bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2022–08–07
33 papers selected by
Dylan Ryan, University of Cambridge
  1. Mitochondrial ROS promotes susceptibility to infection via gasdermin D-mediated necroptosis.
  2. CD24-Siglec axis is an innate immune checkpoint against metaflammation and metabolic disorder.
  3. Aconitate decarboxylase 1 regulates glucose homeostasis and obesity in mice.
  4. Macrophage Polarization, Metabolic Reprogramming, and Inflammatory Effects in Ischemic Heart Disease.
  5. Glutamine metabolism modulates chondrocyte inflammatory response.
  6. Immune cell cholinergic signaling in adipose thermoregulation and immunometabolism.
  7. Protein Kinase CK2 Controls CD8+ T Cell Effector and Memory Function during Infection.
  8. T cell metabolism as interpreted in obesity-associated inflammation.
  9. Effects of Metabolism on Macrophage Polarization Under Different Disease Backgrounds.
  10. α2-3 Sialic acid binding and uptake by human monocyte-derived dendritic cells alters metabolism and cytokine release and initiates tolerizing T cell programming.
  11. T-bet B or not T-bet B, is that the question in obesity-related metabolic disease?
  12. The IRG1/itaconate/TFEB axis: A new weapon in macrophage antibacterial defense.
  13. Glycogen metabolism reprogramming promotes inflammation in coal dust-exposed lung.
  14. Linking B cell metabolism to immune regulation: the neurotransmitter GABA.
  15. Inhibition of Glycolysis Impairs Retinoic Acid-Inducible Gene I-Mediated Antiviral Responses in Primary Human Dendritic Cells.
  16. Immuno-antibiotics: targeting microbial metabolic pathways sensed by unconventional T cells.
  17. Editorial: The role of immunometabolism in autoimmune mediated and autoinflammatory disorders.
  18. Obesity and Fatty Acids Promote Mitochondrial Translocation of STAT3 Through ROS-Dependent Mechanisms.
  19. Bile acid restrained T cell activation explains cholestasis aggravated hepatitis B virus infection.
  20. Iron controls T helper cell pathogenicity by promoting glucose metabolism in autoimmune myopathy.
  21. mTOR Participates in the Formation, Maintenance, and Function of Memory CD8+T Cells Regulated by Glycometabolism.
  22. Editor's Note: Relates to: 'Immuno-antibiotics: targeting microbial metabolic pathways sensed by unconventional T cells'.
  23. Selenoprotein I deficiency in T cells promotes differentiation into tolerant phenotypes while decreasing Th17 pathology.
  24. Loss of myeloid lipoprotein lipase exacerbates adipose tissue fibrosis with collagen VI deposition and hyperlipidemia in leptin-deficient obese mice.
  25. Acidic Cannabinoids Suppress Proinflammatory Cytokine Release by Blocking Store-operated Calcium Entry.
  26. Store-operated calcium entry controls innate and adaptive immune cell function in inflammatory bowel disease.
  27. Gut microbiota-derived metabolites confer protection against SARS-CoV-2 infection.
  28. Elp3-mediated codon-dependent translation promotes mTORC2 activation and regulates macrophage polarization.
  29. The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis.
  30. Chlamydia trachomatis development requires both host glycolysis and oxidative phosphorylation but has only minor effects on these pathways.
  31. lncRNA HITT Inhibits Lactate Production by Repressing PKM2 Oligomerization to Reduce Tumor Growth and Macrophage Polarization.
  32. Francisella tularensis Exploits AMPK Activation to Harvest Host-Derived Nutrients Liberated from Host Lipolysis.
  33. Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis.
  1. Cell. 2022 Jul 29. pii: S0092-8674(22)00790-5. [Epub ahead of print]
    Mitochondrial ROS promotes susceptibility to infection via gasdermin D-mediated necroptosis.
    Chi G Weindel, Eduardo L Martinez, Xiao Zhao, Cory J Mabry, Samantha L Bell, Krystal J Vail, Aja K Coleman, Jordyn J VanPortfliet, Baoyu Zhao, Allison R Wagner, Sikandar Azam, Haley M Scott, Pingwei Li, A Phillip West, Jason Karpac, Kristin L Patrick, Robert O Watson.
      Although mutations in mitochondrial-associated genes are linked to inflammation and susceptibility to infection, their mechanistic contributions to immune outcomes remain ill-defined. We discovered that the disease-associated gain-of-function allele Lrrk2G2019S (leucine-rich repeat kinase 2) perturbs mitochondrial homeostasis and reprograms cell death pathways in macrophages. When the inflammasome is activated in Lrrk2G2019S macrophages, elevated mitochondrial ROS (mtROS) directs association of the pore-forming protein gasdermin D (GSDMD) to mitochondrial membranes. Mitochondrial GSDMD pore formation then releases mtROS, promoting a switch to RIPK1/RIPK3/MLKL-dependent necroptosis. Consistent with enhanced necroptosis, infection of Lrrk2G2019S mice with Mycobacterium tuberculosis elicits hyperinflammation and severe immunopathology. Our findings suggest a pivotal role for GSDMD as an executer of multiple cell death pathways and demonstrate that mitochondrial dysfunction can direct immune outcomes via cell death modality switching. This work provides insights into how LRRK2 mutations manifest or exacerbate human diseases and identifies GSDMD-dependent necroptosis as a potential target to limit Lrrk2G2019S-mediated immunopathology.
    Keywords:  Drosophila melanogaster; LRRK2; Mycobacterium tuberculosis; Parkinson’s disease; RIPK3; immunometabolism; inflammasome; inflammation; innate immunity; pyroptosis
    DOI:  https://doi.org/10.1016/j.cell.2022.06.038
  2. Cell Metab. 2022 Aug 02. pii: S1550-4131(22)00304-7. [Epub ahead of print]34(8): 1088-1103.e6
    CD24-Siglec axis is an innate immune checkpoint against metaflammation and metabolic disorder.
    Xu Wang, Mingyue Liu, Jifeng Zhang, Nicholas K Brown, Peng Zhang, Yan Zhang, Heng Liu, Xuexiang Du, Wei Wu, Martin Devenport, Weng Tao, Yang Mao-Draayer, Guo-Yun Chen, Y Eugene Chen, Pan Zheng, Yang Liu.
      The molecular interactions that regulate chronic inflammation underlying metabolic disease remain largely unknown. Since the CD24-Siglec interaction regulates inflammatory response to danger-associated molecular patterns (DAMPs), we have generated multiple mouse strains with single or combined mutations of Cd24 or Siglec genes to explore the role of the CD24-Siglec interaction in metaflammation and metabolic disorder. Here, we report that the CD24-Siglec-E axis, but not other Siglecs, is a key suppressor of obesity-related metabolic dysfunction. Inactivation of the CD24-Siglec-E pathway exacerbates, while CD24Fc treatment alleviates, diet-induced metabolic disorders, including obesity, dyslipidemia, insulin resistance, and nonalcoholic steatohepatitis (NASH). Mechanistically, sialylation-dependent recognition of CD24 by Siglec-E induces SHP-1 recruitment and represses metaflammation to protect against metabolic syndrome. A first-in-human study of CD24Fc (NCT02650895) supports the significance of this pathway in human lipid metabolism and inflammation. These findings identify the CD24-Siglec-E axis as an innate immune checkpoint against metaflammation and metabolic disorder and suggest a promising therapeutic target for metabolic disease.
    Keywords:  CD24; NASH; Siglec-E; Siglecs; insulin resistance; metabolic syndrome; metaflammation; obesity; sialic acid-binding immunoglobulin-like lectins; sialylation
    DOI:  https://doi.org/10.1016/j.cmet.2022.07.005
  3. Obesity (Silver Spring). 2022 Aug 04.
    Aconitate decarboxylase 1 regulates glucose homeostasis and obesity in mice.
    Ryan A Frieler, Thomas M Vigil, Jianrui Song, Christy Leung, Daniel R Goldstein, Carey N Lumeng, Richard M Mortensen.
       OBJECTIVE: The intersection between immunology and metabolism contributes to the pathogenesis of obesity-associated metabolic diseases as well as molecular control of inflammatory responses. The metabolite itaconate and the cell-permeable derivatives have robust anti-inflammatory effects; therefore, it is hypothesized that cis-aconitate decarboxylase (Acod1)-produced itaconate has a protective, anti-inflammatory effect during diet-induced obesity and metabolic disease.
    METHODS: Wild-type and Acod1-/- mice were subjected to diet-induced obesity. Glucose metabolism was analyzed by glucose tolerance tests, insulin tolerance tests, and indirect calorimetry. Gene expression and transcriptome analysis was performed using quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and RNA sequencing.
    RESULTS: Wild-type and Acod1-/- mice on high-fat diet had equivalent weight gain, but Acod1-/- mice had impaired glucose metabolism. Insulin tolerance tests and glucose tolerance tests after 12 weeks on high-fat diet revealed significantly higher blood glucose levels in Acod1-/- mice. This was associated with significant enrichment of inflammatory gene sets and a reduction in genes related to adipogenesis and fatty acid metabolism. Analysis of naive Acod1-/- mice showed a significant increase in fat deposition at 3 and 6 months of age and obesity and insulin resistance by 12 months.
    CONCLUSIONS: The data show that Acod1 has an important role in the regulation of glucose homeostasis and obesity under normal and high-fat diet conditions.
    DOI:  https://doi.org/10.1002/oby.23509
  4. Front Immunol. 2022 ;13 934040
    Macrophage Polarization, Metabolic Reprogramming, and Inflammatory Effects in Ischemic Heart Disease.
    Xiaoqian Sun, Yanqin Li, Qiong Deng, Yueyao Hu, Jianteng Dong, Wei Wang, Yong Wang, Chun Li.
      Macrophages are highly plastic cells, and the polarization-activating actions that represent their functional focus are closely related to metabolic reprogramming. The metabolic reprogramming of macrophages manifests itself as a bias toward energy utilization, transforming their inflammatory phenotype by changing how they use energy. Metabolic reprogramming effects crosstalk with the biological processes of inflammatory action and are key to the inflammatory function of macrophages. In ischemic heart disease, phenotypic polarization and metabolic shifts in circulating recruitment and tissue-resident macrophages can influence the balance of inflammatory effects in the heart and determine disease regression and prognosis. In this review, we present the intrinsic link between macrophage polarization and metabolic reprogramming, discussing the factors that regulate macrophages in the inflammatory effects of ischemic heart disease. Our aim is to estabilsh reliable regulatory pathways that will allow us to better target the macrophage metabolic reprogramming process and improve the symptoms of ischemic heart disease.
    Keywords:  inflammation; ischemic heart disease; macrophage; metabolic reprogramming; polarization
    DOI:  https://doi.org/10.3389/fimmu.2022.934040
  5. Elife. 2022 Aug 02. pii: e80725. [Epub ahead of print]11
    Glutamine metabolism modulates chondrocyte inflammatory response.
    Manoj Arra, Gaurav Swarnkar, Naga Suresh Adapala, Syeda-Kanwal Batool Naqvi, Lei Cai, Muhammad Farooq Rai, Srikanth Singamaneni, Gabriel Mbalaviele, Robert Brophy, Yousef Abu-Amer.
      Osteoarthritis is the most common joint disease in the world with significant societal consequences, but lacks effective disease modifying interventions. The pathophysiology consists of a prominent inflammatory component that can be targeted to prevent cartilage degradation and structural defects. Intracellular metabolism has emerged as a culprit of the inflammatory response in chondrocytes, with both processes co-regulating each other. The role of glutamine metabolism in chondrocytes, especially in the context of inflammation, lacks a thorough understanding and is the focus of this work. We display that mouse chondrocytes utilize glutamine for energy production and anabolic processes. Furthermore, we show that glutamine deprivation itself causes metabolic reprogramming and decreases the inflammatory response of chondrocytes through inhibition of NF-κB activity. Finally, we display that glutamine deprivation promotes autophagy and that ammonia is an inhibitor of autophagy. Overall, we identify a relationship between glutamine metabolism and inflammatory signaling and display the need for increased study of chondrocyte metabolic systems.
    Keywords:  immunology; inflammation; mouse
    DOI:  https://doi.org/10.7554/eLife.80725
  6. Trends Immunol. 2022 Aug 03. pii: S1471-4906(22)00143-0. [Epub ahead of print]
    Immune cell cholinergic signaling in adipose thermoregulation and immunometabolism.
    Yingxu Ma, Heejin Jun, Jun Wu.
      Research focusing on adipose immunometabolism has been expanded from inflammation in white fat during obesity development to immune cell function regulating thermogenic fat, energy expenditure, and systemic metabolism. This opinion discusses our current understanding of how resident immune cells within the thermogenic fat niche may regulate whole-body energy homeostasis. Furthermore, various types of immune cells can synthesize acetylcholine (ACh) and regulate important physiological functions. We highlight a unique subset of cholinergic macrophages within subcutaneous adipose tissue, termed cholinergic adipose macrophages (ChAMs); these macrophages interact with beige adipocytes through cholinergic receptor nicotinic alpha 2 subunit (CHRNA2) signaling to induce adaptive thermogenesis. We posit that these newly identified thermoregulatory macrophages may broaden our view of immune system functions for maintaining metabolic homeostasis and potentially treating obesity and metabolic disorders.
    Keywords:  CHRNA2; ChAT; acetylcholine; beige adipocyte; cholinergic adipose macrophage; metabolic homeostasis; non-neuronal cholinergic signaling; thermogenesis
    DOI:  https://doi.org/10.1016/j.it.2022.07.006
  7. J Immunol. 2022 Aug 01. pii: ji2101080. [Epub ahead of print]
    Protein Kinase CK2 Controls CD8+ T Cell Effector and Memory Function during Infection.
    Wei Yang, Hairong Wei, Gloria A Benavides, William J Turbitt, Jessica A Buckley, Xiaosen Ouyang, Lianna Zhou, Jianhua Zhang, Laurie E Harrington, Victor M Darley-Usmar, Hongwei Qin, Etty N Benveniste.
      Protein kinase CK2 is a serine/threonine kinase composed of two catalytic subunits (CK2α and/or CK2α') and two regulatory subunits (CK2β). CK2 promotes cancer progression by activating the NF-κB, PI3K/AKT/mTOR, and JAK/STAT pathways, and also is critical for immune cell development and function. The potential involvement of CK2 in CD8+ T cell function has not been explored. We demonstrate that CK2 protein levels and kinase activity are enhanced upon mouse CD8+ T cell activation. CK2α deficiency results in impaired CD8+ T cell activation and proliferation upon TCR stimulation. Furthermore, CK2α is involved in CD8+ T cell metabolic reprogramming through regulating the AKT/mTOR pathway. Lastly, using a mouse Listeria monocytogenes infection model, we demonstrate that CK2α is required for CD8+ T cell expansion, maintenance, and effector function in both primary and memory immune responses. Collectively, our study implicates CK2α as an important regulator of mouse CD8+ T cell activation, metabolic reprogramming, and differentiation both in vitro and in vivo.
    DOI:  https://doi.org/10.4049/jimmunol.2101080
  8. Endocrinology. 2022 Aug 06. pii: bqac124. [Epub ahead of print]
    T cell metabolism as interpreted in obesity-associated inflammation.
    Leena P Bharath, Samantha Hart, Barbara S Nikolajczyk.
      The appreciation of metabolic regulation of T cell function has exploded over the past decade, as has our understanding of how inflammation fuels comorbidities of obesity, including type 2 diabetes. The likelihood that obesity fundamentally alters T cell metabolism and thus chronic obesity-associated inflammation is high, but studies testing causal relationships remain under-represented. We searched PubMed for key words including mitochondria, obesity, T cell, type 2 diabetes, cristae, fission, fusion, redox, and reactive oxygen species to identify foundational and more recent studies that address these topics or cite foundational work. We investigated primary papers cited by reviews found in these searches, and highlight recent work with >100 citations to illustrate the state of the art in understanding mechanisms that control metabolism and thus function of various T cell subsets in obesity. However, "popularity" of a paper over the first 5 years after publication cannot assess long-term impact; thus some likely important work with fewer citations is also highlighted. We feature studies of human cells, supplementing with studies from animal models that suggest future directions for human cell research. This approach identified gaps in the literature that will need filled before we can estimate efficacy of mitochondria-targeted drugs in clinical trials to alleviate pathogenesis of obesity-associated inflammation.
    Keywords:  human; mitochondria; prediabetes; type 2 diabetes
    DOI:  https://doi.org/10.1210/endocr/bqac124
  9. Front Immunol. 2022 ;13 880286
    Effects of Metabolism on Macrophage Polarization Under Different Disease Backgrounds.
    Jia-Xue Sun, Xiang-Hong Xu, Liping Jin.
      Macrophages are versatile immune cells associated with various diseases, and their phenotypes and functions change on the basis of the surrounding environments. Reprogramming of metabolism is required for the proper polarization of macrophages. This review will focus on basic metabolic pathways, the effects of key enzymes and specific products, relationships between cellular metabolism and macrophage polarization in different diseases and the potential prospect of therapy targeted key metabolic enzymes. In particular, the types and characteristics of macrophages at the maternal-fetal interface and their effects on a successful conception will be discussed.
    Keywords:  macrophage; maternal-fetal interface; metabolism; polarization; pregnancy
    DOI:  https://doi.org/10.3389/fimmu.2022.880286
  10. Immunother Adv. 2021 Jan;1(1): ltab012
    α2-3 Sialic acid binding and uptake by human monocyte-derived dendritic cells alters metabolism and cytokine release and initiates tolerizing T cell programming.
    Joyce Lübbers, Rui-Jún Eveline Li, Friederike S Gorki, Sven C M Bruijns, Ashley Gallagher, Hakan Kalay, Martino Ambrosini, Douwe Molenaar, Jan Van den Bossche, Sandra J van Vliet, Yvette van Kooyk.
      Dendritic cells (DCs) are key in the initiation of the adaptive T cell responses to tailor adequate immunity that corresponds to the type of pathogen encountered. Oppositely, DCs control the resolution phase of inflammation and are able to induce tolerance after receiving anti-inflammatory cytokines or upon encounter of self-associated molecular patterns, such as α2-3 linked sialic acid (α2-3sia).
    OBJECTIVE: We here investigated whether α2-3sia, that bind immune inhibitory Siglec receptors, would alter signaling and reprogramming of LPS-stimulated human monocyte-derived DCs (moDCs).
    METHODS AND RESULTS: Transcriptomic analysis of moDCs stimulated with α2-3sia-conjugated dendrimers revealed differentially expressed genes related to metabolic pathways, cytokines, and T cell differentiation. An increase in genes involved in ATPase regulator activity, oxidoreductase activity, and glycogen metabolic processes was detected. Metabolic extracellular flux analysis confirmed a more energetic moDC phenotype upon α2-3sia binding as evidenced by an increase in both glycolysis and mitochondrial oxidative phosphorylation. TH1 differentiation promoting genes IFNL and IL27, were significantly downregulated in the presence of α2-3sia. Functional assays confirmed that α2-3sia binding to moDCs induced phosphorylation of Siglec-9, reduced production of inflammatory cytokines IL-12 and IL-6, and increased IL-10. Surprisingly, α2-3sia-differentiated moDCs promoted FoxP3+CD25+/-CD127- regulatory T cell differentiation and decreased FoxP3-CD25-CD127- effector T cell proliferation.
    CONCLUSIONS: In conclusion, we demonstrate that α2-3sia binding to moDCs, phosphorylates Siglec-9, alters metabolic pathways, cytokine signaling, and T cell differentiation processes in moDCs and promotes regulatory T cells. The sialic acid-Siglec axis on DCs is therefore, a novel target to induce tolerance and to explore for immunotherapeutic interventions aimed to restore inflammatory processes.
    Keywords:  Sialic acids and Siglecs; dendritic cells; glycolysis; regulatory T cells; tolerance
    DOI:  https://doi.org/10.1093/immadv/ltab012
  11. Cell Metab. 2022 Aug 02. pii: S1550-4131(22)00307-2. [Epub ahead of print]34(8): 1081-1082
    T-bet B or not T-bet B, is that the question in obesity-related metabolic disease?
    Michael P Cancro.
      Obesity is linked to inflammation and downstream metabolic dysregulation. In this issue of Cell Metabolism, Hägglöf et al. show that iNKT cells enable the accumulation of T-bet+ B cells in white adipose tissue, which in turn produce chemokine and antibody mediators that exacerbate the onset and severity of metabolic disease.
    DOI:  https://doi.org/10.1016/j.cmet.2022.07.008
  12. Mol Cell. 2022 Aug 04. pii: S1097-2765(22)00545-7. [Epub ahead of print]82(15): 2732-2734
    The IRG1/itaconate/TFEB axis: A new weapon in macrophage antibacterial defense.
    José A Martina, Rosa Puertollano.
      Zhang et al. (2022) report that itaconate, a mitochondrial metabolite produced by macrophages upon inflammatory stimuli, activates the master regulator of lysosomal biogenesis TFEB to facilitate clearance of invading bacteria and efficient immune response.
    DOI:  https://doi.org/10.1016/j.molcel.2022.06.009
  13. Ecotoxicol Environ Saf. 2022 Jul 27. pii: S0147-6513(22)00753-9. [Epub ahead of print]242 113913
    Glycogen metabolism reprogramming promotes inflammation in coal dust-exposed lung.
    Wenyang Wang, Min Mu, Yuanjie Zou, Songsong Deng, Yuting Lu, Qinglong Li, Zeyu Li, Huihui Tao, Yun Wang, Xinrong Tao.
      Long-term coal dust exposure triggers complex inflammatory processes in the coal workers' pneumoconiosis (CWP) lungs. The progress of the inflammation is reported to be affected by disordered cell metabolism. However, the changes in the metabolic reprogramming associated with the pulmonary inflammation induced by the coal dust particles are unknown. Herein, we show that coal dust exposure causes glycogen accumulation and the reprogramming of glucose metabolism in the CWP lung. The glycogen accumulation caused by coal dust is mainly due to macrophages, which reprogram glycogen metabolism and trigger an inflammatory response. In addition, 2-deoxy-D-glucose (2-DG) reduced glycogen content in macrophages, which was accompanied by mitigated inflammation and restrained NF-κB activation. Accordingly, we have pinpointed a novel and crucial metabolic pathway that is an essential regulator of the inflammatory phenotype of coal dust-exposed macrophages. These results shed light on new ways to regulate CWP inflammation.
    Keywords:  2-DG; Coal workers’ pneumoconiosis; Glycogen metabolism; Pulmonary inflammation; scMetabolism; scRNA-seq
    DOI:  https://doi.org/10.1016/j.ecoenv.2022.113913
  14. Signal Transduct Target Ther. 2022 Aug 01. 7(1): 260
    Linking B cell metabolism to immune regulation: the neurotransmitter GABA.
    Yang Shi.
      
    DOI:  https://doi.org/10.1038/s41392-022-01120-w
  15. Front Cell Infect Microbiol. 2022 ;12 910864
    Inhibition of Glycolysis Impairs Retinoic Acid-Inducible Gene I-Mediated Antiviral Responses in Primary Human Dendritic Cells.
    Alessandra Zevini, Enrico Palermo, Daniele Di Carlo, Magdalini Alexandridi, Serena Rinaldo, Alessio Paone, Francesca Cutruzzola, Marilena P Etna, Eliana M Coccia, David Olagnier, John Hiscott.
      Dendritic cells (DCs) are important mediators of the induction and regulation of adaptive immune responses following microbial infection and inflammation. Sensing environmental danger signals including viruses, microbial products, or inflammatory stimuli by DCs leads to the rapid transition from a resting state to an activated mature state. DC maturation involves enhanced capturing and processing of antigens for presentation by major histocompatibility complex (MHC) class I and class II, upregulation of chemokines and their receptors, cytokines and costimulatory molecules, and migration to lymphoid tissues where they prime naive T cells. Orchestrating a cellular response to environmental threats requires a high bioenergetic cost that accompanies the metabolic reprogramming of DCs during activation. We previously demonstrated that DCs undergo a striking functional transition after stimulation of the retinoic acid-inducible gene I (RIG-I) pathway with a synthetic 5' triphosphate containing RNA (termed M8), consisting of the upregulation of interferon (IFN)-stimulated antiviral genes, increased DC phagocytosis, activation of a proinflammatory phenotype, and induction of markers associated with immunogenic cell death. In the present study, we set out to determine the metabolic changes associated with RIG-I stimulation by M8. The rate of glycolysis in primary human DCs was increased in response to RIG-I activation, and glycolytic reprogramming was an essential requirement for DC activation. Pharmacological inhibition of glycolysis in monocyte-derived dendritic cells (MoDCs) impaired type I IFN induction and signaling by disrupting the TBK1-IRF3-STAT1 axis, thereby countering the antiviral activity induced by M8. Functionally, the impaired IFN response resulted in enhanced viral replication of dengue, coronavirus 229E, and Coxsackie B5.
    Keywords:  RIG-I; glycolysis; immunometabolism; innate immunity; moDC; viral infection
    DOI:  https://doi.org/10.3389/fcimb.2022.910864
  16. Immunother Adv. 2021 Jan;1(1): ltab005
    Immuno-antibiotics: targeting microbial metabolic pathways sensed by unconventional T cells.
    Matthias Eberl, Eric Oldfield, Thomas Herrmann.
      Human Vγ9/Vδ2 T cells, mucosal-associated invariant T (MAIT) cells, and other unconventional T cells are specialised in detecting microbial metabolic pathway intermediates that are absent in humans. The recognition by such semi-invariant innate-like T cells of compounds like (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), the penultimate metabolite in the MEP isoprenoid biosynthesis pathway, and intermediates of the riboflavin biosynthesis pathway and their metabolites allows the immune system to rapidly sense pathogen-associated molecular patterns that are shared by a wide range of micro-organisms. Given the essential nature of these metabolic pathways for microbial viability, they have emerged as promising targets for the development of novel antibiotics. Here, we review recent findings that link enzymatic inhibition of microbial metabolism with alterations in the levels of unconventional T cell ligands produced by treated micro-organisms that have given rise to the concept of 'immuno-antibiotics': combining direct antimicrobial activity with an immunotherapeutic effect via modulation of unconventional T cell responses.
    Keywords:  MAIT cells; antibiotics; immunotherapy; microbial infection; γδ T cells
    DOI:  https://doi.org/10.1093/immadv/ltab005
  17. Front Immunol. 2022 ;13 969939
    Editorial: The role of immunometabolism in autoimmune mediated and autoinflammatory disorders.
    Valentina Pucino, Monica Guma.
      
    Keywords:  autoimmune disease; bioenergetic; cell metabolism; immunometabolism; inflammation
    DOI:  https://doi.org/10.3389/fimmu.2022.969939
  18. Front Aging. 2022 ;3 924003
    Obesity and Fatty Acids Promote Mitochondrial Translocation of STAT3 Through ROS-Dependent Mechanisms.
    Rachel Conway, Jack Donato Rockhold, Sara SantaCruz-Calvo, Emelia Zukowski, Gabriella H Pugh, Hatice Hasturk, Philip A Kern, Barbara S Nikolajczyk, Leena P Bharath.
      Obesity promotes the onset and progression of metabolic and inflammatory diseases such as type 2 diabetes. The chronic low-grade inflammation that occurs during obesity triggers multiple signaling mechanisms that negatively affect organismal health. One such mechanism is the persistent activation and mitochondrial translocation of STAT3, which is implicated in inflammatory pathologies and many types of cancers. STAT3 in the mitochondria (mitoSTAT3) alters electron transport chain activity, thereby influencing nutrient metabolism and immune response. PBMCs and CD4+ T cells from obese but normal glucose-tolerant (NGT) middle-aged subjects had higher phosphorylation of STAT3 on residue serine 727 and more mitochondrial accumulation of STAT3 than cells from lean subjects. To evaluate if circulating lipid overabundance in obesity is responsible for age- and sex-matched mitoSTAT3, cells from lean subjects were challenged with physiologically relevant doses of the saturated and monounsaturated fatty acids, palmitate and oleate, respectively. Fatty acid treatment caused robust accumulation of mitoSTAT3 in all cell types, which was independent of palmitate-induced impairments in autophagy. Co-treatment of cells with fatty acid and trehalose prevented STAT3 phosphorylation and mitochondrial accumulation in an autophagy-independent but cellular peroxide-dependent mechanism. Pharmacological blockade of mitoSTAT3 either by a mitochondria-targeted STAT3 inhibitor or ROS scavenging prevented obesity and fatty acid-induced production of proinflammatory cytokines IL-17A and IL-6, thus establishing a mechanistic link between mitoSTAT3 and inflammatory cytokine production.
    Keywords:  ROS; T cells; cytokines; inflammation; mitochondrial STAT3; obesity; peroxide
    DOI:  https://doi.org/10.3389/fragi.2022.924003
  19. FASEB J. 2022 Sep;36(9): e22468
    Bile acid restrained T cell activation explains cholestasis aggravated hepatitis B virus infection.
    Chujie Ding, Yu Hong, Yuan Che, Tianyu He, Yun Wang, Shule Zhang, Jiawei Wu, Wanfeng Xu, Jingyi Hou, Haiping Hao, Lijuan Cao.
      Cholestasis is a common complication of hepatitis B virus (HBV) infection, characterized by increased intrahepatic and plasma bile acid levels. Cholestasis was found negatively associated with hepatitis outcome, however, the exact mechanism by which cholestasis impacts anti-viral immunity and impedes HBV clearance remains elusive. Here, we found that cholestatic mice are featured with dysfunctional T cells response, as indicated by decreased sub-population of CD25+ /CD69+ CD4+ and CD8+ cells, while CTLA-4+ CD4+ and CD8+ subsets were increased. Mechanistically, bile acids disrupt intracellular calcium homeostasis via inhibiting mitochondria calcium uptake and elevating cytoplasmic Ca2+ concentration, leading to STIM1 and ORAI1 decoupling and impaired store-operated Ca2+ entry which is essential for NFAT signaling and T cells activation. Moreover, in a transgenic mouse model of HBV infection, we confirmed that cholestasis compromised both CD4+ and CD8+ T cells activation resulting in poor viral clearance. Collectively, our results suggest that bile acids play pivotal roles in anti-HBV infection via controlling T cells activation and metabolism and that targeting the regulation of bile acids may be a therapeutic strategy for host-virus defense.
    Keywords:  SOCE; T cell activation; bile acid; hepatitis B virus
    DOI:  https://doi.org/10.1096/fj.202200332R
  20. Clin Transl Med. 2022 Aug;12(8): e999
    Iron controls T helper cell pathogenicity by promoting glucose metabolism in autoimmune myopathy.
    Yimei Lai, Siyuan Zhao, Binfeng Chen, Yuefang Huang, Chaohuan Guo, Mengyuan Li, Baokui Ye, Shuyi Wang, Hui Zhang, Niansheng Yang.
       BACKGROUND: T helper cells in patients with autoimmune disease of idiopathic inflammatory myopathies (IIM) are characterized with the proinflammatory phenotypes. The underlying mechanisms remain unknown.
    METHODS: RNA sequencing was performed for differential expression genes. Gene expression in CD4+ T-cells was confirmed by quantitative real-time PCR. CD4+ T-cells from IIM patients or healthy controls were evaluated for metabolic activities by Seahorse assay. Glucose uptake, T-cell proliferation and differentiation were evaluated and measured by flow cytometry. Human CD4+ T-cells treated with iron chelators or Pfkfb4 siRNA were measured for glucose metabolism, proliferation and differentiation. Signalling pathway activation was evaluated by western blot and flow cytometry. Mouse model of experimental autoimmune myositis (EAM) were induced and treated with iron chelator or rapamycin. CD4+ T-cell differentiation and muscle inflammation in the EAM mice were evaluated.
    RESULTS: RNA-sequencing analysis revealed that iron was involved with glucose metabolism and CD4+ T-cell differentiation. IIM patient-derived CD4+ T-cells showed enhanced glycolysis and mitochondrial respiration, which was inhibited by iron chelation. CD4+ T-cells from patients with IIM was proinflammatory and iron chelation suppressed the differentiation of interferon gamma (IFNγ)- and interleukin (IL)-17A-producing CD4+ T-cells, which resulted in an increased percentage of regulatory T (Treg) cells. Mechanistically, iron promoted glucose metabolism by an upregulation of PFKFB4 through AKT-mTOR signalling pathway. Notably, the knockdown of Pfkfb4 decreased glucose influx and thus suppressed the differentiation of IFNγ- and IL-17A-producing CD4+ T-cells. In vivo, iron chelation inhibited mTOR signalling pathway and reduced PFKFB4 expression in CD4+ T-cells, resulting in reduced proinflammatory IFNγ- and IL-17A-producing CD4+ T-cells and increased Foxp3+ Treg cells, leading to ameliorated muscle inflammation.
    CONCLUSIONS: Iron directs CD4+ T-cells into a proinflammatory phenotype by enhancing glucose metabolism. Therapeutic targeting of iron metabolism should have the potential to normalize glucose metabolism in CD4+ T-cells and reverse their proinflammatory phenotype in IIM.
    Keywords:  PFKFB4; T helper cells; autoimmune myopathy; glucose metabolism; iron
    DOI:  https://doi.org/10.1002/ctm2.999
  21. Biochem Pharmacol. 2022 Aug 01. pii: S0006-2952(22)00291-X. [Epub ahead of print] 115197
    mTOR Participates in the Formation, Maintenance, and Function of Memory CD8+T Cells Regulated by Glycometabolism.
    Xuepei Cai, Haokun Li, Manyi Wang, Edward Chu, Ning Wei, Jiayu Lin, Yun Hu, Jingtao Dai, Aijie Chen, Hua Zheng, Qianbing Zhang, Yuxia Zhong, Ruoshui Chang, Sha Wu, Yaomu Xiao, Chufeng Liu.
      Memory CD8+T cells participate in the fight against infection and tumorigenesis as well as in autoimmune disease progression because of their efficient and rapid immune response, long-term survival, and continuous differentiation. At each stage of their formation, maintenance, and function, the cell metabolism must be adjusted to match the functional requirements of the specific stage. Notably, enhanced glycolytic metabolism can generate sufficient levels of adenosine triphosphate (ATP) to form memory CD8+T cells, countering the view that glycolysis prevents the formation of memory CD8+T cells. This review focuses on how glycometabolism regulates memory CD8+T cells and highlights the key mechanisms through which the mammalian target of rapamycin (mTOR) signaling pathway affects memory CD8+T cell formation, maintenance, and function by regulating glycometabolism. In addition, different subpopulations of memory CD8+T cells exhibit different metabolic flexibility during their formation, survival, and functional stages, during which the energy metabolism may be critical. These findings which may explain why enhanced glycolytic metabolism can give rise to memory CD8+T cells. Modulating the metabolism of memory CD8+T cells to influence specific cell fates may be useful for disease treatment.
    Keywords:  Glycolysis; Glycometabolism; Memory CD8(+)T cell; mTOR
    DOI:  https://doi.org/10.1016/j.bcp.2022.115197
  22. Immunother Adv. 2021 Jan;1(1): ltab023
    Editor's Note: Relates to: 'Immuno-antibiotics: targeting microbial metabolic pathways sensed by unconventional T cells'.
    Matthias Eberl, Eric Oldfield, Thomas Herrmann.
      
    DOI:  https://doi.org/10.1093/immadv/ltab023
  23. J Leukoc Biol. 2022 Aug 02.
    Selenoprotein I deficiency in T cells promotes differentiation into tolerant phenotypes while decreasing Th17 pathology.
    Chi Ma, FuKun W Hoffmann, Lance G Nunes, Frank Urena, Anastasia Andrukhiv, Mariana Gerschenson, Matthew W Pitts, Peter R Hoffmann.
      Selenoprotein I (SELENOI) is an ethanolamine phospholipid transferase contributing to cellular metabolism and the synthesis of glycosylphosphatidylinositol (GPI) anchors. SELENOI knockout (KO) in T cells has been shown to impair metabolic reprogramming during T cell activation and reduce GPI-anchored Thy-1 levels, which are both crucial for Th17 differentiation. This suggests SELENOI may be important for Th17 differentiation, and we found that SELENOI was indeed up-regulated early during the activation of naïve CD4+ T cells in Th17 conditions. SELENOI KO reduced RORγt mRNA levels by decreasing SOX5 and STAT3 binding to promoter and enhancer regions in the RORC gene encoding this master regulator of Th17 cell differentiation. Differentiation of naïve CD4+ T cells into inflammatory versus tolerogenic Th cell subsets was analyzed and results showed that SELENOI deficiency skewed differentiation away from pathogenic Th17 cells (RORγt+ and IL-17A+ ) while promoting tolerogenic phenotypes (Foxp3+ and IL-10+ ). Wild-type and T cell-specific SELENOI KO mice were subjected to experimental autoimmune encephalitis (EAE), with KO mice exhibiting diminished clinical symptoms, reduced CNS pathology and decreased T cell infiltration. Flow cytometry showed that SELENOI T cell KO mice exhibited lower CD4+ RORγt+ and CD4+ IL-17A+ T cells and higher CD4+ CD25+ FoxP3+ T cells in CNS tissues of mice subjected to EAE. Thus, the metabolic enzyme SELENOI is up-regulated to promote RORγt transcription that drives Th17 differentiation, and SELENOI deficiency shifts differentiation toward tolerogenic phenotypes while protecting against pathogenic Th17 responses.
    Keywords:  autoimmunity; ethanolamine phospholipid transferase; inflammation; metabolism; phosphatidylethanolamine
    DOI:  https://doi.org/10.1002/JLB.1A0122-080R
  24. J Biol Chem. 2022 Aug 01. pii: S0021-9258(22)00764-5. [Epub ahead of print] 102322
    Loss of myeloid lipoprotein lipase exacerbates adipose tissue fibrosis with collagen VI deposition and hyperlipidemia in leptin-deficient obese mice.
    Manabu Takahashi, Daisuke Yamamuro, Tetsuji Wakabayashi, Akihito Takei, Shoko Takei, Shuichi Nagashima, Hiroaki Okazaki, Ken Ebihara, Hiroaki Yagyu, Yuki Takayanagi, Tatsushi Onaka, Ira J Goldberg, Shun Ishibashi.
      During obesity, tissue macrophages increase in number and become pro-inflammatory, thereby contributing to metabolic dysfunction. Lipoprotein lipase (LPL), which hydrolyzes triglyceride (TG) in lipoproteins, is secreted by macrophages. However, the role of macrophage-derived LPL in adipose tissue remodeling and lipoprotein metabolism is largely unknown. To clarify these issues, we crossed leptin-deficient Lepob/ob mice with mice lacking the Lpl gene in myeloid cells (Lplm-/m-) to generate Lplm-/m-;Lepob/ob mice. We found the weight of perigonadal white adipose tissue (WAT) was increased in Lplm-/m-;Lepob/ob mice compared with Lepob/ob mice due to substantial accumulation of both adipose tissue macrophages (ATMs) and collagen that surrounded necrotic adipocytes. In the fibrotic epidydimal WAT of Lplm-/m-;Lepob/ob mice, we observed an increase in collagen VI and high mobility group box 1 (HMGB1), while α-smooth muscle cell actin, a marker of myofibroblasts, was almost undetectable, suggesting that the adipocytes were the major source of the collagens. Furthermore the ATMs from Lplm-/m-;Lepob/ob mice showed increased expression of genes related to fibrosis and inflammation. In addition, we determined Lplm-/m-;Lepob/ob mice were more hypertriglyceridemic than Lepob/ob mice. Lplm-/m-;Lepob/ob mice also showed slower weight gain than Lepob/ob mice, which was primarily due to reduced food intake. In conclusion, we discovered that the loss of myeloid Lpl led to extensive fibrosis of perigonadal WAT and hypertriglyceridemia. In addition to illustrating an important role of macrophage LPL in regulation of circulating TG levels, these data show that macrophage LPL protects against fibrosis in obese adipose tissues.
    Keywords:  adipose tissues; collagen; fibrosis; hypertriglyceridemia; inflammation; leptin; lipoprotein lipase; macrophages; obesity
    DOI:  https://doi.org/10.1016/j.jbc.2022.102322
  25. Function (Oxf). 2022 ;3(4): zqac033
    Acidic Cannabinoids Suppress Proinflammatory Cytokine Release by Blocking Store-operated Calcium Entry.
    Malika Faouzi, Clay Wakano, Mahealani K Monteilh-Zoller, Ram P Neupane, John G Starkus, Jayanti Bhandari Neupane, Aaron J Cullen, Brandon E Johnson, Andrea Fleig, Reinhold Penner.
      Cannabis sativa has long been known to affect numerous biological activities. Although plant extracts, purified cannabinoids, or synthetic cannabinoid analogs have shown therapeutic potential in pain, inflammation, seizure disorders, appetite stimulation, muscle spasticity, and treatment of nausea/vomiting, the underlying mechanisms of action remain ill-defined. In this study we provide the first comprehensive overview of the effects of whole-plant Cannabis extracts and various pure cannabinoids on store-operated calcium (Ca2+) entry (SOCE) in several different immune cell lines. Store-operated Ca2+ entry is one of the most significant Ca2+ influx mechanisms in immune cells, and it is critical for the activation of T lymphocytes, leading to the release of proinflammatory cytokines and mediating inflammation and T cell proliferation, key mechanisms for maintaining chronic pain. While the two major cannabinoids cannabidiol and trans-Δ9-tetrahydrocannabinol were largely ineffective in inhibiting SOCE, we report for the first time that several minor cannabinoids, mainly the carboxylic acid derivatives and particularly cannabigerolic acid, demonstrated high potency against SOCE by blocking calcium release-activated calcium currents. Moreover, we show that this inhibition of SOCE resulted in a decrease of nuclear factor of activated T-cells activation and Interleukin 2 production in human T lymphocytes. Taken together, these results indicate that cannabinoid-mediated inhibition of a proinflammatory target such as SOCE may at least partially explain the anti-inflammatory and analgesic effects of Cannabis.
    Keywords:  Interleukin-2; calcium inhibitor; calcium-release activated calcium; cannabigerolic acid; cannabinoids; inflammation
    DOI:  https://doi.org/10.1093/function/zqac033
  26. EMBO Mol Med. 2022 Aug 02. e15687
    Store-operated calcium entry controls innate and adaptive immune cell function in inflammatory bowel disease.
    IBDome Researchers
      Inflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune responses. Using mass cytometry (CyTOF) to analyze the immune cell composition in the lamina propria (LP) of patients with ulcerative colitis (UC) and Crohn's disease (CD), we observed an enrichment of CD4+ effector T cells producing IL-17A and TNF, CD8+ T cells producing IFNγ, T regulatory (Treg) cells, and innate lymphoid cells (ILC). The function of these immune cells is regulated by store-operated Ca2+ entry (SOCE), which results from the opening of Ca2+ release-activated Ca2+ (CRAC) channels formed by ORAI and STIM proteins. We observed that the pharmacologic inhibition of SOCE attenuated the production of proinflammatory cytokines including IL-2, IL-4, IL-6, IL-17A, TNF, and IFNγ by human colonic T cells and ILCs, reduced the production of IL-6 by B cells and the production of IFNγ by myeloid cells, but had no effect on the viability, differentiation, and function of intestinal epithelial cells. T cell-specific deletion of CRAC channel genes in mice showed that Orai1, Stim1, and Stim2-deficient T cells have quantitatively distinct defects in SOCE, which correlate with gradually more pronounced impairment of cytokine production by Th1 and Th17 cells and the severity of IBD. Moreover, the pharmacologic inhibition of SOCE with a selective CRAC channel inhibitor attenuated IBD severity and colitogenic T cell function in mice. Our data indicate that SOCE inhibition may be a suitable new approach for the treatment of IBD.
    Keywords:  Crohn's disease; T cell transfer models of colitis; mass cytometry; store-operated calcium entry (SOCE); ulcerative colitis
    DOI:  https://doi.org/10.15252/emmm.202215687
  27. Gut Microbes. 2022 Jan-Dec;14(1):14(1): 2105609
    Gut microbiota-derived metabolites confer protection against SARS-CoV-2 infection.
    Julia A Brown, Katherine Z Sanidad, Serena Lucotti, Carolin M Lieber, Robert M Cox, Aparna Ananthanarayanan, Srijani Basu, Justin Chen, Mengrou Shan, Mohammed Amir, Fabian Schmidt, Yiska Weisblum, Michele Cioffi, Tingting Li, Florencia Madorsky Rowdo, M Laura Martin, Chun-Jun Guo, Costas Lyssiotis, Brian T Layden, Andrew J Dannenberg, Paul D Bieniasz, Benhur Lee, Naohiro Inohara, Irina Matei, Richard K Plemper, Melody Y Zeng.
      The gut microbiome is intricately coupled with immune regulation and metabolism, but its role in Coronavirus Disease 2019 (COVID-19) is not fully understood. Severe and fatal COVID-19 is characterized by poor anti-viral immunity and hypercoagulation, particularly in males. Here, we define multiple pathways by which the gut microbiome protects mammalian hosts from SARS-CoV-2 intranasal infection, both locally and systemically, via production of short-chain fatty acids (SCFAs). SCFAs reduced viral burdens in the airways and intestines by downregulating the SARS-CoV-2 entry receptor, angiotensin-converting enzyme 2 (ACE2), and enhancing adaptive immunity via GPR41 and 43 in male animals. We further identify a novel role for the gut microbiome in regulating systemic coagulation response by limiting megakaryocyte proliferation and platelet turnover via the Sh2b3-Mpl axis. Taken together, our findings have unraveled novel functions of SCFAs and fiber-fermenting gut bacteria to dampen viral entry and hypercoagulation and promote adaptive antiviral immunity.
    DOI:  https://doi.org/10.1080/19490976.2022.2105609
  28. EMBO J. 2022 Aug 03. e109353
    Elp3-mediated codon-dependent translation promotes mTORC2 activation and regulates macrophage polarization.
    Dawei Chen, Ivan Nemazanyy, Olivier Peulen, Kateryna Shostak, Xinyi Xu, Seng Chuan Tang, Caroline Wathieu, Silvia Turchetto, Sylvia Tielens, Laurent Nguyen, Pierre Close, Christophe Desmet, Sebastian Klein, Alexandra Florin, Reinhard Büttner, Georgios Petrellis, Benjamin Dewals, Alain Chariot.
      Macrophage polarization is a process whereby macrophages acquire distinct effector states (M1 or M2) to carry out multiple and sometimes opposite functions. We show here that translational reprogramming occurs during macrophage polarization and that this relies on the Elongator complex subunit Elp3, an enzyme that modifies the wobble uridine base U34 in cytosolic tRNAs. Elp3 expression is downregulated by classical M1-activating signals in myeloid cells, where it limits the production of pro-inflammatory cytokines via FoxO1 phosphorylation, and attenuates experimental colitis in mice. In contrast, alternative M2-activating signals upregulate Elp3 expression through a PI3K- and STAT6-dependent signaling pathway. The metabolic reprogramming linked to M2 macrophage polarization relies on Elp3 and the translation of multiple candidates, including the mitochondrial ribosome large subunit proteins Mrpl3, Mrpl13, and Mrpl47. By promoting translation of its activator Ric8b in a codon-dependent manner, Elp3 also regulates mTORC2 activation. Elp3 expression in myeloid cells further promotes Wnt-driven tumor initiation in the intestine by maintaining a pool of tumor-associated macrophages exhibiting M2 features. Collectively, our data establish a functional link between tRNA modifications, mTORC2 activation, and macrophage polarization.
    Keywords:  Elp3; mTORC2; macrophage polarization; mitochondrial translation; tRNA modifications
    DOI:  https://doi.org/10.15252/embj.2021109353
  29. JCI Insight. 2022 Aug 02. pii: e155552. [Epub ahead of print]
    The TBK1/IKKε inhibitor amlexanox improves dyslipidemia and prevents atherosclerosis.
    Peng Zhao, Xiaoli Sun, Zhongji Liao, Hong Yu, Dan Li, Zeyang Shen, Christopher K Glass, Joseph L Witztum, Alan R Saltiel.
      Cardiovascular diseases, especially atherosclerosis and its complications, are a leading cause of death. Inhibition of the non-canonical IκB kinases TBK1 and IKKε with amlexanox restores insulin sensitivity and glucose homeostasis in diabetic mice and human subjects. Here we report that amlexanox improves diet-induced hypertriglyceridemia and hypercholesterolemia in Western diet (WD)-fed Ldlr-/- mice, and protects against atherogenesis. Amlexanox ameliorates dyslipidemia, inflammation and vascular dysfunction through synergistic actions that involve upregulation of bile acid synthesis to increase cholesterol excretion. Transcriptomic profiling demonstrates an elevated expression of key bile acid synthesis genes. Furthermore, we found that amlexanox attenuates monocytosis, eosinophilia and vascular dysfunction during WD-induced atherosclerosis. These findings demonstrate the potential of amlexanox as a new therapy for hypercholesterolemia and atherosclerosis.
    Keywords:  Cardiovascular disease; Cholesterol; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.155552
  30. J Biol Chem. 2022 Aug 02. pii: S0021-9258(22)00780-3. [Epub ahead of print] 102338
    Chlamydia trachomatis development requires both host glycolysis and oxidative phosphorylation but has only minor effects on these pathways.
    Maimouna D N'Gadjaga, Stéphanie Perrinet, Michael G Connor, Giulia Bertolin, Gaël A Millot, Agathe Subtil.
      The obligate intracellular bacteria Chlamydia trachomatis obtain all nutrients from the cytoplasm of their epithelial host cells and stimulate glucose uptake by these cells. They even hijack host ATP, exerting a strong metabolic pressure on their host at the peak of the proliferative stage of their developmental cycle. However, it is largely unknown whether infection modulates the metabolism of the host cell. Also, the reliance of the bacteria on host metabolism might change during their progression through their biphasic developmental cycle. Herein, using primary epithelial cells and two cell lines of non-tumoral origin, we showed that between the two main ATP-producing pathways of the host, oxidative phosphorylation (OxPhos) remained stable and glycolysis was slightly increased. Inhibition of either pathway strongly reduced bacterial proliferation, implicating that optimal bacterial growth required both pathways to function at full capacity. While we found C. trachomatis displayed some degree of energetic autonomy in the synthesis of proteins expressed at the onset of infection, functional host glycolysis was necessary for the establishment of early inclusions, whereas OxPhos contributed less. These observations correlated with the relative contributions of the pathways in maintaining ATP levels in epithelial cells, with glycolysis contributing the most. Altogether, this work highlights the dependence of C. trachomatis on both host glycolysis and OxPhos for efficient bacterial replication. However, ATP consumption appears at equilibrium with the normal production capacity of the host and the bacteria, so that no major shift between these pathways is required to meet bacterial needs.
    Keywords:  ATP; Chlamydia trachomatis; glycolysis; host-pathogen interaction; metabolism; oxidative phosphorylation
    DOI:  https://doi.org/10.1016/j.jbc.2022.102338
  31. Research (Wash D C). 2022 ;2022 9854904
    lncRNA HITT Inhibits Lactate Production by Repressing PKM2 Oligomerization to Reduce Tumor Growth and Macrophage Polarization.
    Kunming Zhao, Xingwen Wang, Dong Zhao, Qingyu Lin, Yi Zhang, Ying Hu.
      Lactic acid acidifies the tumor microenvironment and promotes multiple critical oncogenic processes, including immune evasion. Pyruvate kinase M2 (PKM2) is a dominant form of pyruvate kinase (PK) expressed in cancers that plays essential roles in metabolic reprograming and lactate production, rendering it as an attractive therapeutic target of cancer. However, the mechanism underlying PKM2 regulation remains unclear. Here, we show that long noncoding RNA (lncRNA) HIF-1α inhibitor at transcription level (HITT) inhibits lactate production in a PKM2-dependent manner. Mechanistically, it physically interacts with PKM2 mapped to a region that has been involved in both dimer (less-active) and tetramer (more-active) formation, inhibiting PKM2 oligomerization and leading to dramatic reduction of PK activity. Under glucose starvation, HITT was reduced as a result of miR-106 induction, which subsequently facilitates PKM2 oligomerization and increases vulnerability to apoptosis under glucose starvation stress. In addition, the interaction also reduces lactate secretion from cancer cells, which subsequently polarizes macrophages toward an M2-like anti-inflammatory phenotype and thus possibly contributes to immune escape in vivo. This study highlights an important role of an lncRNA in regulating PKM2 activity and also reveals a metabolic regulatory effect of PKM2 on macrophage polarization.
    DOI:  https://doi.org/10.34133/2022/9854904
  32. Infect Immun. 2022 Aug 02. e0015522
    Francisella tularensis Exploits AMPK Activation to Harvest Host-Derived Nutrients Liberated from Host Lipolysis.
    Sedelia R Dominguez, Shannon Whiles, Kelly N Deobald, Thomas Kawula.
      Francisella tularensis is a zoonotic, facultative intracellular bacterial pathogen that replicates in a variety of cell types during infection. Following entry into the cell and phagosome escape, the bacterium replicates rapidly in the cytoplasm. F. tularensis intracellular growth depends on the availability of metabolizable essential nutrients to support replication. However, the mechanism by which metabolizable nutrients become available to the bacterium in the intracellular environment is not fully understood. We found that F. tularensis-infected cells had significantly smaller and fewer lipid droplets than uninfected cells. Inhibition of triacylglycerol degradation significantly reduced bacterial growth, whereas inhibition of triacylglycerol formation did not reduce bacterial growth, suggesting that triacylglycerols sequestered within lipid droplets are important nutrient sources for F. tularensis. We found that F. tularensis-infected cells had increased activation of lipolysis and the upstream regulatory protein AMP protein kinase (AMPK). These data suggest that F. tularensis exploits AMPK activation and lipid metabolism to use host-derived nutrients. Finally, we found that AMPK activation is correlated with an increased bacterial burden, which suggests that it is a host-mediated response to nutrient starvation that results from increased bacterial replication. Altogether, we conclude that F. tularensis exploits AMPK activation to access nutrients sequestered in lipid droplets, specifically glycerol and fatty acids, to undergo efficient bacterial replication and cause successful infection.
    Keywords:  Francisella tularensis; carbon metabolism; host-pathogen interactions; infectious disease; nutritional immunity; zoonotic infections
    DOI:  https://doi.org/10.1128/iai.00155-22
  33. Cell Metab. 2022 Aug 02. pii: S1550-4131(22)00305-9. [Epub ahead of print]34(8): 1201-1213.e5
    Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis.
    Hong Gao, Zhongmou Jin, Gautam Bandyopadhyay, Gaowei Wang, Dinghong Zhang, Karina Cunha E Rocha, Xiao Liu, Huayi Zhao, Tatiana Kisseleva, David A Brenner, Michael Karin, Wei Ying.
      Hepatocytes have important roles in liver iron homeostasis, abnormalities in which are tightly associated with liver steatosis and fibrosis. Here, we show that non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) are characterized by iron-deficient hepatocytes and iron overload in hepatic stellate cells (HSCs). Iron deficiency enhances hepatocyte lipogenesis and insulin resistance through HIF2α-ATF4 signaling. Elevated secretion of iron-containing hepatocyte extracellular vesicles (EVs), which are normally cleared by Kupffer cells, accounts for hepatocyte iron deficiency and HSC iron overload in NAFLD/NASH livers. Iron accumulation results in overproduction of reactive oxygen species that promote HSC fibrogenic activation. Conversely, blocking hepatocyte EV secretion or depleting EV iron cargo restores liver iron homeostasis, concomitant with mitigation of NAFLD/NASH-associated liver steatosis and fibrosis. Taken together, these studies show that iron distribution disorders contribute to the development of liver metabolic diseases.
    Keywords:  NAFLD; NASH; extracellular vesicle; hepatic stellate cell; hepatocyte; iron; liver fibrosis; liver steatosis
    DOI:  https://doi.org/10.1016/j.cmet.2022.07.006
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