bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2023‒11‒19
twenty-one papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Inhibition of the proline metabolism rate-limiting enzyme P5CS allows proliferation of glutamine-restricted cancer cells.
  2. MCUb is an inducible regulator of calcium-dependent mitochondrial metabolism and substrate utilization in muscle.
  3. Fatty acid desaturation and lipoxygenase pathways support trained immunity.
  4. Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis.
  5. Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation.
  6. Metabolic predictors of response to immune checkpoint blockade therapy.
  7. A bacteria-derived tetramerized protein ameliorates nonalcoholic steatohepatitis in mice via binding and relocating acetyl-coA carboxylase.
  8. SMPDL3A links cholesterol metabolism to the cGAS-STING pathway.
  9. NAD+ regulates nucleotide metabolism and genomic DNA replication.
  10. Prostate cancer cell-derived exosomal IL-8 fosters immune evasion by disturbing glucolipid metabolism of CD8+ T cell.
  11. Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function.
  12. Ketone body β-hydroxybutyrate (BHB) preserves mitochondrial bioenergetics.
  13. mTOR inhibition suppresses salinomycin-induced ferroptosis in breast cancer stem cells by ironing out mitochondrial dysfunctions.
  14. RNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis.
  15. Adipose tissue macrophage dysfunction is associated with a breach of vascular integrity in NASH.
  16. Host extracellular vesicles confer cytosolic access to systemic LPS licensing non-canonical inflammasome sensing and pyroptosis.
  17. Vitamin B12 emerges as key player during cellular reprogramming.
  18. The extracellular matrix dictates regional competence for tumour initiation.
  19. Structure and mechanism of a eukaryotic ceramide synthase complex.
  20. Fiber-deficient diet inhibits colitis through the regulation of the niche and metabolism of a gut pathobiont.
  21. Vitamin B12 is a limiting factor for induced cellular plasticity and tissue repair.
  1. Nat Metab. 2023 Nov 13.
    Inhibition of the proline metabolism rate-limiting enzyme P5CS allows proliferation of glutamine-restricted cancer cells.
    Samantha J Linder, Tiziano Bernasocchi, Bárbara Martínez-Pastor, Kelly D Sullivan, Matthew D Galbraith, Caroline A Lewis, Christina M Ferrer, Ruben Boon, Giorgia G Silveira, Hyo Min Cho, Charles Vidoudez, Stuti Shroff, Joao P Oliveira-Costa, Kenneth N Ross, Rami Massri, Yusuke Matoba, Eugene Kim, Bo R Rueda, Shannon L Stott, Eyal Gottlieb, Joaquin M Espinosa, Raul Mostoslavsky.
      Glutamine is a critical metabolite for rapidly proliferating cells as it is used for the synthesis of key metabolites necessary for cell growth and proliferation. Glutamine metabolism has been proposed as a therapeutic target in cancer and several chemical inhibitors are in development or in clinical trials. How cells subsist when glutamine is limiting is poorly understood. Here, using an unbiased screen, we identify ALDH18A1, which encodes P5CS, the rate-limiting enzyme in the proline biosynthetic pathway, as a gene that cells can downregulate in response to glutamine starvation. Notably, P5CS downregulation promotes de novo glutamine synthesis, highlighting a previously unrecognized metabolic plasticity of cancer cells. The glutamate conserved from reducing proline synthesis allows cells to produce the key metabolites necessary for cell survival and proliferation under glutamine-restricted conditions. Our findings reveal an adaptive pathway that cancer cells acquire under nutrient stress, identifying proline biosynthesis as a previously unrecognized major consumer of glutamate, a pathway that could be exploited for developing effective metabolism-driven anticancer therapies.
    DOI:  https://doi.org/10.1038/s42255-023-00919-3
  2. Cell Rep. 2023 Nov 16. pii: S2211-1247(23)01477-8. [Epub ahead of print]42(11): 113465
    MCUb is an inducible regulator of calcium-dependent mitochondrial metabolism and substrate utilization in muscle.
    Jiuzhou Huo, Vikram Prasad, Kelly M Grimes, Davy Vanhoutte, N Scott Blair, Suh-Chin Lin, Michael J Bround, Donald M Bers, Jeffery D Molkentin.
      Mitochondria use the electron transport chain to generate high-energy phosphate from oxidative phosphorylation, a process also regulated by the mitochondrial Ca2+ uniporter (MCU) and Ca2+ levels. Here, we show that MCUb, an inhibitor of MCU-mediated Ca2+ influx, is induced by caloric restriction, where it increases mitochondrial fatty acid utilization. To mimic the fasted state with reduced mitochondrial Ca2+ influx, we generated genetically altered mice with skeletal muscle-specific MCUb expression that showed greater fatty acid usage, less fat accumulation, and lower body weight. In contrast, mice lacking Mcub in skeletal muscle showed increased pyruvate dehydrogenase activity, increased muscle malonyl coenzyme A (CoA), reduced fatty acid utilization, glucose intolerance, and increased adiposity. Mechanistically, pyruvate dehydrogenase kinase 4 (PDK4) overexpression in muscle of Mcub-deleted mice abolished altered substrate preference. Thus, MCUb is an inducible control point in regulating skeletal muscle mitochondrial Ca2+ levels and substrate utilization that impacts total metabolic balance.
    Keywords:  CP: Metabolism; metabolism; mitochondria; obesity; skeletal muscle; substrate utilization
    DOI:  https://doi.org/10.1016/j.celrep.2023.113465
  3. Nat Commun. 2023 Nov 15. 14(1): 7385
    Fatty acid desaturation and lipoxygenase pathways support trained immunity.
    Anaísa V Ferreira, Juan Carlos Alarcon-Barrera, Jorge Domínguez-Andrés, Özlem Bulut, Gizem Kilic, Priya A Debisarun, Rutger J Röring, Hatice N Özhan, Eva Terschlüsen, Athanasios Ziogas, Sarantos Kostidis, Yassene Mohammed, Vasiliki Matzaraki, George Renieris, Evangelos J Giamarellos-Bourboulis, Mihai G Netea, Martin Giera.
      Infections and vaccines can induce enhanced long-term responses in innate immune cells, establishing an innate immunological memory termed trained immunity. Here, we show that monocytes with a trained immunity phenotype, due to exposure to the Bacillus Calmette-Guérin (BCG) vaccine, are characterized by an increased biosynthesis of different lipid mediators (LM) derived from long-chain polyunsaturated fatty acids (PUFA). Pharmacological and genetic approaches show that long-chain PUFA synthesis and lipoxygenase-derived LM are essential for the BCG-induced trained immunity responses of human monocytes. Furthermore, products of 12-lipoxygenase activity increase in monocytes of healthy individuals after BCG vaccination. Grasping the underscoring lipid metabolic pathways contributes to our understanding of trained immunity and may help to identify therapeutic tools and targets for the modulation of innate immune responses.
    DOI:  https://doi.org/10.1038/s41467-023-43315-x
  4. Nat Commun. 2023 Nov 16. 14(1): 7427
    Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis.
    Sadiya Parveen, Jessica Shen, Shichun Lun, Liang Zhao, Jesse Alt, Benjamin Koleske, Robert D Leone, Rana Rais, Jonathan D Powell, John R Murphy, Barbara S Slusher, William R Bishai.
      As one of the most successful human pathogens, Mycobacterium tuberculosis (Mtb) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomic analysis of lungs from JHU083-treated Mtb-infected mice reveals citrulline accumulation, suggesting elevated nitric oxide (NO) synthesis, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. JHU083-treated macrophages also produce more NO potentiating their antibacterial activity. When tested in an immunocompromised mouse model of Mtb infection, JHU083 loses its therapeutic efficacy suggesting the drug's host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.
    DOI:  https://doi.org/10.1038/s41467-023-43304-0
  5. Nat Commun. 2023 Nov 17. 14(1): 7471
    Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation.
    Marlies Cortés, Agnese Brischetto, M C Martinez-Campanario, Chiara Ninfali, Verónica Domínguez, Sara Fernández, Raquel Celis, Anna Esteve-Codina, Juan J Lozano, Julia Sidorova, Gloria Garrabou, Anna-Maria Siegert, Carlos Enrich, Belén Pintado, Manuel Morales-Ruiz, Pedro Castro, Juan D Cañete, Antonio Postigo.
      Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and metabolic reprogramming of immune cells. The anti-diabetic drug Metformin inhibits acute and chronic inflammation through mechanisms still not fully understood. Here, we report that the anti-inflammatory and reactive-oxygen-species-inhibiting effects of Metformin depend on the expression of the plasticity factor ZEB1 in macrophages. Using mice lacking Zeb1 in their myeloid cells and human patient samples, we show that ZEB1 plays a dual role, being essential in both initiating and resolving inflammation by inducing macrophages to transition into an immunosuppressed state. ZEB1 mediates these diverging effects in inflammation and immunosuppression by modulating mitochondrial content through activation of autophagy and inhibition of mitochondrial protein translation. During the transition from inflammation to immunosuppression, Metformin mimics the metabolic reprogramming of myeloid cells induced by ZEB1. Mechanistically, in immunosuppression, ZEB1 inhibits amino acid uptake, leading to downregulation of mTORC1 signalling and a decrease in mitochondrial translation in macrophages. These results identify ZEB1 as a driver of myeloid cell metabolic plasticity, suggesting that targeting its expression and function could serve as a strategy to modulate dysregulated inflammation and immunosuppression.
    DOI:  https://doi.org/10.1038/s41467-023-42277-4
  6. iScience. 2023 Nov 17. 26(11): 108188
    Metabolic predictors of response to immune checkpoint blockade therapy.
    Ofir Shorer, Keren Yizhak.
      Metabolism of immune cells in the tumor microenvironment (TME) plays a critical role in cancer patient response to immune checkpoint inhibitors (ICI). Yet, a metabolic characterization of immune cells in the TME of patients treated with ICI is lacking. To bridge this gap we performed a semi-supervised analysis of ∼1700 metabolic genes using single-cell RNA-seq data of > 1 million immune cells from ∼230 samples of cancer patients treated with ICI. When clustering cells based on their metabolic gene expression, we found that similar immunological cellular states are found in different metabolic states. Most importantly, we found metabolic states that are significantly associated with patient response. We then built a metabolic predictor based on a dozen gene signature, which significantly differentiates between responding and non-responding patients across different cancer types (AUC = 0.8-0.92). Taken together, our results demonstrate the power of metabolism in predicting patient response to ICI.
    Keywords:  Cancer; Human metabolism; Immunology
    DOI:  https://doi.org/10.1016/j.isci.2023.108188
  7. Cell Rep. 2023 Nov 16. pii: S2211-1247(23)01465-1. [Epub ahead of print]42(11): 113453
    A bacteria-derived tetramerized protein ameliorates nonalcoholic steatohepatitis in mice via binding and relocating acetyl-coA carboxylase.
    Yan Lin, Mingkun Yang, Li Huang, Fan Yang, Jiachen Fan, Yulong Qiang, Yuting Chang, Wenjie Zhou, Leilei Yan, Jie Xiong, Jie Ping, Shizhen Chen, Dong Men, Feng Li.
      Increased de novo lipogenesis (DNL) is a major feature of nonalcoholic steatohepatitis (NASH). None of the drugs targeting the catalytic activity of acetyl-CoA carboxylase (ACC), the rate-limiting enzyme in the DNL process, have been approved by the FDA. Whether cytosolic ACC1 can be regulated spatially remains to be explored. Herein, we find that streptavidin (SA), which is a bacterium-derived tetrameric protein, forms cytosolic condensates and efficiently induces a spatial re-localization of ACC1 in liver cells, concomitant with inhibited lipid accumulation. Both SA tetrameric structure and multivalent protein interaction are required for condensate formation. Interestingly, the condensates are further characterized as gel-like membraneless organelle (SAGMO) and significantly restrict the cytosolic dispersion of ACC1 and fatty acid synthase. Notably, AAV-mediated delivery of SA partially blocks mouse liver DNL and ameliorates NASH without eliciting hypertriglyceridemia. In summary, our study shows that insulating lipogenesis-related proteins by SAGMO might be effective for NASH treatment.
    Keywords:  CP: Metabolism; CP: Microbiology; acetyl-CoA carboxylase; de novo lipogenesis; membraneless organelle; nonalcoholic steatohepatitis; streptavidin
    DOI:  https://doi.org/10.1016/j.celrep.2023.113453
  8. Immunity. 2023 Nov 14. pii: S1074-7613(23)00455-7. [Epub ahead of print]56(11): 2459-2461
    SMPDL3A links cholesterol metabolism to the cGAS-STING pathway.
    Heegwon Shin, Hachung Chung.
      Liver X receptor (LXR), well known for its role in cholesterol metabolism, also has anti-inflammatory properties. In this issue of Immunity, Hou et al. demonstrate that LXR signaling induces SMPDL3A, a cGAMP-degrading enzyme that restricts cGAS-cGAMP-STING innate immune signaling, providing a mechanistic link between lipid metabolism and inflammation.
    DOI:  https://doi.org/10.1016/j.immuni.2023.10.015
  9. Nat Cell Biol. 2023 Nov 13.
    NAD+ regulates nucleotide metabolism and genomic DNA replication.
    Sebastian Howen Nesgaard Munk, Joanna Maria Merchut-Maya, Alba Adelantado Rubio, Arnaldur Hall, George Pappas, Giacomo Milletti, MyungHee Lee, Lea Giørtz Johnsen, Per Guldberg, Jiri Bartek, Apolinar Maya-Mendoza.
      The intricate orchestration of enzymatic activities involving nicotinamide adenine dinucleotide (NAD+) is essential for maintaining metabolic homeostasis and preserving genomic integrity. As a co-enzyme, NAD+ plays a key role in regulating metabolic pathways, such as glycolysis and Kreb's cycle. ADP-ribosyltransferases (PARPs) and sirtuins rely on NAD+ to mediate post-translational modifications of target proteins. The activation of PARP1 in response to DNA breaks leads to rapid depletion of cellular NAD+ compromising cell viability. Therefore, the levels of NAD+ must be tightly regulated. Here we show that exogenous NAD+, but not its precursors, has a direct effect on mitochondrial activity. Short-term incubation with NAD+ boosts Kreb's cycle and the electron transport chain and enhances pyrimidine biosynthesis. Extended incubation with NAD+ results in depletion of pyrimidines, accumulation of purines, activation of the replication stress response and cell cycle arrest. Moreover, a combination of NAD+ and 5-fluorouridine selectively kills cancer cells that rely on de novo pyrimidine synthesis. We propose an integrated model of how NAD+ regulates nucleotide metabolism, with relevance to healthspan, ageing and cancer therapy.
    DOI:  https://doi.org/10.1038/s41556-023-01280-z
  10. Cell Rep. 2023 Nov 13. pii: S2211-1247(23)01436-5. [Epub ahead of print]42(11): 113424
    Prostate cancer cell-derived exosomal IL-8 fosters immune evasion by disturbing glucolipid metabolism of CD8+ T cell.
    Fan Xu, Xiumei Wang, Ying Huang, Xiaoqian Zhang, Wenbo Sun, Yuanyuan Du, Zhi Xu, Hengyuan Kou, Shuyi Zhu, Caidong Liu, Xiaowei Wei, Xiao Li, Qin Jiang, Yong Xu.
      Depletion of CD8+ T cells is a major obstacle in immunotherapy; however, the relevant mechanisms remain largely unknown. Here, we showed that prostate cancer (PCa) cell-derived exosomes hamper CD8+ T cell function by transporting interleukin-8 (IL-8). Compared to the low IL-8 levels detected in immune cells, PCa cells secreted the abundance of IL-8 and further accumulated in exosomes. The delivery of PCa cell-derived exosomes into CD8+ T cells exhausted the cells through enhanced starvation. Mechanistically, exosomal IL-8 overactivated PPARα in recipient cells, thereby decreasing glucose utilization by downregulating GLUT1 and HK2 but increasing fatty acid catabolism via upregulation of CPT1A and ACOX1. PPARα further activates uncoupling protein 1 (UCP1), leading to fatty acid catabolism for thermogenesis rather than ATP synthesis. Consequently, inhibition of PPARα and UCP1 restores CD8+ T cell proliferation by counteracting the effect of exosomal IL-8. This study revealed that the tumor exosome-activated IL-8-PPARα-UCP1 axis harms tumor-infiltrating CD8+ T cells by interfering with energy metabolism.
    Keywords:  CD8(+) T cell; CP: Cancer; CP: Immunology; PPARα; exosome; glucolipid metabolism; interleukin-8; prostate cancer
    DOI:  https://doi.org/10.1016/j.celrep.2023.113424
  11. Circulation. 2023 Nov 14.
    Novel Pan-ERR Agonists Ameliorate Heart Failure Through Enhancing Cardiac Fatty Acid Metabolism and Mitochondrial Function.
    Weiyi Xu, Cyrielle Billon, Hui Li, Andrea Wilderman, Lei Qi, Andrea Graves, Jernie Rae Dela Cruz Rideb, Yuanbiao Zhao, Matthew Hayes, Keyang Yu, McKenna Losby, Carissa S Hampton, Christiana M Adeyemi, Seok Jae Hong, Eleni Nasiotis, Chen Fu, Tae Gyu Oh, Weiwei Fan, Michael Downes, Ryan D Welch, Ronald M Evans, Aleksandar Milosavljevic, John K Walker, Brian C Jensen, Liming Pei, Thomas Burris, Lilei Zhang.
      BACKGROUND: Cardiac metabolic dysfunction is a hallmark of heart failure (HF). Estrogen-related receptors ERRα and ERRγ are essential regulators of cardiac metabolism. Therefore, activation of ERR could be a potential therapeutic intervention for HF. However, in vivo studies demonstrating the potential usefulness of ERR agonist for HF treatment are lacking, because compounds with pharmacokinetics appropriate for in vivo use have not been available.METHODS: Using a structure-based design approach, we designed and synthesized 2 structurally distinct pan-ERR agonists, SLU-PP-332 and SLU-PP-915. We investigated the effect of ERR agonist on cardiac function in a pressure overload-induced HF model in vivo. We conducted comprehensive functional, multi-omics (RNA sequencing and metabolomics studies), and genetic dependency studies both in vivo and in vitro to dissect the molecular mechanism, ERR isoform dependency, and target specificity.
    RESULTS: Both SLU-PP-332 and SLU-PP-915 significantly improved ejection fraction, ameliorated fibrosis, and increased survival associated with pressure overload-induced HF without affecting cardiac hypertrophy. A broad spectrum of metabolic genes was transcriptionally activated by ERR agonists, particularly genes involved in fatty acid metabolism and mitochondrial function. Metabolomics analysis showed substantial normalization of metabolic profiles in fatty acid/lipid and tricarboxylic acid/oxidative phosphorylation metabolites in the mouse heart with 6-week pressure overload. ERR agonists increase mitochondria oxidative capacity and fatty acid use in vitro and in vivo. Using both in vitro and in vivo genetic dependency experiments, we show that ERRγ is the main mediator of ERR agonism-induced transcriptional regulation and cardioprotection and definitively demonstrated target specificity. ERR agonism also led to downregulation of cell cycle and development pathways, which was partially mediated by E2F1 in cardiomyocytes.
    CONCLUSIONS: ERR agonists maintain oxidative metabolism, which confers cardiac protection against pressure overload-induced HF in vivo. Our results provide direct pharmacologic evidence supporting the further development of ERR agonists as novel HF therapeutics.
    Keywords:  cell cycle; heart failure; metabolism
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.066542
  12. Sci Rep. 2023 11 11. 13(1): 19664
    Ketone body β-hydroxybutyrate (BHB) preserves mitochondrial bioenergetics.
    I Llorente-Folch, H Düssmann, O Watters, N M C Connolly, Jochen H M Prehn.
      The ketogenic diet is an emerging therapeutic approach for refractory epilepsy, as well as certain rare and neurodegenerative disorders. The main ketone body, β-hydroxybutyrate (BHB), is the primary energy substrate endogenously produced in a ketogenic diet, however, mechanisms of its therapeutic actions remain unknown. Here, we studied the effects of BHB on mitochondrial energetics, both in non-stimulated conditions and during glutamate-mediated hyperexcitation. We found that glutamate-induced hyperexcitation stimulated mitochondrial respiration in cultured cortical neurons, and that this response was greater in cultures supplemented with BHB than with glucose. BHB enabled a stronger and more sustained maximal uncoupled respiration, indicating that BHB enables neurons to respond more efficiently to increased energy demands such as induced during hyperexcitation. We found that cytosolic Ca2+ was required for BHB-mediated enhancement of mitochondrial function, and that this enhancement was independent of the mitochondrial glutamate-aspartate carrier, Aralar/AGC1. Our results suggest that BHB exerts its protective effects against hyperexcitation by enhancing mitochondrial function through a Ca2+-dependent, but Aralar/AGC1-independent stimulation of mitochondrial respiration.
    DOI:  https://doi.org/10.1038/s41598-023-46776-8
  13. Cell Death Dis. 2023 Nov 15. 14(11): 744
    mTOR inhibition suppresses salinomycin-induced ferroptosis in breast cancer stem cells by ironing out mitochondrial dysfunctions.
    Emma Cosialls, Emeline Pacreau, Clémence Duruel, Sara Ceccacci, Rima Elhage, Christophe Desterke, Kevin Roger, Chiara Guerrera, Romane Ducloux, Sylvie Souquere, Gérard Pierron, Ivan Nemazanyy, Mairead Kelly, Elise Dalmas, Yunhua Chang, Vincent Goffin, Maryam Mehrpour, Ahmed Hamaï.
      Ferroptosis constitutes a promising therapeutic strategy against cancer by efficiently targeting the highly tumorigenic and treatment-resistant cancer stem cells (CSCs). We previously showed that the lysosomal iron-targeting drug Salinomycin (Sal) was able to eliminate CSCs by triggering ferroptosis. Here, in a well-established breast CSCs model (human mammary epithelial HMLER CD24low/CD44high), we identified that pharmacological inhibition of the mechanistic target of rapamycin (mTOR), suppresses Sal-induced ferroptosis. Mechanistically, mTOR inhibition modulates iron cellular flux and thereby limits iron-mediated oxidative stress. Furthermore, integration of multi-omics data identified mitochondria as a key target of Sal action, leading to profound functional and structural alteration prevented by mTOR inhibition. On top of that, we found that Sal-induced metabolic plasticity is mainly dependent on the mTOR pathway. Overall, our findings provide experimental evidence for the mechanisms of mTOR as a crucial effector of Sal-induced ferroptosis pointing not only that metabolic reprogramming regulates ferroptosis, but also providing proof-of-concept that careful evaluation of such combination therapy (here mTOR and ferroptosis co-targeting) is required in the development of an effective treatment.
    DOI:  https://doi.org/10.1038/s41419-023-06262-5
  14. Nat Commun. 2023 Nov 13. 14(1): 7328
    RNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis.
    Xiao Han, Lijuan Liu, Saihua Huang, Wenfeng Xiao, Yajing Gao, Weitao Zhou, Caiyan Zhang, Hongmei Zheng, Lan Yang, Xueru Xie, Qiuyan Liang, Zikun Tu, Hongmiao Yu, Jinrong Fu, Libo Wang, Xiaobo Zhang, Liling Qian, Yufeng Zhou.
      N6-methyladenosine (m6A), the most prevalent mRNA modification, has an important function in diverse biological processes. However, the involvement of m6A in allergic asthma and macrophage homeostasis remains largely unknown. Here we show that m6A methyltransferases METTL3 is expressed at a low level in monocyte-derived macrophages from childhood allergic asthma patients. Conditional knockout of Mettl3 in myeloid cells enhances Th2 cell response and aggravates allergic airway inflammation by facilitating M2 macrophage activation. Loss and gain functional studies confirm that METTL3 suppresses M2 macrophage activation partly through PI3K/AKT and JAK/STAT6 signaling. Mechanistically, m6A-sequencing shows that loss of METTL3 impairs the m6A-YTHDF3-dependent degradation of PTX3 mRNA, while higher PTX3 expression positively correlates with asthma severity through promoting M2 macrophage activation. Furthermore, the METTL3/YTHDF3-m6A/PTX3 interactions contribute to autophagy maturation in macrophages by modulating STX17 expression. Collectively, this study highlights the function of m6A in regulating macrophage homeostasis and identifies potential targets in controlling allergic asthma.
    DOI:  https://doi.org/10.1038/s41467-023-43219-w
  15. J Hepatol. 2023 Nov 15. pii: S0168-8278(23)05271-6. [Epub ahead of print]
    Adipose tissue macrophage dysfunction is associated with a breach of vascular integrity in NASH.
    Markus Boesch, Andreas Lindhorst, Rita Feio-Azevedo, Paola Brescia, Alessandra Silvestri, Matthias Lannoo, Ellen Deleus, Joris Jaekers, Halit Topal, Baki Topal, Tessa Ostyn, Marie Wallays, Lena Smets, Lukas Van Melkebeke, Anetta Härtlova, Tania Roskams, Pierre Bedossa, Jef Verbeek, Olivier Govaere, Sven Francque, Alejandro Sifrim, Thierry Voet, Maria Rescigno, Martin Gericke, Hannelie Korf, Schalk van der Merwe.
      BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions, fueled by the obesity pandemic. In NAFLD, monocytes infiltrate visceral adipose tissue that promote local and hepatic inflammation. It however remains unclear what drives inflammation and how the immune landscape in adipose tissue differs across the NAFLD severity spectrum. We aimed to assimilate the adipose tissue macrophage (ATM) heterogeneity in a NAFLD cohort.METHODS: Visceral adipose tissue macrophages from lean and obese patients stratified into NAFLD phenotypes underwent single-cell RNA sequencing. Adipose tissue vascular integrity and breaching was assessed on protein level for targets of interest via immunohistochemistry and immunofluorescence.
    RESULTS: We discovered multiple ATM populations, including resident vasculature-associated macrophages (ResVAMs) and distinct metabolically active macrophages (MMacs). Using trajectory analysis, we show that ResVAMs and MMacs replenish from a common transitional macrophage subtype (TransMac) and during NASH, MMacs are not effectively replenished by TransMac precursors. We postulate an accessory role for MMac and ResVAMs in protecting the adipose tissue vascular barrier, since they both interact with endothelial cells and localize around the vasculature. Across the NAFLD severity spectrum however, both these subsets become altered and this coincided with an adipose tissue vasculature breach characterized by albumin extravasation into the perivascular tissue.
    CONCLUSIONS: NAFLD-related macrophage dysfunction coincide with a loss of adipose tissue vascular integrity providing a strong plausible mechanism by which tissue inflammation is perpetuated in adipose tissue and downstream in the liver.
    IMPACT AND IMPLICATIONS: Our study describe for the first time the myeloid cell landscape in human visceral adipose tissue at single cell level within a cohort of well-characterised NAFLD patients. We report unique NASH-specific transcriptional changes within metabolically active macrophages (MMacs) and resident vasculature-associated macrophages (ResVAM) and we demonstrate their spatial location surrounding the vasculature. These dysfunctional transcriptional macrophage states, coincided with the loss of adipose tissue vascular integrity, providing a strong plausible mechanism by which tissue inflammation is perpetuated in adipose tissue and downstream in the liver. Our study provide a theoretical basis for new therapeutic strategies to be directed towards reinstating ResVAM and MMac endogenous metabolic and homeostatic and cytoprotective mechanisms including their function to protect the vascular integrity and barrier.
    Keywords:  Non-alcoholic fatty liver disease; adipose tissue; macrophages; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.jhep.2023.10.039
  16. Nat Cell Biol. 2023 Nov 16.
    Host extracellular vesicles confer cytosolic access to systemic LPS licensing non-canonical inflammasome sensing and pyroptosis.
    Puja Kumari, Swathy O Vasudevan, Ashley J Russo, Skylar S Wright, Víctor Fraile-Ágreda, Dylan Krajewski, Evan R Jellison, Ignacio Rubio, Michael Bauer, Atsushi Shimoyama, Koichi Fukase, Yuanpeng Zhang, Joel S Pachter, Sivapriya Kailasan Vanaja, Vijay A Rathinam.
      Intracellular surveillance for systemic microbial components during homeostasis and infections governs host physiology and immunity. However, a long-standing question is how circulating microbial ligands become accessible to intracellular receptors. Here we show a role for host-derived extracellular vesicles (EVs) in this process; human and murine plasma-derived and cell culture-derived EVs have an intrinsic capacity to bind bacterial lipopolysaccharide (LPS). Remarkably, circulating host EVs capture blood-borne LPS in vivo, and the LPS-laden EVs confer cytosolic access for LPS, triggering non-canonical inflammasome activation of gasdermin D and pyroptosis. Mechanistically, the interaction between the lipid bilayer of EVs and the lipid A of LPS underlies EV capture of LPS, and the intracellular transfer of LPS by EVs is mediated by CD14. Overall, this study demonstrates that EVs capture and escort systemic LPS to the cytosol licensing inflammasome responses, uncovering EVs as a previously unrecognized link between systemic microbial ligands and intracellular surveillance.
    DOI:  https://doi.org/10.1038/s41556-023-01269-8
  17. Nat Metab. 2023 Nov 16.
    Vitamin B12 emerges as key player during cellular reprogramming.
    Alba Vílchez-Acosta, Gabriela Desdín-Micó, Alejandro Ocampo.
      
    DOI:  https://doi.org/10.1038/s42255-023-00917-5
  18. Nature. 2023 Nov 15.
    The extracellular matrix dictates regional competence for tumour initiation.
    Nordin Bansaccal, Pauline Vieugue, Rahul Sarate, Yura Song, Esmeralda Minguijon, Yekaterina A Miroshnikova, Dagmar Zeuschner, Amandine Collin, Justine Allard, Dan Engelman, Anne-Lise Delaunois, Mélanie Liagre, Leona de Groote, Evy Timmerman, Delphi Van Haver, Francis Impens, Isabelle Salmon, Sara A Wickström, Alejandro Sifrim, Cédric Blanpain.
      The skin epidermis is constantly renewed throughout life1,2. Disruption of the balance between renewal and differentiation can lead to uncontrolled growth and tumour initiation3. However, the ways in which oncogenic mutations affect the balance between renewal and differentiation and lead to clonal expansion, cell competition, tissue colonization and tumour development are unknown. Here, through multidisciplinary approaches that combine in vivo clonal analysis using intravital microscopy, single-cell analysis and functional analysis, we show how SmoM2-a constitutively active oncogenic mutant version of Smoothened (SMO) that induces the development of basal cell carcinoma-affects clonal competition and tumour initiation in real time. We found that expressing SmoM2 in the ear epidermis of mice induced clonal expansion together with tumour initiation and invasion. By contrast, expressing SmoM2 in the back-skin epidermis led to a clonal expansion that induced lateral cell competition without dermal invasion and tumour formation. Single-cell analysis showed that oncogene expression was associated with a cellular reprogramming of adult interfollicular cells into an embryonic hair follicle progenitor (EHFP) state in the ear but not in the back skin. Comparisons between the ear and the back skin revealed that the dermis has a very different composition in these two skin types, with increased stiffness and a denser collagen I network in the back skin. Decreasing the expression of collagen I in the back skin through treatment with collagenase, chronic UV exposure or natural ageing overcame the natural resistance of back-skin basal cells to undergoing EHFP reprogramming and tumour initiation after SmoM2 expression. Altogether, our study shows that the composition of the extracellular matrix regulates how susceptible different regions of the body are to tumour initiation and invasion.
    DOI:  https://doi.org/10.1038/s41586-023-06740-y
  19. EMBO J. 2023 Nov 13. e114889
    Structure and mechanism of a eukaryotic ceramide synthase complex.
    Tian Xie, Qi Fang, Zike Zhang, Yanfei Wang, Feitong Dong, Xin Gong.
      Ceramide synthases (CerS) catalyze ceramide formation via N-acylation of a sphingoid base with a fatty acyl-CoA and are attractive drug targets for treating numerous metabolic diseases and cancers. Here, we present the cryo-EM structure of a yeast CerS complex, consisting of a catalytic Lac1 subunit and a regulatory Lip1 subunit, in complex with C26-CoA substrate. The CerS holoenzyme exists as a dimer of Lac1-Lip1 heterodimers. Lac1 contains a hydrophilic reaction chamber and a hydrophobic tunnel for binding the CoA moiety and C26-acyl chain of C26-CoA, respectively. Lip1 interacts with both the transmembrane region and the last luminal loop of Lac1 to maintain the proper acyl chain binding tunnel. A lateral opening on Lac1 serves as a potential entrance for the sphingoid base substrate. Our findings provide a template for understanding the working mechanism of eukaryotic ceramide synthases and may facilitate the development of therapeutic CerS modulators.
    Keywords:  Lac1; Lip1; ceramide; ceramide synthase; cryo-EM
    DOI:  https://doi.org/10.15252/embj.2023114889
  20. Cell Host Microbe. 2023 Nov 08. pii: S1931-3128(23)00420-1. [Epub ahead of print]
    Fiber-deficient diet inhibits colitis through the regulation of the niche and metabolism of a gut pathobiont.
    Peter Kuffa, Joseph M Pickard, Austin Campbell, Misa Yamashita, Sadie R Schaus, Eric C Martens, Thomas M Schmidt, Naohiro Inohara, Gabriel Núñez, Roberta Caruso.
      Exclusive enteral nutrition (EEN) with fiber-free diets is an effective steroid-sparing treatment to induce clinical remission in children with Crohn's disease (CD). However, the mechanism underlying the beneficial effects of EEN remains obscure. Using a model of microbiota-dependent colitis with the hallmarks of CD, we find that the administration of a fiber-free diet prevents the development of colitis and inhibits intestinal inflammation in colitic animals. Remarkably, fiber-free diet alters the intestinal localization of Mucispirillum schaedleri, a mucus-dwelling pathobiont, which is required for triggering disease. Mechanistically, the absence of dietary fiber reduces nutrient availability and impairs the dissimilatory nitrate reduction to ammonia (DNRA) metabolic pathway of Mucispirillum, leading to its exclusion from the mucus layer and disease remission. Thus, appropriate localization of the specific pathobiont in the mucus layer is critical for disease development, which is disrupted by fiber exclusion. These results suggest strategies to treat CD by targeting the intestinal niche and metabolism of disease-causing microbes.
    Keywords:  Crohn’s disease; Mucispirillum schaedleri; Ruminococcus torques; dissimilatory nitrate reduction to ammonia; exclusive enteral nutrition; fiber-free diet; mucus-dwelling pathobiont
    DOI:  https://doi.org/10.1016/j.chom.2023.10.016
  21. Nat Metab. 2023 Nov 16.
    Vitamin B12 is a limiting factor for induced cellular plasticity and tissue repair.
    Marta Kovatcheva, Elena Melendez, Dafni Chondronasiou, Federico Pietrocola, Raquel Bernad, Adrià Caballe, Alexandra Junza, Jordi Capellades, Adrián Holguín-Horcajo, Neus Prats, Sylvere Durand, Meritxell Rovira, Oscar Yanes, Camille Stephan-Otto Attolini, Guido Kroemer, Manuel Serrano.
      Transient reprogramming by the expression of OCT4, SOX2, KLF4 and MYC (OSKM) is a therapeutic strategy for tissue regeneration and rejuvenation, but little is known about its metabolic requirements. Here we show that OSKM reprogramming in mice causes a global depletion of vitamin B12 and molecular hallmarks of methionine starvation. Supplementation with vitamin B12 increases the efficiency of reprogramming both in mice and in cultured cells, the latter indicating a cell-intrinsic effect. We show that the epigenetic mark H3K36me3, which prevents illegitimate initiation of transcription outside promoters (cryptic transcription), is sensitive to vitamin B12 levels, providing evidence for a link between B12 levels, H3K36 methylation, transcriptional fidelity and efficient reprogramming. Vitamin B12 supplementation also accelerates tissue repair in a model of ulcerative colitis. We conclude that vitamin B12, through its key role in one-carbon metabolism and epigenetic dynamics, improves the efficiency of in vivo reprogramming and tissue repair.
    DOI:  https://doi.org/10.1038/s42255-023-00916-6
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