose tissue from PWH had reduced populations of metabolically activated CD9+ ATMs compared to that of uninfected controls (P < 0.001). PBMCs of PWH had lower fatty acid metabolism compared to those of uninfected controls (P < 0.01). Analysis of murine macrophages revealed that dolutegravir reduced lipid metabolism (P < 0.001) and increased expression of the fatty acid beta-oxidation enzyme enoyl-CoA hydratase, short chain 1 (P < 0.05).
    CONCLUSIONS: We report the loss of metabolically beneficial ATM populations in PWH on ART, altered fatty acid metabolism of blood immune cells, and evidence that dolutegravir alters macrophage fatty acid metabolism. Future studies should examine direct or indirect effects and mechanisms of dolutegravir, and other integrase inhibitors and ART classes, on fatty acid beta-oxidation.
    GRAPHICAL ABSTRACT: http://links.lww.com/QAD/C537.
    DOI:  https://doi.org/10.1097/QAD.0000000000003278
  15. Front Cell Infect Microbiol. 2022 ;12 935205
    EBV Infection and Its Regulated Metabolic Reprogramming in Nasopharyngeal Tumorigenesis.
    Tingting Yang, Chanping You, Shuhui Meng, Zhengquan Lai, Weipeng Ai, Jun Zhang.
      Viral oncogenes may drive cellular metabolic reprogramming to modulate the normal epithelia cell malignant transformation. Understanding the viral oncogene-mediated signaling transduction dysregulation that involves in metabolic reprogramming may provide new therapeutic targets for virus-associated cancer treatment. Latent EBV infection and expression of viral oncogenes, including latent membrane proteins 1 and 2 (LMP1/2), and EBV-encoded BamH I-A rightward transcripts (BART) microRNAs (miR-BARTs), have been demonstrated to play fundamental roles in altering host cell metabolism to support nasopharyngeal carcinoma (NPC) pathogenesis. Yet, how do EBV infection and its encoded oncogenes facilitated the metabolic shifting and their roles in NPC carcinogenesis remains unclear. In this review, we will focus on delineating how EBV infection and its encoded oncoproteins altered the metabolic reprograming of infected cells to support their malignances. Furthermore, based on the understanding of the host's metabolic signaling alterations induced by EBV, we will provide a new perspective on the interplay between EBV infection and these metabolic pathways and offering a potential therapeutic intervention strategy in the treatment of EBV-associated malignant diseases.
    Keywords:  EBV infection; NPC pathogenesis; metabolic reprogramming; nasopharyngeal carcinoma; therapeutic strategies
    DOI:  https://doi.org/10.3389/fcimb.2022.935205
  16. Front Immunol. 2022 ;13 935465
    T Cell-Intrinsic Vitamin A Metabolism and Its Signaling Are Targets for Memory T Cell-Based Cancer Immunotherapy.
    Fumihiro Fujiki, Soyoko Morimoto, Akiko Katsuhara, Akane Okuda, Saeka Ogawa, Eriko Ueda, Maki Miyazaki, Ayako Isotani, Masahito Ikawa, Sumiyuki Nishida, Hiroko Nakajima, Akihiro Tsuboi, Yoshihiro Oka, Jun Nakata, Naoki Hosen, Atsushi Kumanogoh, Yusuke Oji, Haruo Sugiyama.
      Memory T cells play an essential role in infectious and tumor immunity. Vitamin A metabolites such as retinoic acid are immune modulators, but the role of vitamin A metabolism in memory T-cell differentiation is unclear. In this study, we identified retinol dehydrogenase 10 (Rdh10), which metabolizes vitamin A to retinal (RAL), as a key molecule for regulating T cell differentiation. T cell-specific Rdh10 deficiency enhanced memory T-cell formation through blocking RAL production in infection model. Epigenetic profiling revealed that retinoic acid receptor (RAR) signaling activated by vitamin A metabolites induced comprehensive epigenetic repression of memory T cell-associated genes, including TCF7, thereby promoting effector T-cell differentiation. Importantly, memory T cells generated by Rdh deficiency and blocking RAR signaling elicited potent anti-tumor responses in adoptive T-cell transfer setting. Thus, T cell differentiation is regulated by vitamin A metabolism and its signaling, which should be novel targets for memory T cell-based cancer immunotherapy.
    Keywords:  RDH10; cancer immunotherapy; effector T cell; memory T cell; retinoic acid; vitamin A; vitamin A metabolism
    DOI:  https://doi.org/10.3389/fimmu.2022.935465
  17. Cell Biol Int. 2022 Jul 16.
    Biology of macrophage fate decision: Implication in inflammatory disorders.
    Sarika Yadav, Ashish Dwivedi, Anurag Tripathi.
      The activation of immune cells in response to stimuli present in their microenvironment is regulated by their metabolic profile. Unlike the signal transduction events, which overlap to a huge degree in diverse cellular processes, the metabolome of a cell reflects a more precise picture of cell physiology and function. Different factors governing the cellular metabolome include receptor signaling, macro and micronutrients, normoxic and hypoxic conditions, energy needs, and biomass demand. Macrophages have enormous plasticity and can perform diverse functions depending upon their phenotypic state. This review presents recent updates on the cellular metabolome and molecular patterns associated with M1 and M2 macrophages, also termed "classically activated macrophages" and "alternatively activated macrophages," respectively. M1 macrophages are proinflammatory in nature and predominantly Th1-specific immune responses induce their polarization. On the contrary, M2 macrophages are anti-inflammatory in nature and primarily participate in Th2-specific responses. Interestingly, the same macrophage cell can adapt to the M1 or M2 phenotype depending upon the clues from its microenvironment. We elaborate on the various tissue niche-specific factors, which govern macrophage metabolism and heterogeneity. Furthermore, the current review provides an in-depth account of deregulated macrophage metabolism associated with pathological disorders such as cancer, obesity, and atherosclerosis. We further highlight significant differences in various metabolic pathways governing the cellular bioenergetics and their impact on macrophage effector functions and associated disorders.
    Keywords:  alternatively activated macrophages; classically activated macrophages; immunometabolism; inflammatory disorders; macrophage polarization; therapeutic targeting
    DOI:  https://doi.org/10.1002/cbin.11854
  18. Mol Cell Neurosci. 2022 Jul 19. pii: S1044-7431(22)00064-1. [Epub ahead of print] 103758
    Dimethyl itaconate reprograms neurotoxic to neuroprotective primary astrocytes through the regulation of NLRP3 inflammasome and Nrf-2/HO-1 pathways.
    Mohammad Darvish Khadem, Mohammad Reza Tabandeh, Arvand Haschemi, Alireza Kheirollah, Ali Shahriari.
      The activation of neurotoxic reactive astrocytes contributes to the pathogenesis of many neurodegenerative diseases. Itaconate, a product of cellular metabolism, is released from activated macrophage/microglia and has been shown to regulate inflammatory responses in several mammalian cells. This study was designed to investigate the impact of cell-permeable dimethyl itaconate (DI) on reactive astrocyte-dependent neurotoxicity. Primary murine astrocyte cells were isolated and stimulated with lipopolysaccharide (LPS) to generate reactive astrocytes. Treating these activated cells with DI was able to diminish the neurotoxic phenotype of reactive astrocytes, as we found reduced LPS-induced Nod-like receptor protein 3 (NLRP3) inflammasome activation and interleukin-1β (IL-1β) secretion. DI reduced the level of inflammasome components, attenuated inflammasome assembly and subsequently reduced caspase-1 cleavage and IL-1β levels. Additionally, DI attenuated nuclear factor-kappa B (NF-κB) phosphorylation in LPS-activated astrocytes and also protected astrocytes from LPS-induced cytotoxicity, including a lowering of Bax and caspase3. DI-treated reactive astrocytes showed an elevated GSH/GSSG ratio and improved antioxidant defense factors including catalase and superoxide dismutase, while lipid peroxidation was reduced. We found that DI activated the nuclear factor 2 (NRF2) and heme oxygenase-1 (HO-1) pathway in astrocytes and thereby potentially control redox-regulation and the inflammatory state of astrocytes. Collectively, these results indicate the neuroprotective role of DI by reprogramming astrocytes from neurotoxic A1 to neuroprotective A2 states and thereby reveal a novel potential strategy for the treatment of neurodegenerative diseases.
    Keywords:  Apoptosis; Astrocyte; Immunometabolite; Inflammation; Itaconate; Oxidative stress
    DOI:  https://doi.org/10.1016/j.mcn.2022.103758
  19. Front Mol Biosci. 2022 ;9 917818
    Reprogramming Macrophage Metabolism and its Effect on NLRP3 Inflammasome Activation in Sepsis.
    Ruiheng Luo, Xizhe Li, Dan Wang.
      Sepsis, the most common life-threatening multi-organ dysfunction syndrome secondary to infection, lacks specific therapeutic strategy due to the limited understanding of underlying mechanisms. It is currently believed that inflammasomes play critical roles in the development of sepsis, among which NLRP3 inflammasome is involved to most extent. Recent studies have revealed that dramatic reprogramming of macrophage metabolism is commonly occurred in sepsis, and this dysregulation is closely related with the activation of NLRP3 inflammasome. In view of the fact that increasing evidence demonstrates the mechanism of metabolism reprogramming regulating NLRP3 activation in macrophages, the key enzymes and metabolites participated in this regulation should be clearer for better interpreting the relationship of NLRP3 inflammasome and sepsis. In this review, we thus summarized the detail mechanism of the metabolic reprogramming process and its important role in the NLRP3 inflammasome activation of macrophages in sepsis. This mechanism summarization will reveal the applicational potential of metabolic regulatory molecules in the treatment of sepsis.
    Keywords:  NLRP3 inflammasome; macrophages; metabolism reprogramming; sepsis; targeted therapy
    DOI:  https://doi.org/10.3389/fmolb.2022.917818
  20. Sci Rep. 2022 Jul 22. 12(1): 12506
    Transgenic expression of IL-7 regulates CAR-T cell metabolism and enhances in vivo persistence against tumor cells.
    Li Li, Qing Li, Zi-Xun Yan, Ling-Shuang Sheng, Di Fu, Pengpeng Xu, Li Wang, Wei-Li Zhao.
      Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising novel therapeutic approach. However, primary and secondary resistance to CAR-T cell therapy is commonly encountered in various clinical trials. Despite the comprehensive studies to elucidate the mechanisms of resistance, effective resolution in clinical practice is still elusive. Inadequate persistence and subsequent loss of infused CAR-T cells are proposed major resistance mechanism associated with CAR-T cell treatment failure. Thus, we generated CAR-T cells armored with IL-7 to prolong the persistence of infused T-cells, particularly CD4 + T cells, and enhanced anti-tumor response. IL-7 increased CAR-T-cell persistence in vivo and contributed to the distinct T-cell cytotoxicity profile. Using mass cytometry (CyTOF), we further assessed the phenotypic and metabolic profiles of IL-7-secreting CAR-T cells, along with conventional CAR-T cells at the single-cell level. With in-depth analysis, we found that IL-7 maintained CAR-T cells in a less differentiated T-cell state, regulated distinct metabolic activity, and prevented CAR-T-cell exhaustion, which could be essential for CAR-T cells to maintain their metabolic fitness and anti-tumor response. Our findings thus provided clinical rationale to exploit IL-7 signaling for modulation and metabolic reprogramming of T-cell function to enhance CAR-T cell persistence and induce durable remission upon CAR-T cell therapy.
    DOI:  https://doi.org/10.1038/s41598-022-16616-2
  21. J Leukoc Biol. 2022 Jul 22.
    Sepsis, pyruvate, and mitochondria energy supply chain shortage.
    Charles E McCall, Xuewei Zhu, Manal Zabalawi, David Long, Matthew A Quinn, Barbara K Yoza, Peter W Stacpoole, Vidula Vachharajani.
      Balancing high energy-consuming danger resistance and low energy supply of disease tolerance is a universal survival principle that often fails during sepsis. Our research supports the concept that sepsis phosphorylates and deactivates mitochondrial pyruvate dehydrogenase complex control over the tricarboxylic cycle and the electron transport chain. StimulatIng mitochondrial energetics in septic mice and human sepsis cell models can be achieved by inhibiting pyruvate dehydrogenase kinases with the pyruvate structural analog dichloroacetate. Stimulating the pyruvate dehydrogenase complex by dichloroacetate reverses a disruption in the tricarboxylic cycle that induces itaconate, a key mediator of the disease tolerance pathway. Dichloroacetate treatment increases mitochondrial respiration and ATP synthesis, decreases oxidant stress, overcomes metabolic paralysis, regenerates tissue, organ, and innate and adaptive immune cells, and doubles the survival rate in a murine model of sepsis.
    Keywords:  dichloroacetate; energy shifts; evolution; immunometabolism; inflammation; itaconate; pyruvate; redox
    DOI:  https://doi.org/10.1002/JLB.3MR0322-692RR
  22. Front Immunol. 2022 ;13 908697
    Functional Restoration of Exhausted CD8 T Cells in Chronic HIV-1 Infection by Targeting Mitochondrial Dysfunction.
    Aljawharah Alrubayyi, Elia Moreno-Cubero, Dan Hameiri-Bowen, Rebecca Matthews, Sarah Rowland-Jones, Anna Schurich, Dimitra Peppa.
      CD8 T cell exhaustion is a hallmark of HIV-1 infection, characterized by phenotypic and functional CD8 T cell abnormalities that persist despite years of effective antiretroviral treatment (ART). More recently, the importance of cellular metabolism in shaping T cell antiviral function has emerged as a crucial aspect of immunotherapeutics aimed at re-invigorating exhausted CD8 T cells but remains under-investigated in HIV-1 infection. To gain a better insight into this process and identify new targets for effective CD8 T cell restoration we examined the metabolic profile of exhausted CD8 T cells in HIV-1 infection. We show that relative to HIV-1 elite controllers (EC) and HIV-1 seronegative donors, CD8 T cells from HIV-1 viraemic individuals are skewed toward a PD-1hiEOMEShiT-betlowTIGIT+ phenotype that is maintained during ART. This exhausted signature is enriched in HIV-specific CD8 T cells, compared to CMV-specific CD8 T cell populations, and further delineated by higher expression of the glucose transporter, Glut-1, impaired mitochondrial function and biogenesis, reflecting underlying metabolic defects. A notable improvement in antiviral HIV-specific CD8 T cell function was elicited via mitochondrial antioxidant treatment in combination with pharmacological modulation of mitochondrial dynamics and IL-15 treatment. These findings identify mitochondria as promising targets for combined reconstitution therapies in HIV-1 infection.
    Keywords:  CD8 T cell exhaustion; CMV; HIV-1; immunometabolism; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.3389/fimmu.2022.908697
  23. Cell Rep. 2022 Jul 19. pii: S2211-1247(22)00895-6. [Epub ahead of print]40(3): 111093
    Mucolytic bacteria license pathobionts to acquire host-derived nutrients during dietary nutrient restriction.
    Kohei Sugihara, Sho Kitamoto, Prakaimuk Saraithong, Hiroko Nagao-Kitamoto, Matthew Hoostal, Caroline McCarthy, Alexandra Rosevelt, Chithra K Muraleedharan, Merritt G Gillilland, Jin Imai, Maiko Omi, Shrinivas Bishu, John Y Kao, Christopher J Alteri, Nicolas Barnich, Thomas M Schmidt, Asma Nusrat, Naohiro Inohara, Jonathan L Golob, Nobuhiko Kamada.
      Pathobionts employ unique metabolic adaptation mechanisms to maximize their growth in disease conditions. Adherent-invasive Escherichia coli (AIEC), a pathobiont enriched in the gut mucosa of patients with inflammatory bowel disease (IBD), utilizes diet-derived L-serine to adapt to the inflamed gut. Therefore, the restriction of dietary L-serine starves AIEC and limits its fitness advantage. Here, we find that AIEC can overcome this nutrient limitation by switching the nutrient source from the diet to the host cells in the presence of mucolytic bacteria. During diet-derived L-serine restriction, the mucolytic symbiont Akkermansia muciniphila promotes the encroachment of AIEC to the epithelial niche by degrading the mucus layer. In the epithelial niche, AIEC acquires L-serine from the colonic epithelium and thus proliferates. Our work suggests that the indirect metabolic network between pathobionts and commensal symbionts enables pathobionts to overcome nutritional restriction and thrive in the gut.
    Keywords:  Akkermansia muciniphila; CP: Microbiology; L-serine; adherent-invasive Escherichia coli; inflammatory bowel disease; intestinal mucus barrier
    DOI:  https://doi.org/10.1016/j.celrep.2022.111093
  24. J Virol. 2022 Jul 11. e0068822
    Controlling Herpes Simplex Virus-Induced Immunoinflammatory Lesions Using Metabolic Therapy: a Comparison of 2-Deoxy-d-Glucose with Metformin.
    Engin Berber, Barry T Rouse.
      Herpes simplex virus (HSV) infection of the eye can result in a blinding immunoinflammatory lesion in the cornea called herpetic stromal keratitis (HSK). This lesion is orchestrated by T cells and can be reduced in magnitude by anti-inflammatory drugs and procedures that change the balance of cellular participants in lesions. This report evaluates the effect of drugs that cause metabolic reprogramming on lesion expression using two drugs that affect glucose metabolism: 2-deoxy-d-glucose (2DG) and metformin. Both drugs could limit HSK severity, but 2DG therapy could result in herpes encephalitis if used when replicating virus was still present. The reason metformin was a safer therapy was its lack of marked inhibitory effects on inflammatory cells particularly interferon-γ (IFN-γ)-producing Th1 and CD8 T cells in the trigeminal ganglion (TG), in which HSV latency is established and sustained. Additionally, whereas 2DG in TG cultures with established latency accelerated the termination of latency, this did not occur in the presence of metformin, likely because the inflammatory cells remained functional. Our results support the value of metabolic reprogramming to control viral immunoinflammatory lesions, but the approach used should be chosen with caution. IMPORTANCE Herpes simplex virus (HSV) infection of the eye is an example where damaging lesions are in part the consequence of a host response to the infection. Moreover, it was shown that changing the representation of cellular participants in the inflammatory reaction can minimize lesion severity. This report explores the value of metabolic reprogramming using two drugs that affect glucose metabolism to achieve cellular rebalancing. It showed that two drugs, 2-deoxy-d-glucose (2DG) and metformin, effectively diminished ocular lesion expression, but only metformin avoided the complication of HSV spreading to the central nervous system (CNS) and causing herpetic encephalitis. The report provides some mechanistic explanations for the findings.
    Keywords:  2-deoxy-d-glucose; 2DG; HSK; HSV-1; encephalitis; herpes simplex virus; herpetic stromal keratitis; metformin
    DOI:  https://doi.org/10.1128/jvi.00688-22
  25. Front Microbiol. 2022 ;13 919424
    Mitochondrial Function and Microbial Metabolites as Central Regulators of Intestinal Immune Responses and Cancer.
    Saskia Weber-Stiehl, Lea Järke, Juan Camilo Castrillón-Betancur, Felix Gilbert, Felix Sommer.
      Energy and anabolic metabolism are essential for normal cellular homeostasis but also play an important role in regulating immune responses and cancer development as active immune and cancer cells show an altered metabolic profile. Mitochondria take a prominent position in these metabolic reactions. First, most key energetic reactions take place within or in conjunction with mitochondria. Second, mitochondria react to internal cues from within the cell but also to external cues originating from the microbiota, a vast diversity of associated microorganisms. The impact of the microbiota on host physiology has been largely investigated in the last decade revealing that the microbiota contributes to the extraction of calories from the diet, energy metabolism, maturation of the immune system and cellular differentiation. Thus, changes in the microbiota termed dysbiosis have been associated with disease development including metabolic diseases, inflammation and cancer. Targeting the microbiota to modulate interactions with the mitochondria and cellular metabolism to delay or inhibit disease development and pathogenesis appears an attractive therapeutic approach. Here, we summarize recent advances in developing the therapeutic potential of microbiota-mitochondria interactions for inflammation and cancer.
    Keywords:  cancer; inflammation; metabolites; microbiota; mitochondria
    DOI:  https://doi.org/10.3389/fmicb.2022.919424
  26. Redox Biol. 2022 Jul 14. pii: S2213-2317(22)00176-8. [Epub ahead of print]55 102404
    Inhibition of NLRP3-mediated crosstalk between hepatocytes and liver macrophages by geniposidic acid alleviates cholestatic liver inflammatory injury.
    Meng Song, Zijun Chen, Ruian Qiu, Tingwei Zhi, Wenmin Xie, Yingya Zhou, Nachuan Luo, Fuqian Chen, Fang Liu, Chuangpeng Shen, Sheng Lin, Fengxue Zhang, Yong Gao, Changhui Liu.
      The excessive accumulation of bile acids (BA) in hepatocytes can trigger inflammatory response and recruit macrophages, thereby accelerating cholestatic liver injury. The crosstalk between hepatocytes and macrophages has been recently implicated in the pathogenesis of cholestasis; however, the underlying mechanisms remain unclear. Here, we demonstrated that BA initiate NLRP3 inflammasome activation in hepatocytes to release proinflammatory cytokines and promote the communication between hepatocytes and macrophages, thus enhancing liver inflammation in an NLRP3-dependent manner. NLRP3-inhibition by geniposidic acid (GPA), a novel NLRP3-specific covalent inhibitor that directly interacts with NLRP3, in hepatocytes and macrophages abated BA-induced inflammation. Moreover, NLRP3-deletion or its inhibition mitigated ANIT-induced cholestatic inflammation, whereas disrupting the crosstalk between hepatic macrophages and hepatocytes attenuated the hepatoprotective effect of GPA against ANIT-induced cholestatic inflammation. Therefore, blocking this crosstalk by suppressing NLRP3 inflammasome activation may represent a novel therapeutic strategy for cholestasis.
    DOI:  https://doi.org/10.1016/j.redox.2022.102404
  27. Int Immunopharmacol. 2022 Jul 16. pii: S1567-5769(22)00533-1. [Epub ahead of print]110 109049
    The inhibition of GLUT1-induced glycolysis in macrophage by phloretin participates in the protection during acute lung injury.
    Yiyan Songyang, Wen Li, Wenqiang Li, Ji Yang, TianBao Song.
      The increased level of glycolysis in macrophage aggravates lipopolysaccharide (LPS)-induced acute lung injury (ALI). Glucose transporter 1 (GLUT1) serves as a ubiquitously expressed glucose transporter, which could activate inflammatory response by mediating glycolysis. Phloretin (PHL), an apple polyphenol, is also an inhibitor of GLUT1, possessing potent anti-inflammatory effects in various diseases. However, the potential role of PHL in ALI remains unclear till now. This study aims to investigate the impacts of PHL on ALI as well as its possible mechanisms. A mouse ALI model was established via intratracheal injection of LPS. LPS-induced primary macrophages were used to mimic in vitro ALI. Mice were pretreated with low or high dosage of PHL for 7 days via intragastric administration once a day before LPS injection. The results showed that PHL pretreatment significantly prevented LPS-induced lung pathological injury and inflammatory response. Meantime, PHL pretreatment also decreased the level of glycolysis in macrophage during ALI. In terms of mechanism, PHL inhibited the mRNA and protein expression of GLUT1. In vitro experiments further showed GLUT1 overexpression in macrophage by infection with lentivirus could abolish the inhibition of inflammation and glycolysis mediated by PHL, suggesting that GLUT1 was essential for the protection of PHL. Taken together, PHL pretreatment may protect against LPS-induced ALI by inhibiting glycolysis in macrophage in a GLUT1-dependent manner, which may be a candidate against ALI in the future.
    Keywords:  Acute lung injury; GLUT1; Glycolysis; Macrophage; Phloretin
    DOI:  https://doi.org/10.1016/j.intimp.2022.109049
  28. Immunopharmacol Immunotoxicol. 2022 Jul 18. 1-27
    microRNA-103a-3p promotes inflammation and fibrosis in nonalcoholic fatty liver disease by targeting HBP1.
    Kaifeng Chu, Jie Gu.
      BACKGROUND: As a metabolic-associated disease, non-alcoholic fatty liver disease (NAFLD) development is tightly linked to lipid accumulation, inflammatory response, and fibrosis. Our study was intended to expound the role of microRNA (miR)-103a-3p in the pathogenesis of NAFLD.METHODS: First, potentially relevant genes in NAFLD were screened using microarray analysis. Expression of lipid metabolism-related, inflammatory and liver fibrosis indicators in the serum of patients with NAFLD was analyzed. We established a NAFLD mouse model and analyzed the serum level of lipid metabolism- and inflammation-related factors and fibrosis in the liver tissues of NAFLD mice. The targeting relationship between miR-103a-3p and HBP1 was examined by dual-luciferase reporter gene assay, RT-qPCR and Western blot. Finally, the simultaneous effects of miR-103a-3p and HBP1 on lipid metabolism, inflammatory response and liver fibrosis in NAFLD mice were analyzed by rescue experiments.
    RESULTS: MiR-103a-3p was upregulated in the serum of NAFLD patients and liver tissues of NAFLD mice, with increased lipid accumulation, inflammation and liver fibrosis. HBP1 was reduced in liver tissues of NAFLD mice, and miR-103a-3p bound to and negatively regulated HBP1. Inhibition of miR-103a-3p or promotion of HBP1 improved liver function, decreased lipid accumulation, suppressed inflammatory response, and reduced liver fibrosis in NAFLD mice. Moreover, sh-HBP1 partially reversed the effect of miR-103a-3p inhibitor on NAFLD mice, leading to increased lipid accumulation, elevated inflammation and liver fibrosis in the liver of mice.
    CONCLUSIONS: miR-103a-3p inhibits the expression of HBP1, thus suppressing lipid metabolism, stimulating inflammatory responses, and promoting liver fibrosis in NAFLD.
    Keywords:  HBP1; Inflammatory responses; Lipid metabolism; Liver fibrosis; Non-alcoholic fatty liver disease; microRNA-103a-3p
    DOI:  https://doi.org/10.1080/08923973.2022.2102988
  29. Science. 2022 Jul 07. eabq3297
    Identification and receptor mechanism of TIR-catalyzed small molecules in plant immunity.
    Shijia Huang, Aolin Jia, Wen Song, Giuliana Hessler, Yonggang Meng, Yue Sun, Lina Xu, Henriette Laessle, Jan Jirschitzka, Shoucai Ma, Yu Xiao, Dongli Yu, Jiao Hou, Ruiqi Liu, Huanhuan Sun, Xiaohui Liu, Zhifu Han, Junbiao Chang, Jane E Parker, Jijie Chai.
      Plant nucleotide-binding leucine-rich repeat-containing (NLR) receptors with an N-terminal Toll/interleukin-1 receptor (TIR) domain sense pathogen effectors to enable TIR-encoded NADase activity for immune signaling. TIR-NLR signaling requires helper NLRs N requirement gene 1 (NRG1) and Activated Disease Resistance 1 (ADR1), and Enhanced Disease Susceptibility 1 (EDS1) that forms a heterodimer with each of its paralogs Phytoalexin Deficient 4 (PAD4) and Senescence-Associated Gene101 (SAG101). Here, we show that TIR-containing proteins catalyze production of 2'-(5''-phosphoribosyl)-5'-adenosine mono-/di-phosphate (pRib-AMP/ADP) in vitro and in planta. Biochemical and structural data demonstrate that EDS1-PAD4 is a receptor complex for pRib-AMP/ADP, which allosterically promote EDS1-PAD4 interaction with ADR1-L1 but not NRG1A. Our study identifies TIR-catalyzed pRib-AMP/ADP as a missing link in TIR signaling via EDS1-PAD4 and as likely second messengers for plant immunity.
    DOI:  https://doi.org/10.1126/science.abq3297
  30. Biol Trace Elem Res. 2022 Jul 19.
    Accumulation of Intracellular Ferrous Iron in Inflammatory-Activated Macrophages.
    Huijuan Ma, Qi Shu, Dan Li, Tingqian Wang, Linyi Li, Xiaodong Song, Kaiyan Lou, Huan Xu.
      Macrophages are important innate immune cells which can be polarized into heterogeneous populations. The inflammatory-activated M1 cells are known to be involved in all kinds of inflammatory diseases, which were also found to be associated with dysregulation of iron metabolism. While iron overload is known to induce M1 polarization, the valence states of iron and its intracellular dynamics during macrophage inflammatory activation have not been identified. In this study, THP-1-derived macrophages were polarized into M1, M2a, M2b, M2c, and M2d cells, and intracellular ferrous iron (Fe(II)) was measured by our previously developed ultrasensitive Fe(II) fluorescent probe. Significant accumulation of Fe(II) was only observed in M1 cells, which was different from the alterations of total iron. Time-dependent change of intracellular Fe(II) during the inflammatory activation was also consistent with the expression shifts of transferrin receptor CD71, ferrireductase Steap3, and Fe(II) exporter Slc40a1. In addition, accumulation of Fe(II) was also found in the colon macrophages of mice with ulcerative colitis, which was positively correlated to inflammatory phenotypes, including the productions of NO, IL-1β, TNF-α, and IL-6. Collectively, these results demonstrated the specific accumulation of Fe(II) in inflammatory-activated macrophages, which not only enriched our understanding of iron homeostasis in macrophages, but also indicated that Fe(II) could be further developed as a potential biomarker for inflammatory-activated macrophages.
    Keywords:  Ferrous iron; Inflammatory activation; Iron metabolism; Macrophages; Polarization; Ulcerative colitis
    DOI:  https://doi.org/10.1007/s12011-022-03362-9
  31. Science. 2022 Jul 07. eabq8180
    TIR-catalyzed ADP-ribosylation reactions produce signaling molecules for plant immunity.
    Aolin Jia, Shijia Huang, Wen Song, Junli Wang, Yonggang Meng, Yue Sun, Lina Xu, Henriette Laessle, Jan Jirschitzka, Jiao Hou, Tiantian Zhang, Wenquan Yu, Giuliana Hessler, Ertong Li, Shoucai Ma, Dongli Yu, Jan Gebauer, Ulrich Baumann, Xiaohui Liu, Zhifu Han, Junbiao Chang, Jane E Parker, Jijie Chai.
      Plant pathogen-activated immune signaling by nucleotide-binding leucine-rich repeat (NLR) receptors with an N-terminal Toll/Interleukin-1 receptor (TIR) domain converges on Enhanced Disease Susceptibility 1 (EDS1) and its direct partners Phytoalexin Deficient 4 (PAD4) or Senescence-Associated Gene 101 (SAG101). TIR-encoded NADases produce signaling molecules to promote exclusive EDS1-PAD4 and EDS1-SAG101 interactions with helper NLR sub-classes. Here we show that TIR-containing proteins catalyze adenosine diphosphate (ADP)-ribosylation of adenosine triphosphate (ATP) and ADP ribose (ADPR) via ADPR polymerase-like and NADase activity, forming ADP-ribosylated ATP (ADPr-ATP) and ADPr-ADPR (di-ADPR), respectively. Specific binding of ADPr-ATP or di-ADPR allosterically promotes EDS1-SAG101 interaction with helper NLR N requirement gene 1A (NRG1A) in vitro and in planta. Our data reveal an enzymatic activity of TIRs that enables specific activation of the EDS1-SAG101-NRG1 immunity branch.
    DOI:  https://doi.org/10.1126/science.abq8180
  32. Front Immunol. 2022 ;13 864225
    Nutrient Condition in the Microenvironment Determines Essential Metabolisms of CD8+ T Cells for Enhanced IFNγ Production by Metformin.
    Ruoyu Chao, Mikako Nishida, Nahoko Yamashita, Miho Tokumasu, Weiyang Zhao, Ikuru Kudo, Heiichiro Udono.
      Metformin (Met), a first-line drug for type 2 diabetes, lowers blood glucose levels by suppressing gluconeogenesis in the liver, presumably through the liver kinase B1-dependent activation of AMP-activated protein kinase (AMPK) after inhibiting respiratory chain complex I. Met is also implicated as a drug to be repurposed for cancers; its mechanism is believed identical to that of gluconeogenesis inhibition. However, AMPK activation requires high Met concentrations at more than 1 mM, which are unachievable in vivo. The immune-mediated antitumor response might be the case in a low dose Met. Thus, we proposed activating or expanding tumor-infiltrating CD8+ T cells (CD8TILs) in a mouse model by orally administering Met in free drinking water. Here we showed that Met, at around 10 μM and a physiologically relevant concentration, enhanced production of IFNγ,TNFα and expression of CD25 of CD8+ T cells upon TCR stimulation. Under a glucose-rich condition, glycolysis was exclusively involved in enhancing IFNγ production. Under a low-glucose condition, fatty acid oxidation or autophagy-dependent glutaminolysis, or both, was also involved. Moreover, phosphoenolpyruvate carboxykinase 1 (PCK1), converting oxaloacetate to phosphoenolpyruvate, became essential. Importantly, the enhanced IFNγ production was blocked by a mitochondrial ROS scavenger and not by an inhibitor of AMPK. In addition, IFNγ production by CD8TILs relied on pyruvate translocation to the mitochondria and PCK1. Our results revealed a direct effect of Met on IFNγ production of CD8+ T cells that was dependent on differential metabolic pathways and determined by nutrient conditions in the microenvironment.
    Keywords:  CD8+ T lymphocytes; FAO; IFNg; autophagy +T; glutaminolysis; glycolysis; metformin
    DOI:  https://doi.org/10.3389/fimmu.2022.864225
  33. Proc Natl Acad Sci U S A. 2022 Jul 26. 119(30): e2200512119
    EBNA2-EBF1 complexes promote MYC expression and metabolic processes driving S-phase progression of Epstein-Barr virus-infected B cells.
    Sophie Beer, Lucas E Wange, Xiang Zhang, Cornelia Kuklik-Roos, Wolfgang Enard, Wolfgang Hammerschmidt, Antonio Scialdone, Bettina Kempkes.
      Epstein-Barr virus (EBV) is a human tumor virus which preferentially infects resting human B cells. Upon infection in vitro, EBV activates and immortalizes these cells. The viral latent protein EBV nuclear antigen 2 (EBNA2) is essential for B cell activation and immortalization; it targets and binds the cellular and ubiquitously expressed DNA-binding protein CBF1, thereby transactivating a plethora of viral and cellular genes. In addition, EBNA2 uses its N-terminal dimerization (END) domain to bind early B cell factor 1 (EBF1), a pioneer transcription factor specifying the B cell lineage. We found that EBNA2 exploits EBF1 to support key metabolic processes and to foster cell cycle progression of infected B cells in their first cell cycles upon activation. The α1-helix within the END domain was found to promote EBF1 binding. EBV mutants lacking the α1-helix in EBNA2 can infect and activate B cells efficiently, but activated cells fail to complete the early S phase of their initial cell cycle. Expression of MYC, target genes of MYC and E2F, as well as multiple metabolic processes linked to cell cycle progression are impaired in EBVΔα1-infected B cells. Our findings indicate that EBF1 controls B cell activation via EBNA2 and, thus, has a critical role in regulating the cell cycle of EBV-infected B cells. This is a function of EBF1 going beyond its well-known contribution to B cell lineage specification.
    Keywords:  B cell activation; Epstein-Barr virus; MYC expression; RNA sequencing; transcription factor
    DOI:  https://doi.org/10.1073/pnas.2200512119
  34. Physiol Rep. 2022 Jul;10(14): e15394
    Resistance exercise with different workloads have distinct effects on cellular respiration of peripheral blood mononuclear cells.
    Emilia Ilona Lähteenmäki, Max Koski, Iida Koskela, Elias Lehtonen, Anna Kankaanpää, Heikki Kainulainen, Simon Walker, Maarit Lehti.
      Little is known how acute exercise-induced inflammation and metabolic stress affect immune cell bioenergetics and the portion of its components. Therefore, we investigated acute effects of eccentric-only (E), concentric-only (C) and combined eccentric-concentric resistance exercise (E + C) bouts on cellular respiration of peripheral blood mononuclear cells (PBMCs). Twelve strength-trained young men performed bench press resistance exercises in randomized order. Venous blood samples were drawn at pre-, 5 min post- and 24 h post-exercise. Several PBMC respiration states were measured using high-resolution respirometry. Levels of leukocytes, interleukin 6 (IL-6), C-reactive protein (CRP), creatine kinase (CK), blood lactate and maximum voluntary isometric force were measured from the same time points. Effects of blood lactate and pH change on bioenergetics of PBMCs were investigated ex vivo. PBMC routine respiration (p = 0.017), free routine capacity (p = 0.025) and ET-capacity (p = 0.038) decreased immediately after E + C. E responded in opposite manner 5 min post-exercise compared to E + C (p = 0.013) and C (p = 0.032) in routine respiration, and to E + C in free routine activity (p = 0.013). E + C > C > E was observed for increased lactate levels and decreased isometric force that correlated with routine respiration (R = -0.369, p = 0.035; R = 0.352, p = 0.048). Lactate and pH change did not affect bioenergetics of PBMCs. Acute resistance exercise affected cellular respiration of PBMCs, with training volume and the amount of metabolic stress appear influential. Results suggest that acute inflammation response does not contribute to changes seen in cellular respiration, but the level of peripheral muscle fatigue and metabolic stress could be explaining factors.
    Keywords:  bioenergetics; mitochondria; resistance training; training volume; white blood cells
    DOI:  https://doi.org/10.14814/phy2.15394
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