bims-imicid Biomed News
on Immunometabolism of infection, cancer and immune-mediated disease
Issue of 2022‒07‒10
thirty-two papers selected by
Dylan Ryan
University of Cambridge

  1. Biochim Biophys Acta Mol Basis Dis. 2022 Jul 02. pii: S0925-4439(22)00152-1. [Epub ahead of print] 166481
      Mitochondrial-derived reactive oxygen species are important as antimicrobial agents and redox signals in pro-inflammatory macrophages. Macrophages produce superoxide in response to the TLR4 ligand LPS. However, the mechanism of LPS-induced superoxide generation is not fully understood. Superoxide is produced at complex I and complex III of the electron transport chain. Production of superoxide at either of these sites is highly dependent on the metabolic state of the cell which is dramatically altered by TLR4-induced metabolic reprogramming. This review will outline how metabolism impacts superoxide production in LPS-activated macrophages downstream of TLR4 signalling and address outstanding questions in this field.
    Keywords:  Complex I; Macrophages; Metabolism; Mitochondria; Reverse electron transport; Superoxide
  2. Arthritis Rheumatol. 2022 Jul 06. e42284
      BACKGROUND: Itaconic acid, a Kreb's cycle derived immunometabolite, is synthesized by myeloid cells in response to danger signals to control inflammasome activation, type I Interferon (IFN) responses and oxidative stress. As these pathways are dysregulated in systemic lupus erythematosus (SLE), we investigated the role of an itaconic acid derivative in the treatment of established murine lupus.METHODS: Female New Zealand Black/New Zealand White F1 lupus prone mice were administered 4-octyl itaconate (4-OI) or vehicle starting after clinical onset of disease (30 weeks of age) for 4 weeks (n=10 mice /group). At 34 weeks of age (peak disease activity) animals were euthanized, organs and serum collected, and clinical, metabolic, and immunologic parameters were evaluated.
    RESULTS: Proteinuria, kidney immune complex deposition, renal scores of severity and inflammation and anti-RNP autoantibodies were significantly reduced in 4-OI treatment group compared to vehicle. Splenomegaly decreased in 4-OI group compared to vehicle, with decreases in activation markers in innate and adaptive immunes cells, increases in CD8+ T cell numbers and inhibition of JAK1 activation. Gene expression analysis in splenocytes showed significant decreases in type-I IFN and proinflammatory cytokine genes and increased Treg associated markers in the 4-OI group when compared to vehicle. In human control and lupus myeloid cells, 4-OI in vitro treatment decreased proinflammatory responses and B cell responses.
    CONCLUSIONS: These results support targeting immunometabolism as a potentially viable approach in autoimmune diseases treatment, with 4-OI displaying beneficial roles attenuating immune dysregulation and organ damage in lupus.
  3. Curr Opin Hematol. 2022 Jul 01. 29(4): 209-217
      PURPOSE OF REVIEW: Innate lymphoid cells (ILCs) are specialized immune cells that rapidly sense environmental perturbations and regulate immune responses and tissue homeostasis. ILCs are mainly tissue resident and their crosstalk within tissue microenvironments influences both local and systemic metabolism. Reciprocally, metabolic status conditions ILC phenotype and effector function. In this review, we discuss the role of ILCs as metabolic sentinels and describe how ILC subset-specific activities influence homeostasis and disease. Finally, we highlight emerging challenges in the field of ILC immunometabolism.RECENT FINDINGS: Accumulating evidence suggests that ILCs metabolism, phenotype, and function are shaped by signals from the tissue microenvironment. Dietary, endogenous, and microbial metabolites are sensed by ILC subsets and can impact on ILC-mediated immune responses. Recent studies have found that mitochondria are central regulators of ILC effector function. Furthermore, ILCs have emerged as crucial sensors of metabolic stress, suggesting they might act as metabolic sentinels, coordinating tissue and host metabolism.
    SUMMARY: Our understanding how ILCs mechanistically regulate host metabolism and defenses is still incomplete. Unraveling critical metabolic features of ILCs may lead to novel therapeutic strategies that target these cells in the context of disease.
  4. Int Rev Immunol. 2022 Jul 06. 1-17
      Metabolic reprogramming is a hallmark of solid cancers. Macrophages as major constituents of immune system take important roles in regulation of tumorigenesis. Pro-tumor M2 macrophages preferentially use oxidative phosphorylation (OXPHOS) to meet their metabolic demands, while anti-tumor M1 macrophages use glycolysis as their dominant metabolic source. Dysregulation in metabolic systems is a driving force of skewing macrophages from M1 toward M2 phenotypical state. Hyperactive M1 macrophages, for instance, release metabolic products that are contributed to M2 macrophage polarization. Thus, metabolic remodeling through reinstating normalization in metabolic systems can be an effective tool in cancer therapy. The key focus of this review is over metabolic systems in macrophages and factors influencing their metabolic acquisition and reprogramming in cancer, as well as discussing bout strategies to adjust macrophage metabolism and reeducation toward M1-like phenotype.
    Keywords:  Tumor microenvironment (TME); glycolysis; hypoxia; hypoxia inducible factor (HIF); lactate; macrophage; metabolism; oxidative phosphorylation (OXPHOS)
  5. Front Cell Dev Biol. 2022 ;10 925971
      Adipose tissue macrophages are a major immune cell type contributing to homeostatic maintenance and pathological adipose tissue remodeling. However, the mechanisms underlying macrophage recruitment and polarization in adipose tissue during obesity remain poorly understood. Previous studies have suggested that the gap junctional protein, connexin 43 (Cx43), plays a critical role in macrophage activation and phagocytosis. Herein, we investigated the macrophage-specific roles of Cx43 in high fat diet (HFD)-induced pathological remodeling of adipose tissue. Expression levels of Cx43 were upregulated in macrophages co-cultured with dying adipocytes in vitro, as well as in macrophages associated with dying adipocytes in the adipose tissue of HFD-fed mice. Cx43 knockdown reduced lipopolysaccharide (LPS)-induced ATP release from macrophages and decreased inflammatory responses of macrophages co-cultured with dying adipocytes. Based on global gene expression profiling, macrophage-specific Cx43-knockout (Cx43-MKO) mice were resistant to HFD-induced inflammatory responses in adipose tissue, potentially via P2X7-mediated signaling pathways. Cx43-MKO mice exhibited reduced HFD-induced macrophage recruitment in adipose tissue. Moreover, Cx43-MKO mice showed reduced inflammasome activation in adipose tissues and improved glucose tolerance. Collectively, these findings demonstrate that Cx43 expression in macrophages facilitates inflammasome activation, which, in turn, contributes to HFD-induced metabolic dysfunction.
    Keywords:  adipose tissue remodeling; connexin 43; inflammation; macrophage; obesity
  6. Hemasphere. 2022 Jul;6(7): e740
      Cellular metabolism is a key regulator of hematopoietic stem cell (HSC) maintenance. HSCs rely on anaerobic glycolysis for energy production to minimize the production of reactive oxygen species and shift toward mitochondrial oxidative phosphorylation upon differentiation. However, increasing evidence has shown that HSCs still maintain a certain level of mitochondrial activity in quiescence, and exhibit high mitochondrial membrane potential, which both support proper HSC function. Since glycolysis and the tricarboxylic acid (TCA) cycle are not directly connected in HSCs, other nutrient pathways, such as amino acid and fatty acid metabolism, generate acetyl-CoA and provide it to the TCA cycle. In this review, we discuss recent insights into the regulatory roles of cellular metabolism in HSCs. Understanding the metabolic requirements of healthy HSCs is of critical importance to the development of new therapies for hematological disorders.
  7. Cell Rep. 2022 Jul 05. pii: S2211-1247(22)00826-9. [Epub ahead of print]40(1): 111032
      How mechanistic target of rapamycin complex 1 (mTORC1), a key regulator of cellular metabolism, affects dendritic cell (DC) metabolism and T cell-priming capacity has primarily been investigated in vitro, but how mTORC1 regulates this in vivo remains poorly defined. Here, using mice deficient for mTORC1 component raptor in DCs, we find that loss of mTORC1 negatively affects glycolytic and fatty acid metabolism and maturation of conventional DCs, particularly cDC1s. Nonetheless, antigen-specific CD8+ T cell responses to infection are not compromised and are even enhanced following skin immunization. This is associated with increased activation of Langerhans cells and a subpopulation of EpCAM-expressing cDC1s, of which the latter show an increased physical interaction with CD8+ T cells in situ. Together, this work reveals that mTORC1 limits CD8+ T cell priming in vivo by differentially orchestrating the metabolism and immunogenicity of distinct antigen-presenting cell subsets, which may have implications for clinical use of mTOR inhibitors.
    Keywords:  CD8(+) T cells; CP: Immunology; IL-12; Langerhans cells; MHCI; immunization; mTORC1; metabolism; type 1 conventional dendritic cells
  8. Trends Cell Biol. 2022 Jul 01. pii: S0962-8924(22)00140-4. [Epub ahead of print]
      Peroxisomes are essential metabolic organelles, well known for their roles in the metabolism of complex lipids and reactive ionic species. In the past 10 years, peroxisomes have also been cast as central regulators of immunity. Lipid metabolites of peroxisomes, such as polyunsaturated fatty acids (PUFAs), are precursors for important immune mediators, including leukotrienes (LTs) and resolvins. Peroxisomal redox metabolism modulates cellular immune signaling such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Additionally, peroxisomal β-oxidation and ether lipid synthesis control the development and aspects of the activation of both innate and adaptive immune cells. Finally, peroxisome number and metabolic activity have been linked to inflammatory diseases. These discoveries have opened avenues of investigation aimed at targeting peroxisomes for therapeutic intervention in immune disorders, inflammation, and cancer.
    Keywords:  host–pathogen interaction; immune signaling; immunometabolism; peroxisome; phagocytosis
  9. J Immunother Cancer. 2022 Jul;pii: e004584. [Epub ahead of print]10(7):
      Macrophages are main players of the innate immune system. They show great heterogeneity and play diverse functions that include support to development, sustenance of tissue homeostasis and defense against infections. Dysfunctional macrophages have been described in multiple pathologies including cancer. Indeed tumor-associated macrophages (TAMs) are abundant in most tumors and sustain cancer growth, promote invasion and mediate immune evasion. Importantly, lipid metabolism influences macrophage activation and lipid accumulation confers pathogenic features on macrophages. Notably, a subset of lipid-loaded macrophages has been recently identified in many tumor types. Lipid-loaded TAMs support tumor growth and progression and exert immune-suppressive activities. In this review, we describe the role of lipid metabolism in macrophage activation in physiology and pathology and we discuss the impact of lipid accumulation in macrophages in the context of cancer.
    Keywords:  Immunomodulation; Macrophages; Metabolic Networks and Pathways; Tumor Microenvironment
  10. Sci Rep. 2022 Jul 06. 12(1): 11406
      Previous studies indicated a role of the reconstituting immune system for disease outcome upon high-dose chemotherapy (HDCT) and autologous stem cell transplantation (auto-SCT) in multiple myeloma (MM) and lymphoma patients. Since immune cell metabolism and function are closely interconnected, we used flow-cytometry techniques to analyze key components and functions of the metabolic machinery in reconstituting immune cells upon HDCT/auto-SCT. We observed increased proliferative activity and an upregulation of the glycolytic and fatty acid oxidation (FAO) machinery in immune cells during engraftment. Metabolic activation was more pronounced in T-cells of advanced differentiation stages, in CD56bright NK-cells, and CD14++CD16+ intermediate monocytes. Next, we investigated a potential correlation between the immune cells' metabolic profile and early progression or relapse in lymphoma patients within the first twelve months following auto-SCT. Here, persistently increased metabolic parameters correlated with a rather poor disease course. Taken together, reconstituting immune cells display an upregulated bioenergetic machinery following auto-SCT. Interestingly, a persistently enhanced metabolic immune cell phenotype correlated with reduced PFS. However, it remains to be elucidated, if the clinical data can be confirmed within a larger set of patients and if residual malignant cells not detected by conventional means possibly caused the metabolic activation.
  11. Front Cell Infect Microbiol. 2022 ;12 925746
      Host and pathogen metabolism have a major impact on the outcome of infection. The microenvironment consisting of immune and stromal cells drives bacterial proliferation and adaptation, while also shaping the activity of the immune system. The abundant metabolites itaconate and adenosine are classified as anti-inflammatory, as they help to contain the local damage associated with inflammation, oxidants and proteases. A growing literature details the many roles of these immunometabolites in the pathogenesis of infection and their diverse functions in specific tissues. Some bacteria, notably P. aeruginosa, actively metabolize these compounds, others, such as S. aureus respond by altering their own metabolic programs selecting for optimal fitness. For most of the model systems studied to date, these immunometabolites promote a milieu of tolerance, limiting local immune clearance mechanisms, along with promoting bacterial adaptation. The generation of metabolites such as adenosine and itaconate can be host protective. In the setting of acute inflammation, these compounds also represent potential therapeutic targets to prevent infection.
    Keywords:  adenosine; anti-inflammatory; bacterial infections; infection tolerance; itaconate; metabolism
  12. Curr Opin Hematol. 2022 Jul 01. 29(4): 188-193
      PURPOSE OF REVIEW: Hematopoietic stem cells (HSCs) are endowed with high regenerative potential to supply mature blood cells throughout life, under steady state or stress conditions. HSCs are thought to rely on glycolysis when in a quiescent state and to switch to oxidative phosphorylation to meet their metabolic needs during activation. Recently, a series of important studies reveals a higher degree of complexity that goes well beyond the dichotomy between glycolysis and oxidative phosphorylation. The purpose of this review is to summarize the recent findings highlighting the multifaceted metabolic requirements of HSC homeostasis.RECENT FINDINGS: Emerging evidence points to the importance of lysosomal catabolic activity and noncanonical retinoic acid pathway in maintaining HSC quiescence and stemness. HSC activation into cycle seems to be accompanied by a switch to glycolysis-mitochondrial coupling and to anabolic pathways, including Myc, aspartate-mediated purine synthesis.
    SUMMARY: Knowledge of metabolism of HSCs has dramatically increased in the past 2 years and reveals unexpected needs of HSCs during both their quiescent and activated state. Understanding how HSCs use metabolism for their functions will offer new opportunity for HSC-based therapies.
  13. Int J Mol Sci. 2022 Jul 03. pii: 7417. [Epub ahead of print]23(13):
      Adipocyte iron overload is a maladaptation associated with obesity and insulin resistance. The objective of the current study was to determine whether and how adipose tissue macrophages (ATMs) regulate adipocyte iron concentrations and whether this is impacted by obesity. Using bone marrow-derived macrophages (BMDMs) polarized to M0, M1, M2, or metabolically activated (MMe) phenotypes, we showed that MMe BMDMs and ATMs from obese mice have reduced expression of several iron-related proteins. Furthermore, the bioenergetic response to iron in obese ATMs was hampered. ATMs from iron-injected lean mice increased their glycolytic and respiratory capacities, thus maintaining metabolic flexibility, while ATMs from obese mice did not. Using an isotope-based system, we found that iron exchange between BMDMs and adipocytes was regulated by macrophage phenotype. At the end of the co-culture, MMe macrophages transferred and received more iron from adipocytes than M0, M1, and M2 macrophages. This culminated in a decrease in total iron in MMe macrophages and an increase in total iron in adipocytes compared with M2 macrophages. Taken together, in the MMe condition, the redistribution of iron is biased toward macrophage iron deficiency and simultaneous adipocyte iron overload. These data suggest that obesity changes the communication of iron between adipocytes and macrophages and that rectifying this iron communication channel may be a novel therapeutic target to alleviate insulin resistance.
    Keywords:  adipose tissue macrophage; immunometabolism; iron; obesity; polarization
  14. Eur J Pharmacol. 2022 Jul 01. pii: S0014-2999(22)00379-X. [Epub ahead of print]929 175118
      The atypical cyclin-dependent kinase 5 (CDK5) is considered a neuron-specific kinase that plays important roles in many cellular functions including neuronal migration, neuronal differentiation, synapse development, and synaptic functions. However, the role of CDK5 in microglia under physiological and pathological conditions remains unclear. This study showed that treatment with lipopolysaccharide (LPS) caused the release of pro-inflammatory mediators and increased expression of CDK5 in BV2 microglia in vitro. Moreover, lipopolysaccharide treatment-induced glycolysis by increasing the expression levels of HIF-1α, PFKFB3, and HK2. Application of CDK5 inhibitor roscovitine significantly decreased LPS-induced CDK5 expression and glycolysis, thus suppressing neuroinflammation in the cells. The roscovitine treatment of BV2 cells also significantly blocked the HIF-1 activator, CoCl2-mediated HIF-1α, HK2, and PFKFB3 expression. Finally, we demonstrated that roscovitine inhibited microglial activation, metabolic reprogramming, expression of pro-inflammatory markers, cell apoptosis, and alleviated memory impairment in LPS-injected mice. In summary, our results suggest that inhibition of CDK5 can reduce the neuroinflammation of microglia through modulation of metabolic reprogramming.
    Keywords:  Cyclin-dependent kinase 5; Metabolic reprogramming; Microglia; Neuroinflammation; Roscovitine
  15. Nat Metab. 2022 Jul 04.
      Anti-programmed death-1 (PD-1) immunotherapy that aims to restore T cell activity in cancer patients frequently leads to immune-related adverse events such as colitis. However, the underlying mechanism is still elusive. Here, we find that Pdcd1-deficient mice exhibit disrupted gut microbiota and aggravated dextran sulfate sodium (DSS)-induced colitis. In addition to T cells, PD-1 is also substantially expressed in colonic lymphoid tissue inducer (LTi) cells. During DSS-induced colitis, LTi cell activation is accompanied by increased PD-1 expression, whereas PD-1 deficiency results in reduced interleukin-22 (IL-22) production by LTi cells and exacerbated inflammation. Mechanistically, activated LTi cells reprogram their metabolism toward carbohydrate metabolism and fatty acid synthesis, while fatty acid oxidation (FAO) is unchanged. However, PD-1 deficiency leads to significantly elevated FAO in LTi cells, which in turn attenuates their activation and IL-22 production. Consistently, FAO suppression efficiently restores IL-22 production in Pdcd1-/- LTi cells. Thus, our study provides unforeseen mechanistic insight into colitis occurrence during anti-PD-1 immunotherapy through LTi cell metabolic reconfiguration.
  16. G3 (Bethesda). 2022 Jul 04. pii: jkac163. [Epub ahead of print]
      When infected by intestinal pathogenic bacteria, animals initiate both local and systemic defence responses. These responses are required to reduce pathogen burden and also to alter host physiology and behaviour to promote infection tolerance, and they are often mediated through alterations in host gene expression. Here, we have used transcriptome profiling to examine gene expression changes induced by enteric infection with the gram-negative bacteria Pseudomonas entomophila (P.e) in adult female Drosophila. We find that infection induces a strong upregulation of metabolic gene expression, including gut and fat body-enriched genes involved in lipid transport, lipolysis, and beta-oxidation, as well as glucose and amino acid metabolism genes. Furthermore, we find that the classic innate immune deficiency (Imd)/Relish/NF-KappaB pathway is not required for, and in some cases limits, these infection-mediated increases in metabolic gene expression. We also see that enteric infection with P.e. down regulates the expression of many transcription factors and cell-cell signaling molecules, particularly those previously shown to be involved in gut-to-brain and neuronal signaling. Moreover, as with the metabolic genes, these changes occurred largely independent of the Imd pathway. Together, our study identifies many metabolic, signaling and transcription factor gene expression changes that may contribute to organismal physiological and behavioural responses to enteric pathogen infection.
    Keywords:  Drosophila; Imd pathway; enteric infection; metabolism; neuropeptides; transcription factors; transcriptome
  17. Front Cell Infect Microbiol. 2022 ;12 939828
    Keywords:  Coxiella burnetii; NF-κB; phosphatase; sugar metabolism; type IV secretion system
  18. Front Immunol. 2022 ;13 884148
      The immune system, smartly and surprisingly, saves the exposure of a particular pathogen in its memory and reacts to the pathogen very rapidly, preventing serious diseases. Immunologists have long been fascinated by understanding the ability to recall and respond faster and more vigorously to a pathogen, known as "memory". T-cell populations can be better described by using more sophisticated techniques to define phenotype, transcriptional and epigenetic signatures and metabolic pathways (single-cell resolution), which uncovered the heterogeneity of the memory T-compartment. Phenotype, effector functions, maintenance, and metabolic pathways help identify these different subsets. Here, we examine recent developments in the characterization of the heterogeneity of the memory T cell compartment. In particular, we focus on the emerging role of CD8+ TRM and TSCM cells, providing evidence on how their immunometabolism or modulation can play a vital role in their generation and maintenance in chronic conditions such as infections or autoimmune diseases.
    Keywords:  CD8 TRM cells; CD8 TSCM cells; differentiation; infectious diseases; metabolism
  19. Cancer Discov. 2022 Jul 06. 12(7): 1615-1616
      SUMMARY: In this issue, Hu and colleagues unveil that IFNα administration combined with anti-PD-1 therapy can potentiate murine and human CD8+ T-cell antitumor response in hepatocellular carcinoma, highlighting a novel therapeutic strategy for hepatocellular carcinoma. See related article by Hu et al., p. 1718 (6) .
  20. Metabolomics. 2022 Jul 04. 18(7): 47
      BACKGROUND: The rise of antimicrobial resistance at an alarming rate is outpacing the development of new antibiotics. The worrisome trends of multidrug-resistant Gram-negative bacteria have enormously diminished existing antibiotic activity. Antibiotic treatments may inhibit bacterial growth or lead to induce bacterial cell death through disruption of bacterial metabolism directly or indirectly. In light of this, it is imperative to have a thorough understanding of the relationship of bacterial metabolism with antimicrobial activity and leverage the underlying principle towards development of novel and effective antimicrobial therapies.OBJECTIVE: Herein, we explore studies on metabolic analyses of Gram-negative pathogens upon antibiotic treatment. Metabolomic studies revealed that antibiotic therapy caused changes of metabolites abundance and perturbed the bacterial metabolism. Following this line of thought, addition of exogenous metabolite has been employed in in vitro, in vivo and in silico studies to activate the bacterial metabolism and thus potentiate the antibiotic activity.
    KEY SCIENTIFIC CONCEPTS OF REVIEW: Exogenous metabolites were discovered to cause metabolic modulation through activation of central carbon metabolism and cellular respiration, stimulation of proton motive force, increase of membrane potential, improvement of host immune protection, alteration of gut microbiome, and eventually facilitating antibiotic killing. The use of metabolites as antimicrobial adjuvants may be a promising approach in the fight against multidrug-resistant pathogens.
    Keywords:  Antibiotic susceptibility; Antimicrobial resistance; Gram-negative bacteria; Metabolic modulation; Metabolism
  21. Front Cell Infect Microbiol. 2022 ;12 859814
      Alphaviruses are single stranded, positive sense RNA viruses that are often transmitted through mosquito vectors. With the increasing spread of mosquito populations throughout the world, these arboviruses represent a significant global health concern. Viruses such as Sindbis Virus (SINV), Chikungunya Virus (CHIKV) and Equine Encephalitis Viruses (EEV) are all alphaviruses. As viruses, these pathogens are dependent on the host cell environment for successful viral replication. It has been observed that viruses manipulate cellular metabolism and mitochondrial shape, activity, and dynamics to favor viral infection. This report looked to understand the metabolic changes present during Sindbis virus infection of hamster and human kidney cells. Cells were infected with increasing levels of SINV and at 24 hours post infection the mitochondria morphology was assessed with staining and mitochondrial activity was measured with a real-time Seahorse Bioanalyzer. The relative amount of mitochondrial staining intensity decreased with Sindbis virus infected cells. Both oxygen consumption rate and ATP production were decreased during SINV infection while non-mitochondrial respiration and extracellular acidification rate increased during infection. Collectively, the data indicates that SINV primarily utilizes non-mitochondrial metabolism to support viral infection within the first 24 hours. This understanding of viral preference for host cell metabolism may provide critical targets for antiviral therapies and help further define the nature of alphavirus infection.
    Keywords:  arbovirus; host cell manipulation; metabolism; mitochondria; sindbis virus
  22. J Neuroinflammation. 2022 Jul 07. 19(1): 176
      BACKGROUND: Metabolic dysregulation and disruption of immune homeostasis have been widely associated with perioperative complications including perioperative ischemic stroke. Although immunometabolite S-2-hydroxyglutarate (S-2HG) is an emerging regulator of immune cells and thus triggers the immune response, it is unclear whether and how S-2HG elicits perioperative ischemic brain injury and exacerbates post-stroke cognitive dysfunction.METHODS: Perioperative ischemic stroke was induced by transient middle cerebral artery occlusion for 60 min in C57BL/6 mice 1 day after ileocecal resection. CD8+ T lymphocyte activation and invasion of the cerebrovascular compartment were measured using flow cytometry. Untargeted metabolomic profiling was performed to detect metabolic changes in sorted CD8+ T lymphocytes after ischemia. CD8+ T lymphocytes were transfected with lentivirus ex vivo to mobilize cell proliferation and differentiation before being transferred into recombination activating gene 1 (Rag1-/-) stroke mice.
    RESULTS: The perioperative stroke mice exhibit more severe cerebral ischemic injury and neurological dysfunction than the stroke-only mice. CD8+ T lymphocyte invasion of brain parenchyma and neurotoxicity augment cerebral ischemic injury in the perioperative stroke mice. CD8+ T lymphocyte depletion reverses exacerbated immune-mediated cerebral ischemic brain injury in perioperative stroke mice. Perioperative ischemic stroke triggers aberrant metabolic alterations in peripheral CD8+ T cells, in which S-2HG is more abundant. S-2HG alters CD8+ T lymphocyte proliferation and differentiation ex vivo and modulates the immune-mediated ischemic brain injury and post-stroke cognitive dysfunction by enhancing CD8+ T lymphocyte-mediated neurotoxicity.
    CONCLUSION: Our study establishes that S-2HG signaling-mediated activation and neurotoxicity of CD8+ T lymphocytes might exacerbate perioperative ischemic brain injury and may represent a promising immunotherapy target in perioperative ischemic stroke.
    Keywords:  Brain injury; CD8+ T lymphocyte; Ischemic stroke; Neurotoxicity; Perioperative complication; Perioperative stroke; S-2-Hydroxyglutarate
  23. J Innate Immun. 2022 Jul 07. 1-15
      We have previously demonstrated that Slc6a13-deficient (Slc6a13-/-; KO) mice are resistant to P. multocida infection, which might be in connection with macrophage-mediated inflammation; however, the specific metabolic mechanism is still enigmatic. Here we reproduce the less sensitive to P. multocida infection in overall survival assays as well as reduced bacterial loads, tissue lesions, and inflammation of lungs in KO mice. The transcriptome sequencing analysis of wild-type (WT) and KO mice shows a large number of differentially expressed genes that are enriched in amino acid metabolism by functional analysis. Of note, glycine levels are substantially increased in the lungs of KO mice with or without P. multocida infection in comparison to the WT controls. Interestingly, exogenous glycine supplementation alleviates P. multocida infection-induced inflammation. Mechanistically, glycine reduces the production of inflammatory cytokines in macrophages by blocking the activation of inflammasome (NALP1, NLRP3, NLRC4, AIM2, and Caspase-1). Together, Slc6a13 deficiency attenuates P. multocida infection through lessening the excessive inflammatory responses of macrophages involving glycine-inflammasome signaling.
    Keywords:  Glycine; Inflammasome; Macrophage; Pasteurella multocida; Slc6a13
  24. Nat Rev Nephrol. 2022 Jul 07.
      Kidney tubular epithelial cells (TECs) have a crucial role in the damage and repair response to acute and chronic injury. To adequately respond to constant changes in the environment, TECs have considerable bioenergetic needs, which are supported by metabolic pathways. Although little is known about TEC metabolism, a number of ground-breaking studies have shown that defective glucose metabolism or fatty acid oxidation in the kidney has a key role in the response to kidney injury. Imbalanced use of these metabolic pathways can predispose TECs to apoptosis and dedifferentiation, and contribute to lipotoxicity and kidney injury. The accumulation of lipids and aberrant metabolic adaptations of TECs during kidney disease can also be driven by receptors of the innate immune system. Similar to their actions in innate immune cells, pattern recognition receptors regulate the metabolic rewiring of TECs, causing cellular dysfunction and lipid accumulation. TECs should therefore be considered a specialized cell type - like cells of the innate immune system - that is subject to regulation by immunometabolism. Targeting energy metabolism in TECs could represent a strategy for metabolically reprogramming the kidney and promoting kidney repair.
  25. Cell Mol Life Sci. 2022 Jul 05. 79(8): 396
      In the course of atherogenesis, the spleen plays an important role in the regulation of extramedullary hematopoiesis, and in the control of circulating immune cells, which contributes to plaque progression. Here, we have investigated the role of splenic nucleotide-binding oligomerization domain 1 (NOD1) in the recruitment of circulating immune cells, as well as the involvement of this immune organ in extramedullary hematopoiesis in mice fed on a high-fat high-cholesterol diet (HFD). Under HFD conditions, the absence of NOD1 enhances the mobilization of immune cells, mainly neutrophils, from the bone marrow to the blood. To determine the effect of NOD1-dependent mobilization of immune cells under pro-atherogenic conditions, Apoe-/- and Apoe-/-Nod1-/- mice fed on HFD for 4 weeks were used. Splenic NOD1 from Apoe-/- mice was activated after feeding HFD as inferred by the phosphorylation of the NOD1 downstream targets RIPK2 and TAK1. Moreover, this activation was accompanied by the release of neutrophil extracellular traps (NETs), as determined by the increase in the expression of peptidyl arginine deiminase 4, and the identification of citrullinated histone H3 in this organ. This formation of NETs was significantly reduced in Apoe-/-Nod1-/- mice. Indeed, the presence of Ly6G+ cells and the lipidic content in the spleen of mice deficient in Apoe and Nod1 was reduced when compared to the Apoe-/- counterparts, which suggests that the mobilization and activation of circulating immune cells are altered in the absence of NOD1. Furthermore, confirming previous studies, Apoe-/-Nod1-/- mice showed a reduced atherogenic disease, and diminished recruitment of neutrophils in the spleen, compared to Apoe-/- mice. However, splenic artery ligation reduced the atherogenic burden in Apoe-/- mice an effect that, unexpectedly was lost in Apoe-/-Nod1-/- mice. Together, these results suggest that neutrophil accumulation and activity in the spleen are driven in part by NOD1 activation in mice fed on HFD, contributing in this way to regulating atherogenic progression.
    Keywords:  Atherogenesis; Hypercholesterolemia; NETosis; Partial splenectomy; Spleen
  26. Int Immunopharmacol. 2022 Jun 28. pii: S1567-5769(22)00489-1. [Epub ahead of print]110 109005
      Interleukin-6 (IL-6) is a highly pleiotropic glycoprotein factor that can modulate innate and adaptive immunity as well as various aspects of metabolism, including glycolysis, fatty acid oxidation and oxidative phosphorylation. Recently, the expression and release of IL-6 is shown to be significantly increased in numerous diseases related to virus infection, and this increase is positively correlated with the disease severity. Immunity and metabolism are two highly integrated and interdependent systems, the balance between them plays a pivotal role in maintaining body homeostasis. IL-6-elicited inflammatory response is found to be closely associated with metabolic disorder in patients with viral infection. This brief review summarizes the regulatory role of IL-6 in immunometabolic reprogramming among seven viral infection-associated diseases.
    Keywords:  COVID-19; Immunometabolic reprogramming; Interleukin-6; Viral infection
  27. Autoimmun Rev. 2022 Jul 02. pii: S1568-9972(22)00106-9. [Epub ahead of print] 103136
      There is growing evidence of vitamin D involvement in immune regulation and gut barrier function, suggesting that vitamin D may play a critical role in the development of inflammatory bowel disease (IBD). This review presents advances in the molecular mechanisms of vitamin D and vitamin D receptor (VDR) signaling with respect to barrier integrity and innate/adaptive immunity in the gut, as well as recent findings in uncovering the biological link between vitamin D-associated genetic variants and IBD. Experimental data have revealed a mechanistic basis for the contribution of vitamin D to the pathogenesis of IBD. The vitamin D/VDR complex is involved in the regulation of innate and adaptive immune responses to pathogenic threats by acting as an immunomodulator and alleviating inflammation in experimental IBD models and IBD patients, contributing to intestinal homeostasis. Vitamin D has been associated with the promotion of antimicrobial peptide secretion, down-regulation of dendritic cell activity, induction of tolerogenic rather than pro-inflammatory T-cell differentiation and function, and increased production of anti-inflammatory cytokines, highlighting its potential therapeutic value for IBD. Elucidating the complex interplay between vitamin D/VDR and the pathogenesis of IBD is critical for the development of novel therapeutic interventions and for the potential use of this molecule as a prognostic and diagnostic tool in clinical practice.
    Keywords:  Biologics; Crohn's disease; Cytokines; Immune cells; Ulcerative colitis; vitamin D/VDR
  28. J Clin Invest. 2022 Jul 05. pii: e151540. [Epub ahead of print]
      Mitohormesis defines the increase in fitness mediated by adaptive responses to mild mitochondrial stress. Tetracyclines inhibit not only bacterial but also mitochondrial translation, thus imposing a low level of mitochondrial stress to eukaryotic cells. We demonstrate in cell and germ-free mouse models, that tetracyclines induce a mild adaptive mitochondrial stress response (MSR), involving both the ATF4-mediated integrative stress response and type I interferon (IFN) signaling. To overcome the interferences of tetracyclines with the host microbiome, we identify tetracycline derivatives that have minimal antimicrobial activity, yet retain full capacity to induce the MSR, such as the lead compound, 9-tert-butyldoxycycline (9-TB). The MSR induced by Doxycycline (Dox) and 9-TB improves survival and disease tolerance against lethal influenza virus (IFV) infection when given preventively. 9-TB, unlike Dox, did not affect the gut microbiome and showed also encouraging results against IFV when given in a therapeutic setting. Tolerance to IFV infection is associated with the induction of genes involved in lung epithelial cell and cilia function, and with down-regulation of inflammatory and immune gene sets in lungs, liver, and kidneys. Mitohormesis induced by non-antimicrobial tetracyclines and the ensuing IFN response may dampen excessive inflammation and tissue damage during viral infections, opening innovative therapeutic avenues.
    Keywords:  Drug therapy; Infectious disease; Influenza; Mitochondria
  29. Elife. 2022 Jul 08. pii: e78674. [Epub ahead of print]11
      Viruses generally are defined as lacking the fundamental properties of living organisms in that they do not harbor an energy metabolism system or protein synthesis machinery. However, the discovery of giant viruses of amoeba has fundamentally challenged this view because of their exceptional genome properties, particle sizes and encoding of the enzyme machinery for some steps of protein synthesis. Although giant viruses are not able to replicate autonomously and still require a host for their multiplication, numerous metabolic genes involved in energy production have been recently detected in giant virus genomes from many environments. These findings have further blurred the boundaries that separate viruses and living organisms. Herein, we summarize information concerning genes and proteins involved in cellular metabolic pathways and their orthologues that have, surprisingly, been discovered in giant viruses. The remarkable diversity of metabolic genes described in giant viruses include genes encoding enzymes involved in glycolysis, gluconeogenesis, tricarboxylic acid cycle, photosynthesis, and β-oxidation. These viral genes are thought to have been acquired from diverse biological sources through lateral gene transfer early in the evolution of Nucleo-Cytoplasmic Large DNA Viruses, or in some cases more recently. It was assumed that viruses are capable of hijacking host metabolic networks. But the giant virus auxiliary metabolic genes also may represent another form of host metabolism manipulation, by expanding the catalytic capabilities of the host cells especially in harsh environments, providing the infected host cells with a selective evolutionary advantage compared to non-infected cells and hence favoring the viral replication. However, the mechanism of these genes' functionality remains unclear to date.
    Keywords:  energy production; giant viruses; infectious disease; microbiology; primary metabolism
  30. Metabolomics. 2022 Jul 04. 18(7): 48
      INTRODUCTION: Rheumatoid arthritis (RA) and osteoarthritis (OA) are clinicopathologically different.OBJECTIVES: We aimed to assess the feasibility of metabolomics in differentiating the metabolite profiles of synovial fluid between RA and OA using gas chromatography/time-of-flight mass spectrometry.
    METHODS: We first compared the global metabolomic changes in the synovial fluid of 19 patients with RA and OA. Partial least squares-discriminant, hierarchical clustering, and univariate analyses were performed to distinguish metabolites of RA and OA. These findings were then validated using synovial fluid samples from another set of 15 patients with RA and OA.
    RESULTS: We identified 121 metabolites in the synovial fluid of the first 19 samples. The score plot of PLS-DA showed a clear separation between RA and OA. Twenty-eight crucial metabolites, including hypoxanthine, xanthine, adenosine, citrulline, histidine, and tryptophan, were identified to be capable of distinguishing RA metabolism from that of OA; these were found to be associated with purine and amino acid metabolism.
    CONCLUSION: Our results demonstrated that metabolite profiling of synovial fluid could clearly discriminate between RA and OA, suggesting that metabolomics may be a feasible tool to assist in the diagnosis and advance the comprehension of pathological processes for diseases.
    Keywords:  Gas chromatography–mass spectrometry; Metabolite profiling; Osteoarthritis; Rheumatoid arthritis; Synovial fluid