bims-imicid 2023-02-19 papers

bims-imicid

Biomed News

on Immunometabolism of infection, cancer and immune-mediated disease

Issue of 2023–02–19
thirty-six papers selected by
Dylan Ryan, University of Cambridge

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development.
Mitochondrial function in macrophages controls cardiac repair after myocardial infarction.
Metabolism and epigenetics at the heart of T cell function.
Nicotinamide riboside, an NAD+ precursor, attenuates inflammation and oxidative stress by activating sirtuin 1 in alcohol-stimulated macrophages.
Mitochondrial ACOD1/IRG1 in infection and sterile inflammation.
Role of myeloid cells in system-level immunometabolic dysregulation during prolonged successful HIV-1 treatment.
Human alveolar macrophage metabolism is compromised during Mycobacterium tuberculosis infection.
PFKFB2-mediated glycolysis promotes lactate-driven continual efferocytosis by macrophages.
Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model.
Acidity-mediated induction of FoxP3+ regulatory T cells.
Caspase-11 contributes to site-1 protease cleavage and SREBP1 activation in the inflammatory response of macrophages.
Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory T cell differentiation in vitro.
Maternal γδ T cells shape offspring pulmonary type 2 immunity in a microbiota-dependent manner.
Hexokinase 2-mediated glycolysis supports inflammatory responses to Porphyromonas gingivalis in gingival fibroblasts.
Adipose tissue inflammation and systemic insulin resistance in mice with diet-induced obesity is possibly associated with disruption of PFKFB3 in hematopoietic cells.
Butyrate limits human natural killer cell effector function.
Endothelial Indoleamine-2,3-Dioxygenase-1 is not Critically Involved in Regulating Antitumor Immunity in the Central Nervous System.
Lactate-related metabolic reprogramming and immune regulation in colorectal cancer.
Mitochondrial control of microglial phagocytosis by the translocator protein and hexokinase 2 in Alzheimer's disease.
Newcastle Disease Virus Manipulates Mitochondrial MTHFD2-Mediated Nucleotide Metabolism for Virus Replication.
Exosomal STIMATE derived from type II alveolar epithelial cells controls metabolic reprogramming of tissue-resident alveolar macrophages.
Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation.
Adipocyte autophagy limits gut inflammation by controlling oxylipin and IL-10.
Innate immune cell-intrinsic ketogenesis is dispensable for organismal metabolism and age-related inflammation.
Loss of Lkb1 in CD11c+ myeloid cells protects mice from diet-induced obesity while enhancing glucose intolerance and IL-17/IFN-γ imbalance.
Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages.
gutSMASH predicts specialized primary metabolic pathways from the human gut microbiota.
Targeting first trimester trophoblast cell metabolism modulates its susceptibility to Zika virus infection.
APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes.
Innate immune memory in cardiometabolic disease.
Gut-joint axis: Gut dysbiosis can contribute to the onset of rheumatoid arthritis via multiple pathways.
Network-based multi-omics integration reveals metabolic at-risk profile within treated HIV-infection.
Breathing easy: Dopamine quenches the ILC2 flame.
DSS-induced colitis activates the kynurenine pathway in serum and brain by affecting IDO-1 and gut microbiota.
SLC3A2 Promotes Tumor Associated Macrophage Polarization via Metabolic Reprogramming in Lung Cancer.
Inhibition of inflammatory microglia by dietary fiber and short-chain fatty acids.

Nat Immunol. 2023 Feb 16.

Pyrimidine de novo synthesis inhibition selectively blocks effector but not memory T cell development.

Stefanie Scherer, Susanne G Oberle, Kristiyan Kanev, Ann-Katrin Gerullis, Ming Wu, Gustavo P de Almeida, Daniel J Puleston, Francesc Baixauli, Lilian Aly, Alessandro Greco, Tamar Nizharadze, Nils B Becker, Madlaina V Hoesslin, Lara V Donhauser, Jacqueline Berner, Talyn Chu, Hayley A McNamara, Zeynep Esencan, Patrick Roelli, Christine Wurmser, Ingo Kleiter, Maria J G T Vehreschild, Christoph A Mayer, Percy Knolle, Martin Klingenspor, Valeria Fumagalli, Matteo Iannacone, Martin Prlic, Thomas Korn, Erika L Pearce, Thomas Höfer, Anna M Schulz, Dietmar Zehn.

Blocking pyrimidine de novo synthesis by inhibiting dihydroorotate dehydrogenase is used to treat autoimmunity and prevent expansion of rapidly dividing cell populations including activated T cells. Here we show memory T cell precursors are resistant to pyrimidine starvation. Although the treatment effectively blocked effector T cells, the number, function and transcriptional profile of memory T cells and their precursors were unaffected. This effect occurred in a narrow time window in the early T cell expansion phase when developing effector, but not memory precursor, T cells are vulnerable to pyrimidine starvation. This vulnerability stems from a higher proliferative rate of early effector T cells as well as lower pyrimidine synthesis capacity when compared with memory precursors. This differential sensitivity is a drug-targetable checkpoint that efficiently diminishes effector T cells without affecting the memory compartment. This cell fate checkpoint might therefore lead to new methods to safely manipulate effector T cell responses.

DOI: https://doi.org/10.1038/s41590-023-01436-x
J Clin Invest. 2023 Feb 15. pii: e167079. [Epub ahead of print]133(4):

Mitochondrial function in macrophages controls cardiac repair after myocardial infarction.

David Weissman, Christoph Maack.

Cardiac healing following acute myocardial infarction (MI) involves the mobilization and activation of immune cells, including macrophages. In the early phase after MI, macrophages adopt a proinflammatory phenotype, while polarizing toward a reparative one in the late stage. Although metabolic reprogramming has been observed during this transition, the mechanistic links to macrophage differentiation are still poorly understood. In this issue of the JCI, Cai, Zhao and colleagues demonstrate that mitochondrial function in macrophages governed the resolution of inflammation and tissue repair by modulating the phagocytic removal of apoptotic cells (so-called efferocytosis) as well as myofibroblast activation. These findings provide important mechanistic insights into the potential relevance of metabolic modulation of macrophage functions following MI, which might lead to alternative therapeutic strategies for MI.

DOI: https://doi.org/10.1172/JCI167079
Trends Immunol. 2023 Feb 09. pii: S1471-4906(23)00002-9. [Epub ahead of print]

Metabolism and epigenetics at the heart of T cell function.

Leticia Soriano-Baguet, Dirk Brenner.

  T cell subsets adapt and rewire their metabolism according to their functions and surrounding microenvironment. Whereas naive T cells rely on mitochondrial metabolic pathways characterized by low nutrient requirements, effector T cells induce kinetically faster pathways to generate the biomass and energy needed for proliferation and cytokine production. Recent findings support the concept that alterations in metabolism also affect the epigenetics of T cells. In this review we discuss the connections between T cell metabolism and epigenetic changes such as histone post-translational modifications (PTMs) and DNA methylation, as well as the 'extra-metabolic' roles of metabolic enzymes and molecules. These findings collectively point to a new group of potential therapeutic targets for the treatment of T cell-dependent autoimmune diseases and cancers.

Keywords:  DNA; NAD; T cells; acetylation; epigentics; histone; metabolism; methylation

DOI:  https://doi.org/10.1016/j.it.2023.01.002
Lab Invest. 2021 09;pii: S0023-6837(22)00583-9. [Epub ahead of print]101(9): 1225-1237

Nicotinamide riboside, an NAD+ precursor, attenuates inflammation and oxidative stress by activating sirtuin 1 in alcohol-stimulated macrophages.

Hyunju Kang, Young-Ki Park, Ji-Young Lee.

Macrophages play an essential role in alcohol-induced inflammation and oxidative stress. We investigated the effects of nicotinamide riboside (NR), a natural nicotinamide adenine dinucleotide (NAD+) precursor, on alcohol-induced inflammation and oxidative stress in macrophages. NR significantly decreased ethanol-induced inflammatory gene expression, with a concomitant decrease in nuclear translocation of nuclear factor κB p65 in RAW 264.7 macrophages and mouse bone marrow-derived macrophages (BMDMs). In macrophages incubated with ethanol or acetaldehyde, NR abolished the accumulation of cellular reactive oxygen species. Ethanol decreased sirtuin 1 (SIRT1) expression and activity, and cellular NAD+ level while inducing pro-inflammatory gene expression. However, NR markedly attenuated the changes. SIRT1 inhibition augmented ethanol-induced inflammatory gene expression, but its activation elicited opposing effects. Also, ethanol did not alter glycolysis but increased glycolytic capacity, glycolytic reserve, and non-glycolytic acidification, with concomitant increases in hypoxia-induced factor 1α expression and activity, phosphorylation of pyruvate dehydrogenase, and extracellular lactate levels. Interestingly, ethanol increased mitochondrial respiration and ATP production but decreased maximal respiration and spare respiration capacity. The latter was linked to decreases in mitochondrial copy numbers. NR abolished the ethanol-induced metabolic changes in the glycolytic and oxidative phosphorylation pathways in RAW 264.7 macrophages. In conclusion, NR exerts anti-inflammatory and antioxidant properties by abrogating the inhibitory effects of ethanol on the SIRT1 pathway by increasing Sirt1 expression and its activator, NAD+. Also, SIRT1 activation and normalization of ethanol-induced changes in NAD+/NADH ratios by NR are likely crucial to counteract the changes in energy phenotypes of macrophages exposed to ethanol. Nicotinamide riboside (NR), a natural nicotinamide adenine dinucleotide (NAD+) precursor, exerts anti-inflammatory and antioxidant properties by activating sirtuin 1 in alcohol-stimulated macrophages. Also, NR counteracts hypoxia-induced factor 1α-induced metabolic reprogramming favoring lactate formation. The effects of NR are likely attributable to the replenishment of the cellular NAD+ pool depleted by metabolizing ethanol.

DOI: https://doi.org/10.1038/s41374-021-00599-1
J Intensive Med. 2022 Apr;2(2): 78-88

Mitochondrial ACOD1/IRG1 in infection and sterile inflammation.

Runliu Wu, Rui Kang, Daolin Tang.

  Immunometabolism is a dynamic process involving the interplay of metabolism and immune response in health and diseases. Increasing evidence suggests that impaired immunometabolism contributes to infectious and inflammatory diseases. In particular, the mitochondrial enzyme aconitate decarboxylase 1 (ACOD1, best known as immunoresponsive gene 1 [IRG1]) is upregulated under various inflammatory conditions and serves as a pivotal regulator of immunometabolism involved in itaconate production, macrophage polarization, inflammasome activation, and oxidative stress. Consequently, the activation of the ACOD1 pathway is implicated in regulating the pathogenic process of sepsis and septic shock, which are part of a clinical syndrome of life-threatening organ failure caused by a dysregulated host response to pathogen infection. In this review, we discuss the latest research advances in ACOD1 expression and function, with particular attention to how the ACOD1-itaconate pathway affects infection and sterile inflammation diseases. These new insights may give us a deeper understanding of the role of immunometabolism in innate immunity.

Keywords:  Aconitate decarboxylase 1 (ACOD1); Disease; Inflammation; Metabolism; Sepsis

DOI:  https://doi.org/10.1016/j.jointm.2022.01.001
AIDS. 2023 Feb 09.

Role of myeloid cells in system-level immunometabolic dysregulation during prolonged successful HIV-1 treatment.

Sara Svensson Akusjärvi, Shuba Krishnan, Anoop T Ambikan, Flora Mikaeloff, Sivasankaran Munusamy Ponnan, Jan Vesterbacka, Magda Lourda, Piotr Nowak, Anders Sönnerborg, Ujjwal Neogi.

OBJECTIVE: :Why people living with HIV-1 on ART (PLWH ART ) display convoluted metabolism and immune cell functions during prolonged suppressive therapy is not well evaluated. In this study, we aimed to address this question using multiomics methodologies to investigate immunological and metabolic differences between PLWH ART and HIV-1 negative individuals (HC).
DESIGN: :Cross-sectional study.
METHODS: :Untargeted and targeted metabolomics was performed using gas and liquid chromatography/mass spectrometry, and targeted proteomics using Olink TM inflammation panel on plasma samples. The cellular metabolic state was further investigated using flow cytometry and intracellular metabolic measurement in single-cell populations isolated by EasySep cell isolation. Finally, flow cytometry was performed for deep-immunophenotyping of mononuclear phagocytes.
RESULTS: :We detected increased levels of glutamate, lactate, and pyruvate by plasma metabolomics and increased inflammatory markers (e.g., CCL20 and CCL7) in PLWH ART compared to HC. The metabolite transporter detection by flow cytometry in T-cells and monocytes indicated an increased expression of glucose transporter 1 (Glut1) and monocarboxylate transporter 1 (MCT-1) in PLWH ART . Single cell-type metabolite measurement identified decreased glucose, glutamate, and lactate in monocytic cell populations in PLWH ART . Deep-immunophenotyping of myeloid cell lineages subpopulations showed no difference in cell frequency, but expression levels of CCR5 were increased on classical monocytes and some dendritic cells.
CONCLUSIONS: :Our data thus suggest that the myeloid cell populations potentially contribute significantly to the modulated metabolic environment during suppressive HIV-1 Infection.

DOI: https://doi.org/10.1097/QAD.0000000000003512
Front Immunol. 2022 ;13 1044592

Human alveolar macrophage metabolism is compromised during Mycobacterium tuberculosis infection.

Laura E Mendonca, Erwan Pernet, Nargis Khan, Joaquin Sanz, Eva Kaufmann, Jeffrey Downey, Alexandre Grant, Marianna Orlova, Erwin Schurr, Connie Krawczyk, Russell G Jones, Luis B Barreiro, Maziar Divangahi.

  Pulmonary macrophages have two distinct ontogenies: long-lived embryonically-seeded alveolar macrophages (AM) and bone marrow-derived macrophages (BMDM). Here, we show that after infection with a virulent strain of Mycobacterium tuberculosis (H37Rv), primary murine AM exhibit a unique transcriptomic signature characterized by metabolic reprogramming distinct from conventional BMDM. In contrast to BMDM, AM failed to shift from oxidative phosphorylation (OXPHOS) to glycolysis and consequently were unable to control infection with an avirulent strain (H37Ra). Importantly, healthy human AM infected with H37Ra equally demonstrated diminished energetics, recapitulating our observation in the murine model system. However, the results from seahorse showed that the shift towards glycolysis in both AM and BMDM was inhibited by H37Rv. We further demonstrated that pharmacological (e.g. metformin or the iron chelator desferrioxamine) reprogramming of AM towards glycolysis reduced necrosis and enhanced AM capacity to control H37Rv growth. Together, our results indicate that the unique bioenergetics of AM renders these cells a perfect target for Mtb survival and that metabolic reprogramming may be a viable host targeted therapy against TB.

Keywords:  cell death programs; immunity; immunometabolism; metabolic reprograming; pulmonary macrophages; tuberculosis

DOI:  https://doi.org/10.3389/fimmu.2022.1044592
Nat Metab. 2023 Feb 16.

PFKFB2-mediated glycolysis promotes lactate-driven continual efferocytosis by macrophages.

Maaike Schilperoort, David Ngai, Marina Katerelos, David A Power, Ira Tabas.

Resolving-type macrophages prevent chronic inflammation by clearing apoptotic cells through efferocytosis. These macrophages are thought to rely mainly on oxidative phosphorylation, but emerging evidence suggests a possible link between efferocytosis and glycolysis. To gain further insight into this issue, we investigated molecular-cellular mechanisms involved in efferocytosis-induced macrophage glycolysis and its consequences. We found that efferocytosis promotes a transient increase in macrophage glycolysis that is dependent on rapid activation of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2), which distinguishes this process from glycolysis in pro-inflammatory macrophages. Mice transplanted with activation-defective PFKFB2 bone marrow and then subjected to dexamethasone-induced thymocyte apoptosis exhibit impaired thymic efferocytosis, increased thymic necrosis, and lower expression of the efferocytosis receptors MerTK and LRP1 on thymic macrophages compared with wild-type control mice. In vitro mechanistic studies revealed that glycolysis stimulated by the uptake of a first apoptotic cell promotes continual efferocytosis through lactate-mediated upregulation of MerTK and LRP1. Thus, efferocytosis-induced macrophage glycolysis represents a unique metabolic process that sustains continual efferocytosis in a lactate-dependent manner. The differentiation of this process from inflammatory macrophage glycolysis raises the possibility that it could be therapeutically enhanced to promote efferocytosis and resolution in chronic inflammatory diseases.

DOI: https://doi.org/10.1038/s42255-023-00736-8
Front Oncol. 2023 ;13 1107484

Low-density lipoprotein balances T cell metabolism and enhances response to anti-PD-1 blockade in a HCT116 spheroid model.

Nathalie Babl, Joshua Hofbauer, Carina Matos, Florian Voll, Ayse Nur Menevse, Michael Rechenmacher, Ruth Mair, Philipp Beckhove, Wolfgang Herr, Peter J Siska, Kathrin Renner, Marina Kreutz, Annette Schnell.

   Introduction: The discovery of immune checkpoints and the development of their specific inhibitors was acclaimed as a major breakthrough in cancer therapy. However, only a limited patient cohort shows sufficient response to therapy. Hence, there is a need for identifying new checkpoints and predictive biomarkers with the objective of overcoming immune escape and resistance to treatment. Having been associated with both, treatment response and failure, LDL seems to be a double-edged sword in anti-PD1 immunotherapy. Being embedded into complex metabolic conditions, the impact of LDL on distinct immune cells has not been sufficiently addressed. Revealing the effects of LDL on T cell performance in tumor immunity may enable individual treatment adjustments in order to enhance the response to routinely administered immunotherapies in different patient populations. The object of this work was to investigate the effect of LDL on T cell activation and tumor immunity in-vitro.
Methods: Experiments were performed with different LDL dosages (LDLlow = 50 μg/ml and LDLhigh = 200 μg/ml) referring to medium control. T cell phenotype, cytokines and metabolism were analyzed. The functional relevance of our findings was studied in a HCT116 spheroid model in the context of anti-PD-1 blockade.
Results: The key points of our findings showed that LDLhigh skewed the CD4+ T cell subset into a central memory-like phenotype, enhanced the expression of the co-stimulatory marker CD154 (CD40L) and significantly reduced secretion of IL-10. The exhaustion markers PD-1 and LAG-3 were downregulated on both T cell subsets and phenotypical changes were associated with a balanced T cell metabolism, in particular with a significant decrease of reactive oxygen species (ROS). T cell transfer into a HCT116 spheroid model resulted in a significant reduction of the spheroid viability in presence of an anti-PD-1 antibody combined with LDLhigh.
Discussion: Further research needs to be conducted to fully understand the impact of LDL on T cells in tumor immunity and moreover, to also unravel LDL effects on other lymphocytes and myeloid cells for improving anti-PD-1 immunotherapy. The reason for improved response might be a resilient, less exhausted phenotype with balanced ROS levels.

Keywords:  CD154 (CD40L); LDL (low-density lipoprotein); PD-1; central memory (T) CM; cholesterol; immunotherapy; reactive oxygen species; spheroid model

DOI:  https://doi.org/10.3389/fonc.2023.1107484
Eur J Immunol. 2023 Feb 14. e2250258

Acidity-mediated induction of FoxP3+ regulatory T cells.

Disha Rao, Johanna A Stunnenberg, Ruben Lacroix, Petros Dimitriadis, Joanna Kaplon, Fabienne Verburg, Paula T van Royen, Esmée P Hoefsmit, Kathrin Renner, Christian U Blank, Daniel S Peeper.

  Glucose limitation and increased lactic acid levels are consequences of the elevated glycolytic activity of tumor cells, and constitute a metabolic barrier for the function of tumor infiltrating effector immune cells. The immune-suppressive function of regulatory T cells (Tregs) are unobstructed in lactic-acid rich environments. However, the impact of lactic acid on the induction of Tregs remains unknown. We observed increased TGFβ-mediated induction of FoxP3+ cells in the presence of extracellular lactic acid, in a glycolysis-independent, acidity-dependent manner. These CD4+ FoxP3+ cells expressed Treg-associated markers, including increased expression of CD39, and were capable of exerting suppressive functions. Corroborating these results in vivo, we observed that neutralizing the tumor pH by systemic administration of sodium bicarbonate decreased Treg abundance. We conclude that acidity augments Treg induction and propose that therapeutic targeting of acidity in the tumor microenvironment might reduce Treg-mediated immune suppression within tumors. This article is protected by copyright. All rights reserved.

Keywords:  Lactic acid; Regulatory T cells; Treg metabolism; Tumor microenvironment

DOI:  https://doi.org/10.1002/eji.202250258
Front Immunol. 2023 ;14 1009973

Caspase-11 contributes to site-1 protease cleavage and SREBP1 activation in the inflammatory response of macrophages.

Yinglan Cheng, Ichiro Manabe, Sumio Hayakawa, Yusuke Endo, Yumiko Oishi.

  Sterol regulatory element-binding proteins (SREBPs) are key transcription factors that control fatty acid and cholesterol metabolism. As the major SREBP isoform in macrophages, SREBP1a is also required for inflammatory and phagocytotic functions. However, it is insufficiently understood how SREBP1a is activated by the innate immune response in macrophages. Here, we show that mouse caspase-11 is a novel inflammatory activator of SREBP1a in macrophages. Upon LPS treatment, caspase-11 was found to promote the processing of site-1 protease (S1P), an enzyme that mediates the cleavage and activation of SREBP1. We also determined that caspase-11 directly associates with S1P and cleaves it at a specific site. Furthermore, deletion of the Casp4 gene, which encodes caspase-11, impaired the activation of S1P and SREBP1 as well as altered the expression of genes regulated by SREBP1 in macrophages. These results demonstrate that the caspase-11/S1P pathway activates SREBP1 in response to LPS, thus regulating subsequent macrophage activation.

Keywords:  SREBP (sterol regulatory element-binding protein) pathway; caspase; inflammatory response; macrophage; site-1 protease (S1P)

DOI:  https://doi.org/10.3389/fimmu.2023.1009973
Res Sq. 2023 Jan 27. pii: rs.3.rs-2464392. [Epub ahead of print]

Pyruvate dehydrogenase complex integrates the metabolome and epigenome in memory T cell differentiation in vitro.

Tatiana N Tarasenko, Payal Banerjee, Julio Gomez-Rodriguez, Derek Gildea, Suiyuan Zhang, Tyra Wolfsberg, Lisa M Jenkins, Nisc Comparative Sequencing Program, Peter J McGuire.

Background Modulation of metabolic flux through pyruvate dehydrogenase complex (PDC) plays an important role in T cell activation and differentiation. PDC sits at the transition between glycolysis and the tricarboxylic acid cycle and is a major producer of acetyl-CoA, marking it as a potential metabolic and epigenetic node. Methods To understand the role of pyruvate dehydrogenase complex in T cell differentiation, we generated mice deficient in T cell pyruvate dehydrogenase E1A ( Pdha ) subunit using a CD4-cre recombinase-based strategy. To control for the contribution of exogenous metabolites in vivo, we conducted our T cell functional studies in vitro. T cells were differentiated into memory and effector T cells using standardized protocols. Cells were analyzed using stable isotopic tracing studies, metabolomics, RNAseq, ATACseq, ChIPseq and histone proteomics. Results Herein, we show that genetic ablation of PDC activity in T cells ( TPdh -/- ) leads to marked perturbations in glycolysis, the tricarboxylic acid cycle, and OXPHOS. Due to depressed OXPHOS, TPdh -/- T cells became dependent upon substrate level phosphorylation via glycolysis. Due to the block of PDC activity, histone acetylation was reduced, as were most other types of post translational modifications. Transcriptional and functional profiling revealed abnormal CD8 + memory T cell differentiation in vitro. Conclusions Collectively, our data indicate that PDC integrates the metabolome and epigenome in memory T cell differentiation. Targeting this metabolic and epigenetic node can have widespread ramifications on cellular function.

DOI: https://doi.org/10.21203/rs.3.rs-2464392/v1
Cell Rep. 2023 Feb 07. pii: S2211-1247(23)00085-2. [Epub ahead of print] 112074

Maternal γδ T cells shape offspring pulmonary type 2 immunity in a microbiota-dependent manner.

Pedro H Papotto, Bahtiyar Yilmaz, Gonçalo Pimenta, Sofia Mensurado, Carolina Cunha, Gina J Fiala, Daniel Gomes da Costa, Natacha Gonçalves-Sousa, Brian H K Chan, Birte Blankenhaus, Rita G Domingues, Tânia Carvalho, Matthew R Hepworth, Andrew J Macpherson, Judith E Allen, Bruno Silva-Santos.

  Immune development is profoundly influenced by vertically transferred cues. However, little is known about how maternal innate-like lymphocytes regulate offspring immunity. Here, we show that mice born from γδ T cell-deficient (TCRδ-/-) dams display an increase in first-breath-induced inflammation, with a pulmonary milieu selectively enriched in type 2 cytokines and type 2-polarized immune cells, when compared with the progeny of γδ T cell-sufficient dams. Upon helminth infection, mice born from TCRδ-/- dams sustain an increased type 2 inflammatory response. This is independent of the genotype of the pups. Instead, the offspring of TCRδ-/- dams harbors a distinct intestinal microbiota, acquired during birth and fostering, and decreased levels of intestinal short-chain fatty acids (SCFAs), such as pentanoate and hexanoate. Importantly, exogenous SCFA supplementation inhibits type 2 innate lymphoid cell function and suppresses first-breath- and infection-induced inflammation. Taken together, our findings unravel a maternal γδ T cell-microbiota-SCFA axis regulating neonatal lung immunity.

Keywords:  CP: Immunology; CP: Microbiology; gut-lung axis; helminth infection; innate lymphoid cells; maternal; microbiota; neonatal; short-chain fatty acids; type 2 immunity; γδT cells

DOI:  https://doi.org/10.1016/j.celrep.2023.112074
BMC Oral Health. 2023 Feb 15. 23(1): 103

Hexokinase 2-mediated glycolysis supports inflammatory responses to Porphyromonas gingivalis in gingival fibroblasts.

Wenqi Su, Jingwen Li, Lishan Jiang, Lang Lei, Houxuan Li.

   BACKGROUND: When infected with Porphyromonas gingivalis, gingival fibroblasts undergo metabolic reprogramming, and rely on aerobic glycolysis rather than oxidative phosphorylation for rapid energy replenishment. Hexokinases (HKs) are catalysts for glucose metabolism, and HK2 constitutes the major HK inducible isoform. The objective of this study is to determine whether HK2-mediated glycolysis promotes inflammatory responses in inflamed gingiva.
METHODS: Levels of glycolysis-related genes were assessed in normal and inflamed gingiva. Human gingival fibroblasts were harvested and infected with Porphyromonas gingivalis in order to mimic periodontal inflammation. 2-deoxy-d-glucose, an analogue of glucose, was used to block HK2-mediated glycolysis, while small interfering RNA was used to knock down HK2 expression. The mRNA and protein levels of genes were analyzed by real-time quantitative PCR and western blotting, respectively. HK2 activity and lactate production were assessed by ELISA. Cell proliferation was assessed by confocal microscopy. The generation of reactive oxygen species was assessed by flow cytometry.
RESULTS: Elevated expression of HK2 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 was observed in the inflamed gingiva. P. gingivalis infection was shown to promote glycolysis in human gingival fibroblasts, as evidenced by increased gene transcription of HK2 and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3, cell glucose consumption, and HK2 activity. Inhibition and knockdown of HK2 resulted in reduced cytokine production, cell proliferation, and reactive oxygen species generation. Furthermore, P. gingivalis infection activated the hypoxia-inducible factor-1α signaling pathway, thus promoting HK2-mediated glycolysis and proinflammatory responses.
CONCLUSIONS: HK2-mediated glycolysis promotes inflammatory responses in gingival tissues, and therefore glycolysis can be targeted in order to inhibit the progression of periodontal inflammation.

Keywords:  Gingival fibroblasts; Glycolysis; Hexokinase 2; Periodontitis; Porphyromonas gingivalis

DOI:  https://doi.org/10.1186/s12903-023-02807-4
Lab Invest. 2021 Mar;pii: S0023-6837(22)00298-7. [Epub ahead of print]101(3): 328-340

Adipose tissue inflammation and systemic insulin resistance in mice with diet-induced obesity is possibly associated with disruption of PFKFB3 in hematopoietic cells.

Bilian Zhu, Xin Guo, Hang Xu, Boxiong Jiang, Honggui Li, Yina Wang, Qiongli Yin, Tianhao Zhou, James J Cai, Shannon Glaser, Fanyin Meng, Heather Francis, Gianfranco Alpini, Chaodong Wu.

Obesity-associated inflammation in white adipose tissue (WAT) is a causal factor of systemic insulin resistance; however, precisely how immune cells regulate WAT inflammation in relation to systemic insulin resistance remains to be elucidated. The present study examined a role for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in hematopoietic cells in regulating WAT inflammation and systemic insulin sensitivity. Male C57BL/6J mice were fed a high-fat diet (HFD) or low-fat diet (LFD) for 12 weeks and examined for WAT inducible 6-phosphofructo-2-kinase (iPFK2) content, while additional HFD-fed mice were treated with rosiglitazone and examined for PFKFB3 mRNAs in WAT stromal vascular cells (SVC). Also, chimeric mice in which PFKFB3 was disrupted only in hematopoietic cells and control chimeric mice were also fed an HFD and examined for HFD-induced WAT inflammation and systemic insulin resistance. In vitro, adipocytes were co-cultured with bone marrow-derived macrophages and examined for adipocyte proinflammatory responses and insulin signaling. Compared with their respective levels in controls, WAT iPFK2 amount in HFD-fed mice and WAT SVC PFKFB3 mRNAs in rosiglitazone-treated mice were significantly increased. When the inflammatory responses were analyzed, peritoneal macrophages from PFKFB3-disrputed mice revealed increased proinflammatory activation and decreased anti-inflammatory activation compared with control macrophages. At the whole animal level, hematopoietic cell-specific PFKFB3 disruption enhanced the effects of HFD feeding on promoting WAT inflammation, impairing WAT insulin signaling, and increasing systemic insulin resistance. In vitro, adipocytes co-cultured with PFKFB3-disrupted macrophages revealed increased proinflammatory responses and decreased insulin signaling compared with adipocytes co-cultured with control macrophages. These results suggest that PFKFB3 disruption in hematopoietic cells only exacerbates HFD-induced WAT inflammation and systemic insulin resistance. Using approaches involving chimeric mice and macrophage-adipocyte cocultures, the authors demonstrate that PFKFB3 disruption only in hematopoietic cells exacerbates the severity of diet-induced adipose tissue inflammation and systemic insulin resistance. Mechanistically, macrophage factors generated in response to PFKFB3 disruption act to enhance adipocyte proinflammatory responses and impair adipocyte insulin signaling.

DOI: https://doi.org/10.1038/s41374-020-00523-z
Sci Rep. 2023 Feb 15. 13(1): 2715

Butyrate limits human natural killer cell effector function.

Vanessa Zaiatz-Bittencourt, Fiona Jones, Miriam Tosetto, Caitriona Scaife, Gerard Cagney, Evan Jones, Glen A Doherty, Elizabeth J Ryan.

The gut microbiota regulates chronic inflammation and has been implicated in the pathogenesis of a broad spectrum of disease including autoimmunity and cancer. Microbial short-chain fatty acids (SCFAs) e.g., butyrate have demonstrated immunomodulatory effects and are thought to be key mediators of the host-microbiome interaction. Here, we investigated the effect of butyrate on effector functions of blood derived human NK cells stimulated for 18 h with a combination of IL-12/IL-15, a potent mix of cytokines that drive NK cell activation. We show that butyrate has a strong anti-inflammatory effect on NK cells. NK cells cultured in the presence of butyrate expressed lower levels of activating receptors (TRAIL, NKp30, NKp44) and produced lower levels of cytokines (IFNγ, TNF-α, IL-22, granzyme B, granzyme A, perforin) in response to IL-12/IL-15. Butyrate restricted NK cell function by downregulation of mTORC1 activity, c-Myc mRNA expression and metabolism. Using a shotgun proteomic approach, we confirmed the effect of butyrate on NK cell cytokine signaling and metabolism and identified BRD2, MAT2A and EHD1 as downstream mediators of these effects. This insight into the immunomodulatory activity of butyrate on human NK cell function might help to develop new ways to limit NK cell function during chronic inflammation.

DOI: https://doi.org/10.1038/s41598-023-29731-5
Int J Tryptophan Res. 2023 ;16 11786469231153111

Endothelial Indoleamine-2,3-Dioxygenase-1 is not Critically Involved in Regulating Antitumor Immunity in the Central Nervous System.

A P Abu Hejleh, K Huck, K Jähne, C L Tan, T V Lanz, L Epping, J K Sonner, S G Meuth, A Henneberg, C A Opitz, C Herold-Mende, F Sahm, M Platten, K Sahm.

  The vascular niche of malignant gliomas is a key compartment that shapes the immunosuppressive brain tumor microenvironment (TME). The blood-brain-barrier (BBB) consisting of specialized endothelial cells (ECs) and perivascular cells forms a tight anatomical and functional barrier critically controlling transmigration and effector function of immune cells. During neuroinflammation and tumor progression, the metabolism of the essential amino acid tryptophan (Trp) to metabolites such as kynurenine has long been identified as an important metabolic pathway suppressing immune responses. Previous studies have demonstrated that indoleamine-2,3-dioxygenase-1 (IDO1), a key rate-limiting enzyme in tryptophan catabolism, is expressed within the TME of high-grade gliomas. Here, we investigate the role of endothelial IDO1 (eIDO1) expression for brain tumor immunity. Single-cell RNA sequencing data revealed that in human glioma tissue, IDO1 is predominantly expressed by activated ECs showing a JAK/STAT signaling pathway-related CXCL11+ gene expression signature. In a syngeneic experimental glioma model, eIDO1 is induced by low-dose tumor irradiation. However, cell type-specific ablation of eIDO1 in experimental gliomas did not alter frequency and phenotype of tumor-infiltrating T cells nor tumor growth. Taken together these data argue against a dominant role of eIDO1 for brain tumor immunity.

Keywords:  CNS immunity; Indoleamine-2,3-dioxygenase-1 (IDO1); glioma; tumor vasculature

DOI:  https://doi.org/10.1177/11786469231153111
Front Endocrinol (Lausanne). 2022 ;13 1089918

Lactate-related metabolic reprogramming and immune regulation in colorectal cancer.

Qianhui Sun, Jingyuan Wu, Guanghui Zhu, Tingting Li, Xiaoyu Zhu, Baoyi Ni, Bowen Xu, Xinyi Ma, Jie Li.

  Changes in cellular metabolism involving fuel sources are well-known mechanisms of cancer cell differentiation in the context of carcinogenesis. Metabolic reprogramming is regulated by oncogenic signaling and transcriptional networks and has been identified as an essential component of malignant transformation. Hypoxic and acidified tumor microenvironment contributes mainly to the production of glycolytic products known as lactate. Mounting evidence suggests that lactate in the tumor microenvironment of colorectal cancer(CRC) contributes to cancer therapeutic resistance and metastasis. The contents related to the regulatory effects of lactate on metabolism, immune response, and intercellular communication in the tumor microenvironment of CRC are also constantly updated. Here we summarize the latest studies about the pleiotropic effects of lactate in CRC and the clinical value of targeting lactate metabolism as treatment. Different effects of lactate on various immune cell types, microenvironment characteristics, and pathophysiological processes have also emerged. Potential specific therapeutic targeting of CRC lactate metabolism is also discussed. With increased knowledge, effective druggable targets might be identified, with the aim of improving treatment outcomes by reducing chemoresistance.

Keywords:  colorectal cancer; immune response; immunoregulation; lactate; metabolic reprogramming

DOI:  https://doi.org/10.3389/fendo.2022.1089918
Proc Natl Acad Sci U S A. 2023 Feb 21. 120(8): e2209177120

Mitochondrial control of microglial phagocytosis by the translocator protein and hexokinase 2 in Alzheimer's disease.

Lauren H Fairley, Kei Onn Lai, Jia Hui Wong, Wei Jing Chong, Anselm Salvatore Vincent, Giuseppe D'Agostino, Xiaoting Wu, Roshan R Naik, Anusha Jayaraman, Sarah R Langley, Christiane Ruedl, Anna M Barron.

  Microglial phagocytosis is an energetically demanding process that plays a critical role in the removal of toxic protein aggregates in Alzheimer's disease (AD). Recent evidence indicates that a switch in energy production from mitochondrial respiration to glycolysis disrupts this important protective microglial function and may provide therapeutic targets for AD. Here, we demonstrate that the translocator protein (TSPO) and a member of its mitochondrial complex, hexokinase-2 (HK), play critical roles in microglial respiratory-glycolytic metabolism and phagocytosis. Pharmacological and genetic loss-of-function experiments showed that TSPO is critical for microglial respiratory metabolism and energy supply for phagocytosis, and its expression is enriched in phagocytic microglia of AD mice. Meanwhile, HK controlled glycolytic metabolism and phagocytosis via mitochondrial binding or displacement. In cultured microglia, TSPO deletion impaired mitochondrial respiration and increased mitochondrial recruitment of HK, inducing a switch to glycolysis and reducing phagocytosis. To determine the functional significance of mitochondrial HK recruitment, we developed an optogenetic tool for reversible control of HK localization. Displacement of mitochondrial HK inhibited glycolysis and improved phagocytosis in TSPO-knockout microglia. Mitochondrial HK recruitment also coordinated the inflammatory switch to glycolysis that occurs in response to lipopolysaccharide in normal microglia. Interestingly, cytosolic HK increased phagocytosis independent of its metabolic activity, indicating an immune signaling function. Alzheimer's beta amyloid drastically stimulated mitochondrial HK recruitment in cultured microglia, which may contribute to microglial dysfunction in AD. Thus, targeting mitochondrial HK may offer an immunotherapeutic approach to promote phagocytic microglial function in AD.

Keywords:  Alzheimer’s disease; hexokinase; immunometabolism; mitochondria; translocator protein

DOI:  https://doi.org/10.1073/pnas.2209177120
J Virol. 2023 Feb 16. e0001623

Newcastle Disease Virus Manipulates Mitochondrial MTHFD2-Mediated Nucleotide Metabolism for Virus Replication.

Ning Tang, Pingyi Chen, Changrun Zhao, Panrao Liu, Lei Tan, Cuiping Song, Xusheng Qiu, Ying Liao, Xiufan Liu, Tingrong Luo, Yingjie Sun, Chan Ding.

  Viruses require host cell metabolic reprogramming to satisfy their replication demands; however, the mechanism by which the Newcastle disease virus (NDV) remodels nucleotide metabolism to support self-replication remains unknown. In this study, we demonstrate that NDV relies on the oxidative pentose phosphate pathway (oxPPP) and the folate-mediated one-carbon metabolic pathway to support replication. In concert with [1,2-13C2] glucose metabolic flow, NDV used oxPPP to promote pentose phosphate synthesis and to increase antioxidant NADPH production. Metabolic flux experiments using [2,3,3-2H] serine revealed that NDV increased one-carbon (1C) unit synthesis flux through the mitochondrial 1C pathway. Interestingly, methylenetetrahydrofolate dehydrogenase (MTHFD2) was upregulated as a compensatory mechanism for insufficient serine availability. Unexpectedly, direct knockdown of enzymes in the one-carbon metabolic pathway, except for cytosolic MTHFD1, significantly inhibited NDV replication. Specific complementation rescue experiments on small interfering RNA (siRNA)-mediated knockdown further revealed that only a knockdown of MTHFD2 strongly restrained NDV replication and was rescued by formate and extracellular nucleotides. These findings indicated that NDV replication relies on MTHFD2 to maintain nucleotide availability. Notably, nuclear MTHFD2 expression was increased during NDV infection and could represent a pathway by which NDV steals nucleotides from the nucleus. Collectively, these data reveal that NDV replication is regulated by the c-Myc-mediated 1C metabolic pathway and that the mechanism of nucleotide synthesis for viral replication is regulated by MTHFD2. IMPORTANCE Newcastle disease virus (NDV) is a dominant vector for vaccine and gene therapy that accommodates foreign genes well but can only infect mammalian cells that have undergone cancerous transformation. Understanding the remodeling of nucleotide metabolic pathways in host cells by NDV proliferation provides a new perspective for the precise use of NDV as a vector or in antiviral research. In this study, we demonstrated that NDV replication is strictly dependent on pathways involved in redox homeostasis in the nucleotide synthesis pathway, including the oxPPP and the mitochondrial one-carbon pathway. Further investigation revealed the potential involvement of NDV replication-dependent nucleotide availability in promoting MTHFD2 nuclear localization. Our findings highlight the differential dependence of NDV on enzymes for one-carbon metabolism, and the unique mechanism of action of MTHFD2 in viral replication, thereby providing a novel target for antiviral or oncolytic virus therapy.

Keywords:  MTHFD2; Newcastle disease virus; c-Myc; mitochondrial 1C metabolism; oxPPP

DOI:  https://doi.org/10.1128/jvi.00016-23
Theranostics. 2023 ;13(3): 991-1009

Exosomal STIMATE derived from type II alveolar epithelial cells controls metabolic reprogramming of tissue-resident alveolar macrophages.

Zunyong Feng, Zhou Jing, Qiang Li, Liuxi Chu, YuXin Jiang, Xuanbo Zhang, Liang Yan, Yinhua Liu, Jing Jiang, Ping Xu, Qun Chen, Ming Wang, Hui Yang, Guoren Zhou, Xiaochun Jiang, Xiaoyuan Chen, Hongping Xia.

  Background: Complete abolition of alveolar epithelial cells (AECs) is characteristic of end-stage lung disease. Transplantation therapy of type II AECs (AEC-IIs) or AEC-IIs-derived exosomes (ADEs) have been proposed as a means of repairing injury and preventing fibrosis. However, the mechanism by which ADEs balances airway immunity and alleviates damage and fibrosis remains unknown. Methods: We investigated STIM-activating enhancer-positive ADEs (STIMATE+ ADEs) in the lung of 112 ALI/ARDS and 44 IPF patients, and observed the correlation between STIMATE+ ADEs and subpopulation proportion and metabolic status of tissue-resident alveolar macrophages (TRAMs). We constructed the conditional knockout mice STIMATE sftpc , in which STIMATE was specifically knocked out in mouse AEC-IIs and observed the effects of STIMATE+ ADEs deficiency on disease progression, immune selection and metabolic switching of TRAMs. We constructed a BLM-induced AEC-IIs injury model to observe the salvage treatment of damage/fibrosis progression with STIMATE+ ADEs supplementation. Results: In clinical analysis, the distinct metabolic phenotypes of AMs in ALI/ARFS and IPF were significantly perturbed by STIMATE+ ADEs. The immune and metabolic status of TRAMs in the lungs of STIMATE sftpc mice was imbalanced, resulting in spontaneous inflammatory injury and respiratory disorders. STIMATE+ ADEs are taken up by tissue-resident alveolar macrophages TRAMs to regulate high Ca2+ responsiveness and long-term Ca2+ signal transduction, which maintains M2-like immunophenotype and metabolism selection. This involves calcineurin (CaN)-PGC-1α pathway mediated mitochondrial biogenesis and mtDNA coding. In a bleomycin-induced mouse fibrosis model, supplementation with inhaled STIMATE+ ADEs lessened early acute injury, prevented advanced fibrosis, alleviated ventilatory impairment and reduced mortality.

Keywords:  ALI/ARDS; Alveolar macrophages; Exosome; STIMATE; Type 2 alveolar epithelial.

DOI:  https://doi.org/10.7150/thno.82552
Nat Commun. 2023 Feb 13. 14(1): 721

Repair of airway epithelia requires metabolic rewiring towards fatty acid oxidation.

Stefania Crotta, Matteo Villa, Jack Major, Katja Finsterbusch, Miriam Llorian, Peter Carmeliet, Joerg Buescher, Andreas Wack.

Epithelial tissues provide front-line barriers shielding the organism from invading pathogens and harmful substances. In the airway epithelium, the combined action of multiciliated and secretory cells sustains the mucociliary escalator required for clearance of microbes and particles from the airways. Defects in components of mucociliary clearance or barrier integrity are associated with recurring infections and chronic inflammation. The timely and balanced differentiation of basal cells into mature epithelial cell subsets is therefore tightly controlled. While different growth factors regulating progenitor cell proliferation have been described, little is known about the role of metabolism in these regenerative processes. Here we show that basal cell differentiation correlates with a shift in cellular metabolism from glycolysis to fatty acid oxidation (FAO). We demonstrate both in vitro and in vivo that pharmacological and genetic impairment of FAO blocks the development of fully differentiated airway epithelial cells, compromising the repair of airway epithelia. Mechanistically, FAO links to the hexosamine biosynthesis pathway to support protein glycosylation in airway epithelial cells. Our findings unveil the metabolic network underpinning the differentiation of airway epithelia and identify novel targets for intervention to promote lung repair.

DOI: https://doi.org/10.1038/s41467-023-36352-z
EMBO J. 2023 Feb 16. e112202

Adipocyte autophagy limits gut inflammation by controlling oxylipin and IL-10.

Felix Clemens Richter, Matthias Friedrich, Nadja Kampschulte, Klara Piletic, Ghada Alsaleh, Ramona Zummach, Julia Hecker, Mathilde Pohin, Nicholas Ilott, Irina Guschina, Sarah Karin Wideman, Errin Johnson, Mariana Borsa, Paula Hahn, Christophe Morriseau, Bruce D Hammock, Henk Simon Schipper, Claire M Edwards, Rudolf Zechner, Britta Siegmund, Carl Weidinger, Nils Helge Schebb, Fiona Powrie, Anna Katharina Simon.

  Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, either through their function as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however, whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte-specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti-inflammatory energy substrates. Instead, Atg7-deficient adipose tissues exhibited an oxylipin imbalance, driven through an NRF2-mediated upregulation of Ephx1. This shift reduced secretion of IL-10 from adipose tissues, which was dependent on the cytochrome P450-EPHX pathway, and lowered circulating levels of IL-10 to exacerbate intestinal inflammation. These results suggest an underappreciated fat-gut crosstalk through an autophagy-dependent regulation of anti-inflammatory oxylipins via the cytochrome P450-EPHX pathway, indicating a protective effect of adipose tissues for distant inflammation.

Keywords:  IL-10; adipocyte; autophagy; inflammation; oxylipin

DOI:  https://doi.org/10.15252/embj.2022112202
J Biol Chem. 2023 Feb 10. pii: S0021-9258(23)00137-0. [Epub ahead of print] 103005

Innate immune cell-intrinsic ketogenesis is dispensable for organismal metabolism and age-related inflammation.

Emily L Goldberg, Anudari Letian, Tamara Dlugos, Claire Leveau, Vishwa Deep Dixit.

  Aging is accompanied by chronic low-grade inflammation, but the mechanisms that allow this to persist are not well understood. Ketone bodies are alternative fuels produced when glucose is limited and improve indicators of healthspan in aging mouse models. Moreover, the most abundant ketone body, β-hydroxybutyrate (BHB), inhibits the NLRP3 inflammasome in myeloid cells, a key potentiator of age-related inflammation. Given that myeloid cells express ketogenic machinery, we hypothesized this pathway may serve as a metabolic checkpoint of inflammation. To test this hypothesis, we conditionally ablated ketogenesis by disrupting expression of the terminal enzyme required for ketogenesis, 3-Hydroxy-3-Methylglutaryl-CoA Lyase (HMGCL). By deleting HMGCL in the liver, we validated the functional targeting and establish that the liver is the only organ that can produce the life-sustaining quantities of ketone bodies required for survival during fasting or ketogenic diet feeding. Conditional ablation of HMGCL in neutrophils and macrophages had modest effects on body weight and glucose tolerance in aging, but worsened glucose homeostasis in myeloid cell-specific Hmgcl-deficient mice fed a high-fat diet. Our results suggest that during aging, liver-derived circulating ketone bodies might be more important for deactivating the NLRP3 inflammasome and controlling organismal metabolism.

Keywords:  aging; inflammation; innate immunity; ketone; metabolism

DOI:  https://doi.org/10.1016/j.jbc.2023.103005
Cell Mol Life Sci. 2023 Feb 13. 80(3): 63

Loss of Lkb1 in CD11c+ myeloid cells protects mice from diet-induced obesity while enhancing glucose intolerance and IL-17/IFN-γ imbalance.

Yunyan Sun, Bing Wang, Qianwen Hu, Haixiao Zhang, Xun Lai, Tier Wang, Chunxiao Zhao, Jiali Wang, Xi Zhang, Qing Niu, Baolin He, Erlie Jiang, Mingxia Shi, Xiaoming Feng, Yuechen Luo.

  Adipose tissue CD11c+ myeloid cell is an independent risk factor associated with obesity and metabolic disorders. However, the underlying molecular basis remains elusive. Here, we demonstrated that liver kinase B1 (Lkb1), a key bioenergetic sensor, is involved in CD11c+ cell-mediated immune responses in diet-induced obesity. Loss of Lkb1 in CD11c+ cells results in obesity resistance but lower glucose tolerance, which accompanies tissue-specific immune abnormalities. The accumulation and CD80's expression of Lkb1 deficient adipose-tissue specific dendritic cells but not macrophages is restrained. Additionally, the balance of IL-17A and IFN-γ remarkably tips towards the latter in fat T cells and CD11c- macrophages. Mechanistically, IFN-γ promotes apoptosis of preadipocytes and inhibits their adipogenesis while IL-17A promotes the adipogenesis in vitro, which might account in part for the fat gain resistant phenotype. In summary, these findings reveal that Lkb1 is essential for fat CD11c+ dendritic cells responding to HFD exposure and provides new insights into the IL-17A/IFN-γ balance in HFD-induced obesity.

Keywords:  Dendritic cells; High-fat-diet-induced obesity; IFN-γ; IL-17A; Liver kinase B1; Macrophages; T cells; Visceral adipose tissue

DOI:  https://doi.org/10.1007/s00018-023-04707-w
Front Immunol. 2023 ;14 1113883

Caspase-11 promotes high-fat diet-induced NAFLD by increasing glycolysis, OXPHOS, and pyroptosis in macrophages.

Charles Drummer, Fatma Saaoud, Nirag C Jhala, Ramon Cueto, Yu Sun, Keman Xu, Ying Shao, Yifan Lu, Huimin Shen, Ling Yang, Yan Zhou, Jun Yu, Sheng Wu, Nathaniel W Snyder, Wenhui Hu, Jia 'Joe' Zhuo, Yinghui Zhong, Xiaohua Jiang, Hong Wang, Xiaofeng Yang.

   Introduction: Non-alcoholic fatty liver disease (NAFLD) has a global prevalence of 25% of the population and is a leading cause of cirrhosis and hepatocellular carcinoma. NAFLD ranges from simple steatosis (non-alcoholic fatty liver) to non-alcoholic steatohepatitis (NASH). Hepatic macrophages, specifically Kupffer cells (KCs) and monocyte-derived macrophages, act as key players in the progression of NAFLD. Caspases are a family of endoproteases that provide critical connections to cell regulatory networks that sense disease risk factors, control inflammation, and mediate inflammatory cell death (pyroptosis). Caspase-11 can cleave gasdermin D (GSDMD) to induce pyroptosis and specifically defends against bacterial pathogens that invade the cytosol. However, it's still unknown whether high fat diet (HFD)-facilitated gut microbiota-generated cytoplasmic lipopolysaccharides (LPS) activate caspase-11 and promote NAFLD.
Methods: To examine this hypothesis, we performed liver pathological analysis, RNA-seq, FACS, Western blots, Seahorse mitochondrial stress analyses of macrophages and bone marrow transplantation on HFD-induced NAFLD in WT and Casp11-/- mice.
Results and Discussion: Our results showed that 1) HFD increases body wight, liver wight, plasma cholesterol levels, liver fat deposition, and NAFLD activity score (NAS score) in wild-type (WT) mice; 2) HFD increases the expression of caspase-11, GSDMD, interleukin-1β, and guanylate-binding proteins in WT mice; 3) Caspase-11 deficiency decreases fat liver deposition and NAS score; 4) Caspase-11 deficiency decreases bone marrow monocyte-derived macrophage (MDM) pyroptosis (inflammatory cell death) and inflammatory monocyte (IM) surface GSDMD expression; 5) Caspase-11 deficiency re-programs liver transcriptomes and reduces HFD-induced NAFLD; 6) Caspase-11 deficiency decreases extracellular acidification rates (glycolysis) and oxidative phosphorylation (OXPHOS) in inflammatory fatty acid palmitic acid-stimulated macrophages, indicating that caspase-11 significantly contributes to maintain dual fuel bioenergetics-glycolysis and OXPHOS for promoting pyroptosis in macrophages. These results provide novel insights on the roles of the caspase-11-GSDMD pathway in promoting hepatic macrophage inflammation and pyroptosis and novel targets for future therapeutic interventions involving the transition of NAFLD to NASH, hyperlipidemia, type II diabetes, metabolic syndrome, metabolically healthy obesity, atherosclerotic cardiovascular diseases, autoimmune diseases, liver transplantation, and hepatic cancers.

Keywords:  caspase-11; inflammation; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); pyroptosis

DOI:  https://doi.org/10.3389/fimmu.2023.1113883
Nat Biotechnol. 2023 Feb 13.

gutSMASH predicts specialized primary metabolic pathways from the human gut microbiota.

Victòria Pascal Andreu, Hannah E Augustijn, Lianmin Chen, Alexandra Zhernakova, Jingyuan Fu, Michael A Fischbach, Dylan Dodd, Marnix H Medema.

The gut microbiota produce hundreds of small molecules, many of which modulate host physiology. Although efforts have been made to identify biosynthetic genes for secondary metabolites, the chemical output of the gut microbiome consists predominantly of primary metabolites. Here we introduce the gutSMASH algorithm for identification of primary metabolic gene clusters, and we used it to systematically profile gut microbiome metabolism, identifying 19,890 gene clusters in 4,240 high-quality microbial genomes. We found marked differences in pathway distribution among phyla, reflecting distinct strategies for energy capture. These data explain taxonomic differences in short-chain fatty acid production and suggest a characteristic metabolic niche for each taxon. Analysis of 1,135 individuals from a Dutch population-based cohort shows that the level of microbiome-derived metabolites in plasma and feces is almost completely uncorrelated with the metagenomic abundance of corresponding metabolic genes, indicating a crucial role for pathway-specific gene regulation and metabolite flux. This work is a starting point for understanding differences in how bacterial taxa contribute to the chemistry of the microbiome.

DOI: https://doi.org/10.1038/s41587-023-01675-1
J Cell Physiol. 2023 Feb 15.

Targeting first trimester trophoblast cell metabolism modulates its susceptibility to Zika virus infection.

Diego Kafer, Agostina Marquez, Fátima Merech, Vanesa Hauk, Daniel Paparini, Rosanna Ramhorst, Claudia Pérez Leirós, Cybele Garcia, Daiana Vota.

  In the last 15 years Zika virus (ZIKV) caused several outbreaks of increasing scale in Micronesia, South Pacific islands, and more recently in the Caribbean and South America. The severity of the clinical presentation in neonates from pregnant women infected with ZIKV during the last outbreak supports the relevance of unraveling the mechanism of infection and viral persistence in the placenta with local viral isolates. Here, we investigated the relevance of trophoblast metabolic rewiring for viral multiplication and the role of the vasoactive intestinal peptide (VIP) as an endogenous factor associated with placental restriction to ZIKV infection at early pregnancy. Our in vitro model demonstrated that ZIKV triggers metabolic rewiring in first trimester cytotrophoblast-derived cells by increasing glucose utilization as fuel to sustain its replication, decreasing long-chain polyunsaturated fatty acid uptake, and promoting lipid droplets accumulation to favor its multiplication. Of note, variations in nutrient availability modulated viral spread in trophoblast cultures. The presence of VIP during trophoblast infection impaired ZIKV infective particle production and viral replication, restoring cell migration and metabolism. Moreover, the blockade of endogenous VIP signaling increased viral particle production and the viral entry receptor AXL expression. These results highlight the potential role of VIP as an endogenous antiviral factor related to trophoblast cell permissiveness to ZIKV infection at early pregnancy.

Keywords:  Zika virus; metabolism; placenta; trophoblast; vasoactive intestinal peptide

DOI:  https://doi.org/10.1002/jcp.30970
bioRxiv. 2023 Feb 06. pii: 2023.02.06.527204. [Epub ahead of print]

APOE4 drives transcriptional heterogeneity and maladaptive immunometabolic responses of astrocytes.

Sangderk Lee, Holden C Williams, Amy A Gorman, Nicholas A Devanney, Douglas A Harrison, Adeline E Walsh, Danielle S Goulding, Tony Tuck, James L Schwartz, Diana J Zajac, Shannon L Macauley, Steven Estus, Tcw Julia, Lance A Johnson, Josh M Morganti.

Apolipoprotein E4 (APOE4) is the strongest risk allele associated with the development of late onset Alzheimerâ€™s disease (AD). Across the CNS, astrocytes are the predominant expressor of APOE while also being critical mediators of neuroinflammation and cerebral metabolism. APOE4 has been consistently linked with dysfunctional inflammation and metabolic processes, yet insights into the molecular constituents driving these responses remain unclear. Utilizing complementary approaches across humanized APOE mice and isogenic human iPSC astrocytes, we demonstrate that ApoE4 alters the astrocyte immunometabolic response to pro-inflammatory stimuli. Our findings show that ApoE4-expressing astrocytes acquire distinct transcriptional repertoires at single-cell and spatially-resolved domains, which are driven in-part by preferential utilization of the cRel transcription factor. Further, inhibiting cRel translocation in ApoE4 astrocytes abrogates inflammatory-induced glycolytic shifts and in tandem mitigates production of multiple pro-inflammatory cytokines. Altogether, our findings elucidate novel cellular underpinnings by which ApoE4 drives maladaptive immunometabolic responses of astrocytes.

DOI: https://doi.org/10.1101/2023.02.06.527204
Cardiovasc Res. 2023 Feb 16. pii: cvad030. [Epub ahead of print]

Innate immune memory in cardiometabolic disease.

Harsh Bahrar, Siroon Bekkering, Rinke Stienstra, Mihai G Netea, Niels P Riksen.

  Low-grade systemic inflammation is a key pathophysiological component of atherosclerotic cardiovascular disease (CVD), and long-term activation of myeloid cells is thought to be crucial for these effects. Obesity and associated metabolic complications including hyperglycaemia and dyslipoproteinaemia can induce long-lasting inflammatory reprogramming of the innate immune cells and their bone marrow progenitors, which in turn contributes to atherosclerosis. In this review, we discuss the mechanisms through which innate immune cells undergo long-term changes in their functional, epigenetic, and metabolic characteristics upon even short-term exposure to endogenous ligands, a process also termed 'trained immunity'. Inappropriate induction of trained immunity leads to the development of long-lasting hyperinflammatory and proatherogenic changes in monocytes and macrophages, an important factor in the development of atherosclerosis and CVDs. Knowledge of the specific immune cells and the distinct intracellular molecular pathways involved in the induction of trained immunity will reveal novel pharmacological targets that could be used to prevent or treat CVDs in the future.

Keywords:  Atherosclerosis; Inflammation; Monocytes; Obesity; Trained immunity

DOI:  https://doi.org/10.1093/cvr/cvad030
Front Cell Infect Microbiol. 2023 ;13 1092118

Gut-joint axis: Gut dysbiosis can contribute to the onset of rheumatoid arthritis via multiple pathways.

María Del Socorro Romero-Figueroa, Ninfa Ramírez-Durán, Alvaro José Montiel-Jarquín, Gabriel Horta-Baas.

  Rheumatoid Arthritis (RA) is an autoimmune disease characterized by loss of immune tolerance and chronic inflammation. It is pathogenesis complex and includes interaction between genetic and environmental factors. Current evidence supports the hypothesis that gut dysbiosis may play the role of environmental triggers of arthritis in animals and humans. Progress in the understanding of the gut microbiome and RA. has been remarkable in the last decade. In vitro and in vivo experiments revealed that gut dysbiosis could shape the immune system and cause persistent immune inflammatory responses. Furthermore, gut dysbiosis could induce alterations in intestinal permeability, which have been found to predate arthritis onset. In contrast, metabolites derived from the intestinal microbiota have an immunomodulatory and anti-inflammatory effect. However, the precise underlying mechanisms by which gut dysbiosis induces the development of arthritis remain elusive. This review aimed to highlight the mechanisms by which gut dysbiosis could contribute to the pathogenesis of RA. The overall data showed that gut dysbiosis could contribute to RA pathogenesis by multiple pathways, including alterations in gut barrier function, molecular mimicry, gut dysbiosis influences the activation and the differentiation of innate and acquired immune cells, cross-talk between gut microbiota-derived metabolites and immune cells, and alterations in the microenvironment. The relative weight of each of these mechanisms in RA pathogenesis remains uncertain. Recent studies showed a substantial role for gut microbiota-derived metabolites pathway, especially butyrate, in the RA pathogenesis.

Keywords:   gut microflora; butyrate; gut microbiome; rheumatoid arthritis; short-chain fatty acid

DOI:  https://doi.org/10.3389/fcimb.2023.1092118
Elife. 2023 Feb 16. pii: e82785. [Epub ahead of print]12

Network-based multi-omics integration reveals metabolic at-risk profile within treated HIV-infection.

Flora Mikaeloff, Marco Gelpi, Rui Benfeitas, Andreas D Knudsen, Beate Vestad, Julie Høgh, Johannes R Hov, Thomas Benfield, Daniel Murray, Christian G Giske, Adil Mardinoglu, Marius Trøseid, Susanne D Nielsen, Ujjwal Neogi.

  Multiomics technologies improve the biological understanding of health status in people living with HIV on antiretroviral therapy (PLWH). Still, a systematic and in-depth characterization of metabolic risk profile during successful long-term treatment is lacking. Here, we used multi-omics (plasma lipidomic, metabolomic, and fecal 16S microbiome) data-driven stratification and characterization to identify the metabolic at-risk profile within PLWH. Through network analysis and similarity network fusion (SNF), we identified three groups of PLWH (SNF-1 to 3): healthy (HC)-like (SNF-1), mild at-risk (SNF-3), and severe at-risk (SNF-2). The PLWH in the SNF-2 (45%) had a severe at-risk metabolic profile with increased visceral adipose tissue, BMI, higher incidence of metabolic syndrome (MetS), and increased di- and triglycerides despite having higher CD4+ T-cell counts than the other two clusters. However, the HC-like and the severe at-risk group had a similar metabolic profile differing from HIV-negative controls (HNC), with dysregulation of amino acid metabolism. At the microbiome profile, the HC-like group had a lower α-diversity, a lower proportion of men having sex with men (MSM) and was enriched in Bacteroides. In contrast, in at-risk groups, there was an increase in Prevotella, with a high proportion of MSM, which could potentially lead to higher systemic inflammation and increased cardiometabolic risk profile. The multi-omics integrative analysis also revealed a complex microbial interplay of the microbiome-derived metabolites in PLWH. Those severely at-risk clusters may benefit from personalized medicine and lifestyle intervention to improve their dysregulated metabolic traits, aiming to achieve healthier aging.

Keywords:  computational biology; infectious disease; microbiology; systems biology; viruses

DOI:  https://doi.org/10.7554/eLife.82785
Immunity. 2023 Feb 14. pii: S1074-7613(23)00029-8. [Epub ahead of print]56(2): 229-231

Breathing easy: Dopamine quenches the ILC2 flame.

Franz Puttur, Clare M Lloyd.

Communication between nerves and group 2 innate lymphoid cells (ILC2s) is thought to regulate allergic airway inflammation, but the molecular mechanisms are unclear. In this issue of Immunity, Cao et al. uncover an essential role for dopamine in inhibiting ILC2 function via metabolic restriction, thereby ameliorating key features of asthma pathogenesis.

DOI: https://doi.org/10.1016/j.immuni.2023.01.019
Front Immunol. 2022 ;13 1089200

DSS-induced colitis activates the kynurenine pathway in serum and brain by affecting IDO-1 and gut microbiota.

Li-Ping Zhao, Jian Wu, Wei Quan, Yu Zhou, Hui Hong, Gu-Yu Niu, Ting Li, Shu-Bing Huang, Chen-Meng Qiao, Wei-Jiang Zhao, Chun Cui, Yan-Qin Shen.

  Accumulative studies suggest that inflammatory bowel disease (IBD) may cause multiple central nervous system (CNS) pathologies. Studies have found that indoleamine-2,3-dioxygenase (IDO, rate-limiting enzyme of the kynurenine (Kyn) pathway) deficient mice were protected from endotoxin induced cognitive impairment, and Kyn administration induced cognitive memory deficits in both control and IDO-deficient mice. However, there is no investigation of the brain Kyn pathway in IBD, thus we investigated whether dextran sulfate sodium (DSS)-induced colitis could cause dysregulation of Kyn pathway in brain, and also in serum. C57BL/6J mice were given drinking water with 2% DSS for 10 consecutive days to induce colitis. In serum, we found significant increase in Kyn and kynurenic acid (Kyna) level, which was regulated by IDO-1 and KAT2 (rate-limiting enzymes of Trp-Kyn-Kyna pathway). Similarly, by analyzing GEO datasets, higher IDO-1 levels in peripheral blood monocytes and colon of UC patients was found. Furthermore, the Kyn pathway was significantly upregulated in the cerebral cortex under the action of IDO-1 after DSS treatment, which ultimately induced the neurotoxic phenotype of astrocytes. To investigate whether gut microbiota is involved in IBD-induced Kyn pathway dysregulation, we performed intestinal flora 16S rRNA sequencing and found that DSS-induced colitis significantly altered the composition and diversity of the gut microbiota. Metabolic function analysis also showed that Tryptophan metabolism, NOD-like receptor signaling pathway and MAPK signaling pathway were significantly up-regulated in the 2% DSS group. A significant association between intestinal flora and Trp metabolism (both in serum and brain) was found by correlation analysis. Overall, this study revealed that DSS-induced colitis causes dysregulation of the Kyn pathway in serum and brain by affecting rate-limiting enzymes and intestinal flora.

Keywords:  DSS-induced colitis; gut microbiota; indoleamine-2,3-dioxygenase (IDO); kynurenine pathway (KP); tryptophan metabolism

DOI:  https://doi.org/10.3389/fimmu.2022.1089200
Cancer Sci. 2023 Feb 15.

SLC3A2 Promotes Tumor Associated Macrophage Polarization via Metabolic Reprogramming in Lung Cancer.

Zhuan Li, Songming Chen, Xiang He, Siyuan Gong, Lunquan Sun, Liang Weng.

  Tumor associated macrophages (TAMs) are one of the most abundant immunosuppressive cells in the tumor microenvironment and possess crucial functions in facilitating tumor progression. Emerging evidences indicate that altered metabolic properties in cancer cell support the tumorigenic functions of TAMs. However, mechanisms and mediators underly crosstalk between cancer cell and TAMs remain largely unknown. In present study, we revealed that high Solute Carrier Family 3 Member 2 (SLC3A2) expression in lung cancer patients were associated with TAMs and poor prognosis. Knockdown of SLC3A2 in lung adenocarcinoma cells impaired M2 polarization of macrophages in co-culture system. By using metabolome analysis, we identified that knockdown SLC3A2 altered metabolism of lung cancer cells and changed multiple metabolites including arachidonic acid in the tumor microenvironment. More importantly, we demonstrated that arachidonic acid was responsible for SLC3A2 mediated macrophage polarization in the tumor microenvironment to differentiate into M2 type both in vitro and in vivo. Our data illustrate previously undescribed mechanisms responsible for TAMs polarization and suggest that SLC3A2 acts as a metabolic switch on lung adenocarcinoma cells to induce macrophage phenotypic reprogramming via arachidonic acid.

Keywords:  Arachidonic acid; Lung adenocarcinoma; Macrophage polarization; SLC3A2; Tumor associated macrophage

DOI:  https://doi.org/10.1111/cas.15760
Sci Rep. 2023 Feb 16. 13(1): 2819

Inhibition of inflammatory microglia by dietary fiber and short-chain fatty acids.

Maria Elisa Caetano-Silva, Laurie Rund, Noah T Hutchinson, Jeffrey A Woods, Andrew J Steelman, Rodney W Johnson.

Microglia play a vital role maintaining brain homeostasis but can also cause persistent neuroinflammation. Short-chain fatty acids (SCFAs) produced by the intestinal microbiota have been suggested to regulate microglia inflammation indirectly by signaling through the gut-brain axis or directly by reaching the brain. The present work evaluated the anti-inflammatory effects of SCFAs on lipopolysaccharide (LPS)-stimulated microglia from mice fed inulin, a soluble fiber that is fermented by intestinal microbiota to produce SCFAs in vivo, and SCFAs applied to primary microglia in vitro. Feeding mice inulin increased SCFAs in the cecum and in plasma collected from the hepatic portal vein. Microglia isolated from mice fed inulin and stimulated with LPS in vitro secreted less tumor necrosis factor α (TNF-α) compared to microglia from mice not given inulin. Additionally, when mice were fed inulin and injected i.p with LPS, the ex vivo secretion of TNF-α by isolated microglia was lower than that secreted by microglia from mice not fed inulin and injected with LPS. Similarly, in vitro treatment of primary microglia with acetate and butyrate either alone or in combination downregulated microglia cytokine production with the effects being additive. SCFAs reduced histone deacetylase activity and nuclear factor-κB nuclear translocation after LPS treatment in vitro. Whereas microglia expression of SCFA receptors Ffar2 or Ffar3 was not detected by single-cell RNA sequencing analysis, the SCFA transporters Mct1 and Mct4 were. Nevertheless, inhibiting monocarboxylate transporters on primary microglia did not interfere with the anti-inflammatory effects of SCFAs, suggesting that if SCFAs produced in the gut regulate microglia directly it is likely through an epigenetic mechanism following diffusion.

DOI: https://doi.org/10.1038/s41598-022-27086-x