bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2022‒04‒03
23 papers selected by
Dylan Ryan
University of Cambridge
  1. T cell metabolism and possible therapeutic targets in systemic lupus erythematosus: a narrative review.
  2. Immunometabolic adaptation and immune plasticity in pregnancy and the bi-directional effects of obesity.
  3. T Cell Metabolism in Infection.
  4. Macrophage immunometabolism in inflammatory bowel diseases: From pathogenesis to therapy.
  5. Metabolism in atherosclerotic plaques: immunoregulatory mechanisms in the arterial wall.
  6. Metabolic regulation of CD8+ T cells: from mechanism to therapy.
  7. Neutral ceramidase-dependent regulation of macrophage metabolism directs intestinal immune homeostasis and controls enteric infection.
  8. The Role of Zinc in the T-Cell Metabolism in Infection Requires Further Investigation - An Opinion.
  9. Immunometabolic crosstalk during bacterial infection.
  10. Pro-inflammatory polarization of macrophages is associated with reduced endoplasmic reticulum-mitochondria interaction.
  11. Switching to the cyclic pentose phosphate pathway powers the oxidative burst in activated neutrophils.
  12. The mTORC1 Signaling Support Cellular Metabolism to Dictate Decidual NK Cells Function in Early Pregnancy.
  13. PTIP governs NAD+ metabolism by regulating CD38 expression to drive macrophage inflammation.
  14. Assessing Changes in Human Natural Killer Cell Metabolism Using the Seahorse Extracellular Flux Analyzer.
  15. TOR signaling is required for host lipid metabolic remodelling and survival following enteric infection in Drosophila.
  16. Metabolic Landscape of Bronchoalveolar Lavage Fluid in Coronavirus Disease 2019 at Single Cell Resolution.
  17. Glutamate blunts cell-killing effects of neutrophils in tumor microenvironment.
  18. Obesity alters pathology and treatment response in inflammatory disease.
  19. Fusobacterium nucleatum Accelerates Atherosclerosis via Macrophage-Driven Aberrant Proinflammatory Response and Lipid Metabolism.
  20. Tryptophan and the innate intestinal immunity: Crosstalk between metabolites, host innate immune cells and microbiota.
  21. Itaconate modifies JAK1.
  22. Mitochondrial activity is up-regulated in nonlesional atopic dermatitis and amenable to therapeutic intervention.
  23. SLC7A5 expression is up-regulated in peripheral blood T and B lymphocytes of systemic lupus erythematosus patients, associating with renal damage.
  1. Immunopharmacol Immunotoxicol. 2022 Mar 30. 1-14
    T cell metabolism and possible therapeutic targets in systemic lupus erythematosus: a narrative review.
    Marcela Muñoz-Urbano, Diana C Quintero-González, Gloria Vasquez.
      In the immunopathogenesis of systemic lupus erythematosus (SLE), there is a dysregulation of specific immune cells, including T cells. The metabolic reprogramming in T cells causes different effects. Metabolic programs are critical checkpoints in immune responses and are involved in the etiology of autoimmune disease. For instance, resting lymphocytes generate energy through oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO), whereas activated lymphocytes rapidly shift to the glycolytic pathway. Specifically, mitochondrial dysfunction, oxidative stress, abnormal metabolism (including glucose, lipid, and amino acid metabolism), and mTOR signaling are hallmarks of T lymphocyte metabolic dysfunction in SLE. Herein it is summarized how metabolic defects contribute to T cell responses in SLE, and some epigenetic alterations involved in the disease. Finally, it is shown how metabolic defects could be modified therapeutically.
    Keywords:  SLE; T cell metabolism; fatty acid oxidation; glycolysis; mTOR pathway; mitochondrial dysfunction
    DOI:  https://doi.org/10.1080/08923973.2022.2055568
  2. Clin Exp Immunol. 2022 Feb 24. pii: uxac003. [Epub ahead of print]
    Immunometabolic adaptation and immune plasticity in pregnancy and the bi-directional effects of obesity.
    April Rees, Oliver Richards, Megan Chambers, Benjamin J Jenkins, James G Cronin, Catherine A Thornton.
      Mandatory maternal metabolic and immunological changes are essential to pregnancy success. Parallel changes in metabolism and immune function make immunometabolism an attractive mechanism to enable dynamic immune adaptation during pregnancy. Immunometabolism is a burgeoning field with the underlying principle being that cellular metabolism underpins immune cell function. With whole body changes to the metabolism of carbohydrates, protein and lipids well recognised to occur in pregnancy and our growing understanding of immunometabolism as a determinant of immunoinflammatory effector responses, it would seem reasonable to expect immune plasticity during pregnancy to be linked to changes in the availability and handling of multiple nutrient energy sources by immune cells. While studies of immunometabolism in pregnancy are only just beginning, the recognised bi-directional interaction between metabolism and immune function in the metabolic disorder obesity might provide some of the earliest insights into the role of immunometabolism in immune plasticity in pregnancy. Characterised by chronic low-grade inflammation including in pregnant women, obesity is associated with numerous adverse outcomes during pregnancy and beyond for both mother and child. Concurrent changes in metabolism and immunoinflammation are consistently described but any causative link is not well established. Here we provide an overview of the metabolic and immunological changes that occur in pregnancy and how these might contribute to healthy versus adverse pregnancy outcomes with special consideration of possible interactions with obesity.
    Keywords:  immunometabolism; obesity; plasticity; pregnancy
    DOI:  https://doi.org/10.1093/cei/uxac003
  3. Front Immunol. 2022 ;13 840610
    T Cell Metabolism in Infection.
    Jonas Aakre Wik, Bjørn Steen Skålhegg.
      T lymphocytes (T cells) are divided into two functionally different subgroups the CD4+ T helper cells (Th) and the CD8+ cytotoxic T lymphocytes (CTL). Adequate CD4 and CD8 T cell activation to proliferation, clonal expansion and effector function is crucial for efficient clearance of infection by pathogens. Failure to do so may lead to T cell exhaustion. Upon activation by antigen presenting cells, T cells undergo metabolic reprograming that support effector functions. In this review we will discuss how metabolic reprograming dictates functionality during viral infections using severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human immunodeficiency virus (HIV) as examples. Moreover, we will briefly discuss T cell metabolic programs during bacterial infections exemplified by Mycobacterium tuberculosis (MT) infection.
    Keywords:  COVID-19; HIV; T cells; immunometabolism; infection; metabolism; tuberculosis
    DOI:  https://doi.org/10.3389/fimmu.2022.840610
  4. Pharmacol Ther. 2022 Mar 25. pii: S0163-7258(22)00070-5. [Epub ahead of print] 108176
    Macrophage immunometabolism in inflammatory bowel diseases: From pathogenesis to therapy.
    Xiaohua Pan, Qing Zhu, Xiaoliang Dong, Jiahong Li, He Liu, Zhengran Ren, Binbin Li, Li-Long Pan, Jia Sun.
      Inflammatory bowel disease (IBD), comprised of ulcerative colitis and Crohn's disease, is a chronic relapsing inflammatory disease of the gastrointestinal tract that closely related to immune dysfunction. Macrophages are the key gatekeeper of intestinal immune homeostasis and have vital influence on IBD. Hence, macrophages have been recognized as attractive targets to develop new therapeutic approaches for the disease. Recently, the growing field of immunometabolism has reinforced that metabolism reprogramming is a key determinant that dictates macrophage functions and subsequent disease progression. Herein, we elaborated how metabolic alterations underlie intestinal macrophage phenotype and function during IBD, and how microenvironmental cues trigger their metabolic reprogramming processes. More importantly, we deciphered the distinguishing characteristic of macrophage immunometabolism in IBD from other inflammatory diseases, and also summarized potential therapeutic approaches for IBD by manipulating cellular metabolism of macrophages. Finally, we discussed the major opportunities and challenges of harnessing metabolism to modulate aberrant macrophage responses in IBD. Altogether, our overview provides a framework for understanding the critical roles and potential therapeutic targets of macrophage immunometabolism in IBD.
    Keywords:  Gut microbiota; Immunometabolism; Inflammation; Inflammatory bowel disease; Macrophage; Therapy
    DOI:  https://doi.org/10.1016/j.pharmthera.2022.108176
  5. Clin Sci (Lond). 2022 Mar 31. 136(6): 435-454
    Metabolism in atherosclerotic plaques: immunoregulatory mechanisms in the arterial wall.
    Maria J Forteza, Daniel F J Ketelhuth.
      Over the last decade, there has been a growing interest to understand the link between metabolism and the immune response in the context of metabolic diseases but also beyond, giving then birth to a new field of research. Termed 'immunometabolism', this interdisciplinary field explores paradigms of both immunology and metabolism to provided unique insights into different disease pathogenic processes, and the identification of new potential therapeutic targets. Similar to other inflammatory conditions, the atherosclerotic inflammatory process in the artery has been associated with a local dysregulated metabolic response. Thus, recent studies show that metabolites are more than just fuels in their metabolic pathways, and they can act as modulators of vascular inflammation and atherosclerosis. In this review article, we describe the most common immunometabolic pathways characterised in innate and adaptive immune cells, and discuss how macrophages' and T cells' metabolism may influence phenotypic changes in the plaque. Moreover, we discuss the potential of targeting immunometabolism to prevent and treat cardiovascular diseases (CVDs).
    Keywords:  T-cells; atherosclerosis; cardiovascular disease; immunometabolism; immunomodulation; macrophages
    DOI:  https://doi.org/10.1042/CS20201293
  6. Antioxid Redox Signal. 2022 Mar 29.
    Metabolic regulation of CD8+ T cells: from mechanism to therapy.
    Ying Zheng, Xiaomin Wang, Min Huang.
      SIGNIFICANCE: Cancer immunotherapy has yielded striking anti-tumor effects in many cancers, yet the proportion of benefited patients are still limited. As key mediators of tumor suppression, CD8+ T cells are crucial for cancer immunotherapy. It has been widely appreciated that modulation of CD8+ T cell immunity could be an effective way to further improve the therapeutic benefit of immunotherapy.RECENT ADVANCES: Emerging evidence has underlined a close link between metabolism and immune functions, providing a metabolism-immune axis that is increasingly investigated for understanding CD8+ T cells regulation. On the other hand, growing findings have reported that tumors adopt multiple approaches to induce metabolic reprogramming of CD8+ T cells, leading to the compromised immunotherapy.
    CRITICAL ISSUES: CD8+ T cell metabolism in the tumor microenvironment (TME) is often adapted to diminish anti-tumor immune responses and thereby evade from immune surveillance. A better understanding of metabolic regulation of CD8+ T cells in the TME is believed to hold promise for opening a new therapeutic window to further improve the benefit of immunotherapy. We herein review the mechanistic understanding of how CD8+ T cell metabolism is reprogrammed in the TME, mainly focusing on the impact of nutrient availability and bioactive molecules secreted by surrounding cells.
    FUTURE DIRECTIONS: Future research should pay attention to tumor heterogeneity in the metabolic microenvironment and associated immune responses. It is also important to include the trending opinion of "precision medicine" in cancer immunotherapies to tailor metabolic interventions for individual patients in combination with immunotherapy treatments.
    DOI:  https://doi.org/10.1089/ars.2022.0040
  7. Cell Rep. 2022 Mar 29. pii: S2211-1247(22)00304-7. [Epub ahead of print]38(13): 110560
    Neutral ceramidase-dependent regulation of macrophage metabolism directs intestinal immune homeostasis and controls enteric infection.
    Rui Sun, Xuemei Gu, Chao Lei, Liang Chen, Shenghui Chu, Guangzhong Xu, Mark A Doll, Yi Tan, Wenke Feng, Leah Siskind, Craig J McClain, Zhongbin Deng.
      It is not clear how the complex interactions between diet and intestinal immune cells protect the gut from infection. Neutral ceramidase (NcDase) plays a critical role in digesting dietary sphingolipids. We find that NcDase is an essential factor that controls intestinal immune cell dynamics. Mice lacking NcDase have reduced cluster of differentiation (CD) 8αβ+ T cells and interferon (IFN)-γ+ T cells and increased macrophages in the intestine and fail to clear bacteria after Citrobacter rodentium infection. Mechanistically, cellular NcDase or extracellular vesicle (EV)-related NcDase generates sphingosine, which promotes macrophage-driven Th1 immunity. Loss of NcDase influences sphingosine-controlled glycolytic metabolism in macrophages, which regulates the bactericidal activity of macrophages. Importantly, administration of dietary sphingomyelin and genetic deletion or pharmacological inhibition of SphK1 can protect against C. rodentium infection. Our findings demonstrate that sphingosine profoundly alters macrophage glycolytic metabolism, leading to intestinal macrophage activation and T cell polarization, which prevent pathogen colonization of the gut.
    Keywords:  CP: Immunology; CP: Microbiology; Th1 cells; ceramide; defense; extracellular vesicles; glycolysis; inflammasomes; innate; intestine; mucosal immunology; sphingolipid
    DOI:  https://doi.org/10.1016/j.celrep.2022.110560
  8. Front Immunol. 2022 ;13 865504
    The Role of Zinc in the T-Cell Metabolism in Infection Requires Further Investigation - An Opinion.
    Consolato M Sergi.
      
    Keywords:  T-cell; metabolism; supplementation; thymus; zinc
    DOI:  https://doi.org/10.3389/fimmu.2022.865504
  9. Nat Microbiol. 2022 Apr;7(4): 497-507
    Immunometabolic crosstalk during bacterial infection.
    Gili Rosenberg, Sebastian Riquelme, Alice Prince, Roi Avraham.
      Following detection of bacteria, macrophages switch their metabolism from oxidative respiration through the tricarboxylic acid cycle to high-rate aerobic glycolysis. This immunometabolic shift enables pro-inflammatory and antimicrobial responses and is facilitated by the accumulation of fatty acids, tricarboxylic acid-derived metabolites and catabolism of amino acids. Recent studies have shown that these immunometabolites are co-opted by pathogens as environmental cues for expression of virulence genes. We review mechanisms by which host immunometabolites regulate bacterial pathogenicity and discuss opportunities for the development of therapeutics targeting metabolic host-pathogen crosstalk.
    DOI:  https://doi.org/10.1038/s41564-022-01080-5
  10. Biochem Biophys Res Commun. 2022 Mar 17. pii: S0006-291X(22)00419-3. [Epub ahead of print]606 61-67
    Pro-inflammatory polarization of macrophages is associated with reduced endoplasmic reticulum-mitochondria interaction.
    Leandro Henrique de Paula Assis, Gabriel de Gabriel Dorighello, Helena Coutinho Franco de Oliveira.
      Macrophages play a role in host defense, tissue remodeling and inflammation. Different inflammatory stimuli drive macrophage phenotypes and responses. In this study we investigated the relationship between macrophages immune phenotype and mitochondrial bioenergetics, cell redox state and endoplasmic reticulum (ER)-mitochondria interaction. Bacterial lipopolysaccharide (LPS) and interferon-γ (IFNγ) pro-inflammatory stimuli decreased oxidative metabolism (basal, phosphorylating and maximal conditions) and increased baseline glycolysis (117%) and glycolytic capacity (43%) in THP-1 macrophages. In contrast, interleukin-4 (IL4) and interleukin-13 (IL13) anti-inflammatory stimuli increased the oxygen consumption rates in baseline conditions (21%) and associated with ATP production (19%). LPS + IFNγ stimuli reduced superoxide anion levels by accelerating its conversion into hydrogen peroxide (H2O2) while IL4+IL13 decreased H2O2 release rates. The source of these oxidants was extra-mitochondrial and associated with increased NOX2 and SOD1 gene expression. LPS + IFNγ stimuli decreased ER-mitochondria contact sites as measured by IP3R1-VDAC1 interaction (34%) and markedly upregulated genes involved in mitochondrial fusion (9-10 fold, MFN1 and 2) and fission (∼7 fold, DRP1 and FIS1). Conversely, IL4+IL13 stimuli did not altered ER-mitochondria interactions nor MFN1 and 2 expression. Together, these results unveil ER-mitochondria interaction pattern as a novel feature of macrophage immunological, metabolic and redox profiles.
    Keywords:  Endoplasmic reticulum-mitochondria interaction; Macrophage; Mitochondrial respiration; Oxidants production
    DOI:  https://doi.org/10.1016/j.bbrc.2022.03.086
  11. Nat Metab. 2022 Mar;4(3): 389-403
    Switching to the cyclic pentose phosphate pathway powers the oxidative burst in activated neutrophils.
    Emily C Britt, Jorgo Lika, Morgan A Giese, Taylor J Schoen, Gretchen L Seim, Zhengping Huang, Pui Y Lee, Anna Huttenlocher, Jing Fan.
      Neutrophils are cells at the frontline of innate immunity that can quickly activate effector functions to eliminate pathogens upon stimulation. However, little is known about the metabolic adaptations that power these functions. Here we show rapid metabolic alterations in neutrophils upon activation, particularly drastic reconfiguration around the pentose phosphate pathway, which is specifically and quantitatively coupled to an oxidative burst. During this oxidative burst, neutrophils switch from glycolysis-dominant metabolism to a unique metabolic mode termed 'pentose cycle', where all glucose-6-phosphate is diverted into oxidative pentose phosphate pathway and net flux through upper glycolysis is reversed to allow substantial recycling of pentose phosphates. This reconfiguration maximizes NADPH yield to fuel superoxide production via NADPH oxidase. Disruptions of pentose cycle greatly suppress oxidative burst, the release of neutrophil extracellular traps and pathogen killing by neutrophils. Together, these results demonstrate the remarkable metabolic flexibility of neutrophils, which is essential for their functions as the first responders in innate immunity.
    DOI:  https://doi.org/10.1038/s42255-022-00550-8
  12. Front Immunol. 2022 ;13 771732
    The mTORC1 Signaling Support Cellular Metabolism to Dictate Decidual NK Cells Function in Early Pregnancy.
    Song Yan, Jie Dong, Chenxi Qian, Shuqiang Chen, Qian Xu, Hui Lei, Xiaohong Wang.
      Cellular metabolism plays an important role in regulating both human and murine NK cell functions. However, it remains unclear whether cellular metabolic process impacts on the function of decidual NK cells (dNK), essential tissue-resident immune cells maintaining the homeostasis of maternal-fetal interface. Remarkably, we found that glycolysis blockage enhances dNK VEGF-A production but restrains its proliferation. Furthermore, levels of IFN-γ and TNF-α secreted by dNK get decreased when glycolysis or oxidative phosphorylation (OXPHOS) is inhibited. Additionally, glycolysis, OXPHOS, and fatty acid oxidation disruption has little effects on the secretion and the CD107a-dependent degranulation of dNK. Mechanistically, we discovered that the mammalian target of rapamycin complex 1 (mTORC1) signaling inhibition leads to decreased glycolysis and OXPHOS in dNK. These limited metabolic processes are associated with attenuated dNK functions, which include restricted production of cytokines including IFN-γ and TNF-α, diminished CD107a-dependent degranulation, and restrained dNK proliferation. Finally, we reported that the protein levels of several glycolysis-associated enzymes are altered and the mTORC1 activity is significantly lower in the decidua of women with recurrent pregnancy loss (RPL) compared with normal pregnancy, which might give new insights about the pathogenesis of RPL. Collectively, our data demonstrate that glucose metabolism and mTORC1 signaling support dNK functions in early pregnancy.
    Keywords:  RPL; cytokines; cytotoxicity; decidual NK cells; mTORC1; metabolism
    DOI:  https://doi.org/10.3389/fimmu.2022.771732
  13. Cell Rep. 2022 Mar 29. pii: S2211-1247(22)00351-5. [Epub ahead of print]38(13): 110603
    PTIP governs NAD+ metabolism by regulating CD38 expression to drive macrophage inflammation.
    Qifan Wang, Jin Hu, Guoqiang Han, Peipei Wang, Sha Li, Jiwei Chang, Kexin Gao, Rong Yin, Yashu Li, Tong Zhang, Jihua Chai, Zhuying Gao, Tiantian Zhang, Ying Cheng, Chengli Guo, Jing Wang, Weidong Liu, Manman Cui, Yu Xu, Jinxuan Hou, Quan-Fei Zhu, Yu-Qi Feng, Haojian Zhang.
      NAD+ metabolism is involved in many biological processes. However, the underlying mechanism of how NAD+ metabolism is regulated remains elusive. Here, we find that PTIP governs NAD+ metabolism in macrophages by regulating CD38 expression and is required for macrophage inflammation. Through integrating histone modifications with NAD+ metabolic gene expression profiling, we identify PTIP as a key factor in regulating CD38 expression, the primary NAD+-consuming enzyme in macrophages. Interestingly, we find that PTIP deletion impairs the proinflammatory response of primary murine and human macrophages, promotes their metabolic switch from glycolysis to oxidative phosphorylation, and alters NAD+ metabolism via downregulating CD38 expression. Mechanistically, an intronic enhancer of CD38 is identified. PTIP regulates CD38 expression by cooperating with acetyltransferase p300 in establishing the CD38 active enhancer with enriched H3K27ac. Overall, our findings reveal a critical role for PTIP in fine-tuning the inflammatory responses of macrophages via regulating NAD+ metabolism.
    Keywords:  CD38; CP: Immunology; CP: Metabolism; NAD(+); PTIP; inflammation; macrophage
    DOI:  https://doi.org/10.1016/j.celrep.2022.110603
  14. Methods Mol Biol. 2022 ;2463 165-180
    Assessing Changes in Human Natural Killer Cell Metabolism Using the Seahorse Extracellular Flux Analyzer.
    Javier Traba, Olga M Antón.
      Natural killer (NK) cells are cytotoxic cells that mediate anti-tumor and anti-viral immunity. The response of NK cells to different cytokines and stimuli may involve cell survival, proliferation, and changes in their cytotoxic function. These responses will be supported by changes in cellular metabolism. Therefore, changes in NK metabolic parameters could somehow predict changes in NK cell function and cytotoxicity. In this chapter, we describe a protocol to measure NK cell metabolism in primary human NK cells by using an extracellular flux analyzer. This machine measures pH and oxygen changes in the medium and allows the study of NK cell glycolysis and mitochondrial respiration in real time with a small number of cells.
    Keywords:  Electron transporter chain; Extracellular flux analyzer; Glycolysis; Mitochondrial respiration; Natural killer cell
    DOI:  https://doi.org/10.1007/978-1-0716-2160-8_12
  15. Dis Model Mech. 2022 Apr 01. pii: dmm.049551. [Epub ahead of print]
    TOR signaling is required for host lipid metabolic remodelling and survival following enteric infection in Drosophila.
    Rujuta Deshpande, Byoungchun Lee, Yuemeng Qiao, Savraj S Grewal.
      When infected by enteric pathogenic bacteria, animals need to initiate local and whole-body defence strategies. While most attention has focused on the role innate immune anti-bacterial responses, less is known about how changes in host metabolism contribute to host defence. Using Drosophila as a model system, we identify induction of intestinal target-of-rapamycin (TOR) kinase signaling as a key adaptive metabolic response to enteric infection. We find that enteric infection induces both local and systemic induction of TOR independently of the IMD innate immune pathway, and we see that TOR functions together with IMD signaling to promote infection survival. These protective effects of TOR signaling are associated with re-modelling of host lipid metabolism. Thus, we see that TOR is required to limit excessive infection-mediated wasting of host lipid stores by promoting an increase in the levels of gut- and fat body-expressed lipid synthesis genes. Our data supports a model in which induction of TOR represents a host tolerance response to counteract infection-mediated lipid wasting in order to promote survival.
    Keywords:  Drosophila; Infection; Lipid metabolism; Physiology; TOR
    DOI:  https://doi.org/10.1242/dmm.049551
  16. Front Immunol. 2022 ;13 829760
    Metabolic Landscape of Bronchoalveolar Lavage Fluid in Coronavirus Disease 2019 at Single Cell Resolution.
    Ming-Ming Shao, Meier Shi, Juan Du, Xue-Bin Pei, Bei-Bei Gu, Feng-Shuang Yi.
      Abnormal function of immune cells is one of the key mechanisms leading to severe clinical symptoms in coronavirus disease 2019 patients, and metabolic pathways can destroy the function of the immune system by affecting innate and adaptive immune responses. However, the metabolic characteristics of the immune cells of the SARS-CoV-2 infected organs in situ remaining elusive. We reanalyzed the metabolic-related gene profiles in single-cell RNA sequencing data, drew the metabolic landscape in bronchoalveolar lavage fluid immune cells, and elucidated the metabolic remodeling mechanism that might lead to the progression of COVID-19 and the cytokine storm. Enhanced glycolysis is the most important common metabolic feature of all immune cells in COVID-19 patients. CCL2+ T cells, Group 2 macrophages with high SPP1 expression and myeloid dendritic cells are among the main contributors to the cytokine storm produced by infected lung tissue. Two metabolic analysis methods, including Compass, showed that glycolysis, fatty acid metabolism, bile acid synthesis and purine and pyrimidine metabolism levels of CCL2+ T cells, Group 2 macrophages and myeloid dendritic cells were upregulated and correlated with cytokine storms of COVID-19 patients. This might be the key metabolic regulatory factor for immune cells to produce large quantities of cytokines.
    Keywords:  COVID-19; Metabolic reprogramming; bronchoalveolar lavage fluid; cytokine storm; single cell RNA sequencing
    DOI:  https://doi.org/10.3389/fimmu.2022.829760
  17. Cancer Sci. 2022 Apr 01.
    Glutamate blunts cell-killing effects of neutrophils in tumor microenvironment.
    Tiantian Xiong, Ping He, Mi Zhou, Dan Zhong, Teng Yang, Wenhui He, Zhizhen Xu, Zongtao Chen, Yang-Wuyue Liu, Shuang-Shuang Dai.
      Neutrophils are the first defenders of innate system for injury and infection. It is gradually recognized as important participants in tumor initiation and development due to heterogeneity and plasticity of neutrophils. In tumor microenvironment (TME), neutrophils might exert anti-tumor and pro-tumor functions depending on its surroundings. Tumor cells systemically alter intracellular amino acid (AA) metabolism and extracellular AA distribution to meet their proliferation need, leading to metabolic reprogramming and TME reshaping. However, the underlying mechanisms about how altered AAs affect neutrophils in TME are less-explored. Here, we identified that abundant glutamate releasing from tumor cells blunted neutrophils' cell-killing effects toward tumor cells in vitro and in vivo. Mass spectrometric detection, tumor flow and western experiments proved that increased level of pSTAT3/RAB10/ARF4 mediated by glutamate, were accompanied with immunosuppressive phenotypes of neutrophils in TME. We also discovered that Riluzole, FDA-approved glutamate release inhibitor, significantly inhibited tumor growth by restoring neutrophils' cell-killing effects though decreasing glutamate secretion from tumor cells. These findings highlight the importance of tumor-released glutamate on neutrophils transformation in TME, providing new possible cancer treatment targeting at altered glutamate metabolism.
    Keywords:  Glutamate; Neutrophil; Riluzole; STAT3; Tumor microenvironment
    DOI:  https://doi.org/10.1111/cas.15355
  18. Nature. 2022 Mar 30.
    Obesity alters pathology and treatment response in inflammatory disease.
    Sagar P Bapat, Caroline Whitty, Cody T Mowery, Yuqiong Liang, Arum Yoo, Zewen Jiang, Michael C Peters, Ling-Juan Zhang, Ian Vogel, Carmen Zhou, Vinh Q Nguyen, Zhongmei Li, Christina Chang, Wandi S Zhu, Annette T Hastie, Helen He, Xin Ren, Wenli Qiu, Sarah G Gayer, Chang Liu, Eun Jung Choi, Marlys Fassett, Jarish N Cohen, Jamie L Sturgill, Laura E Crotty Alexander, Jae Myoung Suh, Christopher Liddle, Annette R Atkins, Ruth T Yu, Michael Downes, Sihao Liu, Barbara S Nikolajczyk, In-Kyu Lee, Emma Guttman-Yassky, K Mark Ansel, Prescott G Woodruff, John V Fahy, Dean Sheppard, Richard L Gallo, Chun Jimmie Ye, Ronald M Evans, Ye Zheng, Alexander Marson.
      Decades of work have elucidated cytokine signalling and transcriptional pathways that control T cell differentiation and have led the way to targeted biologic therapies that are effective in a range of autoimmune, allergic and inflammatory diseases. Recent evidence indicates that obesity and metabolic disease can also influence the immune system1-7, although the mechanisms and effects on immunotherapy outcomes remain largely unknown. Here, using two models of atopic dermatitis, we show that lean and obese mice mount markedly different immune responses. Obesity converted the classical type 2 T helper (TH2)-predominant disease associated with atopic dermatitis to a more severe disease with prominent TH17 inflammation. We also observed divergent responses to biologic therapies targeting TH2 cytokines, which robustly protected lean mice but exacerbated disease in obese mice. Single-cell RNA sequencing coupled with genome-wide binding analyses revealed decreased activity of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) in TH2 cells from obese mice relative to lean mice. Conditional ablation of PPARγ in T cells revealed that PPARγ is required to focus the in vivo TH response towards a TH2-predominant state and prevent aberrant non-TH2 inflammation. Treatment of obese mice with a small-molecule PPARγ agonist limited development of TH17 pathology and unlocked therapeutic responsiveness to targeted anti-TH2 biologic therapies. These studies reveal the effects of obesity on immunological disease and suggest a precision medicine approach to target the immune dysregulation caused by obesity.
    DOI:  https://doi.org/10.1038/s41586-022-04536-0
  19. Front Microbiol. 2022 ;13 798685
    Fusobacterium nucleatum Accelerates Atherosclerosis via Macrophage-Driven Aberrant Proinflammatory Response and Lipid Metabolism.
    Jieyu Zhou, Lin Liu, Peiyao Wu, Lei Zhao, Yafei Wu.
      Periodontitis, an oral chronic inflammatory disease, is reported to show an association with atherosclerotic vascular disease. Fusobacterium nucleatum is an oral commensal bacterium that is abundantly implicated in various forms of periodontal diseases; however, its role in the pathogenesis of atherosclerosis is unclear. This study aimed to elucidate the underlying pathogenic mechanisms of atherosclerosis induced by F. nucleatum to provide new insight on the prevention and treatment of atherosclerosis. We used an animal model, that is, ApoE-/- mice were infected with F. nucleatum by oral gavage, and in vitro co-culture models to assess the pathogenicity of F. nucleatum. The results indicate that F. nucleatum ATCC 25586 invaded aortic tissues and substantially increased the progression of atherosclerotic lesions. In addition, F. nucleatum changed plaque composition into a less-stable phenotype, characterized with increased subcutaneous macrophage infiltration, M1 polarization, lipid deposition, cell apoptosis, and reduced extracellular matrix and collagen content. The serum levels of pro-atherosclerotic factors, such as interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, monocyte chemoattractant protein-1 (MCP-1), c-reactive protein, and oxidized low-density lipoprotein (ox-LDL) and microRNAs (miR-146a, miR-155, and miR-23b) were considerably increased after F. nucleatum stimulation, whereas HDL-c level was reduced. F. nucleatum induced in vitro macrophage apoptosis in a time- and dose-dependent manner. F. nucleatum facilitated ox-LDL-induced cholesterol phagocytosis and accumulation by regulating the expression of lipid metabolism-related genes (AR-A1, ACAT1, ABCA1, and ABCG1). F. nucleatum further worsened the atherosclerotic plaque microenvironment by considerably increasing the levels of IL-6; IL-1β; TNF-α; MCP-1; and MMP-2, 8, and 9 and by suppressing fibronectin (FN) 1 levels during foam cell formation. This study shows that F. nucleatum ATCC 25586 is implicated in atherosclerosis by causing aberrant activation and lipid metabolism in macrophage.
    Keywords:  F. nucleatum; atherosclerosis; inflammation; lipid metabolism; macrophage; microRNA; periodontitis; polarization
    DOI:  https://doi.org/10.3389/fmicb.2022.798685
  20. Eur J Immunol. 2022 Apr 01.
    Tryptophan and the innate intestinal immunity: Crosstalk between metabolites, host innate immune cells and microbiota.
    Yunke Li, Ning Liu, Yao Ge, Ying Yang, Fazheng Ren, Zhenlong Wu.
      The intestinal mucosal barrier is critical for the absorption of nutrients and the health of both humans and animals. Recent publications from clinical and experimental studies have shown the importanceof the nutrients-bacteria-host interaction for the intestinal homeostasis. Dysfunction of these interactions has been reported to be associated with metabolic disorders and development of intestinal diseases, such as the irritable bowel syndrome and inflammatory bowel diseases. Tryptophan and its metabolites, including kynurenine, kynurenic acid, and 5-hydroxytrptamine, can influence the proliferation of enterocytes, intestinal integrity and immune response, as well as intestinal microbiota, therefore regulating and contributing to the intestinal health. In this review, we highlight recent findings on the effect of tryptophan and its metabolites on the mucosal barrier and intestinal homeostasis and its regulation of innate immune response. Moreover, we present the signaling pathways related to Trp metabolism, such as mammalian target of rapamycin, aryl hydrocarbon receptor, and pregnane X receptor, that contribute to the intestinal homeostasis and discuss future perspectives on spontaneous interference in host tryptophan metabolism as potential clinical strategies of intestinal diseases. This article is protected by copyright. All rights reserved.
    Keywords:  aryl hydrocarbon receptor; intestinal homeostasis; mammalian target of rapamycin; pregnane X receptor; tryptophan metabolism
    DOI:  https://doi.org/10.1002/eji.202149401
  21. Nat Immunol. 2022 Mar 30.
    Itaconate modifies JAK1.
    Nicholas J Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-022-01181-7
  22. J Invest Dermatol. 2022 Mar 24. pii: S0022-202X(22)00205-6. [Epub ahead of print]
    Mitochondrial activity is up-regulated in nonlesional atopic dermatitis and amenable to therapeutic intervention.
    Geraldine Leman, Petra Pavel, Martin Hermann, Debra Crumrine, Peter M Elias, Deborah Minzaghi, Dominique Goudounèche, Natalia M Roshardt Prieto, Maria Cavinato, Andrea Wanner, Stefan Blunder, Robert Gruber, Pidder Jansen-Dürr, Sandrine Dubrac.
      Previous work has shown increased expression of genes related to oxidative stress in nonlesional atopic dermatitis (ADNL) skin. Although mitochondria are key regulators of reactive oxygen species production, their function in AD has never been investigated. Energy metabolism and the oxidative stress response were studied in keratinocytes (KCs) from patients with ADNL or healthy controls. Moreover, ADNL human epidermal equivalent (HEEs) were treated with Tigecycline or MitoQ. We found that pyruvate and glucose were used as energy substrates by ADNL KCs. Increased mitochondrial oxidation of (very) long chain fatty acids, associated with enhanced complex I and II activities, was observed in ADNL KCs. Metabolomic analysis revealed increased tricarboxylic acid cycle turnover. Increased aerobic metabolism generated oxidative stress in ADNL KCs. ADNL HEEs displayed increased mitochondrial function and an enhanced oxidative stress response compared to controls. Treatment of ADNL HEEs with Tigecycline or MitoQ largely corrected the AD profile, including high p-65NF-κB, abnormal lamellar bodies and cellular damage. Furthermore, we found that glycolysis supports but does not supersede mitochondrial metabolism in ADNL KCs. Thus, aerobic metabolism predominates in ADNL but leads to oxidative stress. Therefore, mitochondria could be a reservoir of potential therapeutic targets in AD.
    Keywords:  Atopic dermatitis; OXPHOS; glycolysis; lipid; metabolism; mitochondria; oxidative stress
    DOI:  https://doi.org/10.1016/j.jid.2022.01.035
  23. Clin Immunol. 2022 Mar 25. pii: S1521-6616(22)00068-7. [Epub ahead of print]237 108987
    SLC7A5 expression is up-regulated in peripheral blood T and B lymphocytes of systemic lupus erythematosus patients, associating with renal damage.
    Juan Tian, Xiaowei Li, Yiru Jiang, Feng Gao, Bomiao Ju, Jiayue Chen, Wenhua Zhu, Lan He, Liesu Meng, Shemin Lu.
      Metabolic reprogramming of immune cells has been proven to be important for systemic lupus erythematosus (SLE). This study aims to understand the role of SLC7A5, an amino acid transporter, in SLE. We analyzed SLC7A5 mRNA expression of SLE patients compared to healthy controls using GEO database, and found that it was increased in CD4+ T cells and CD19+ B cells. We then confirmed the expression up-regulation using flow cytometry and found that the proportion of SLC7A5+ cells and its expression were increased in peripheral blood T and B cells from SLE patients. Importantly, SLC7A5 expression in T and B cells was positively correlated with blood urea nitrogen and serum creatinine. Therefore, we conclude that SLC7A5, up-regulating in circulating T and B cells, correlates with kidney function, suggesting its potential role in mediating renal damage in SLE, which provides novel insight into SLE pathogenesis and provides a potential biomarker for disease.
    Keywords:  B cells; Lupus nephritis; SLC7A5; SLE; T cells
    DOI:  https://doi.org/10.1016/j.clim.2022.108987
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