bims-mepmim Biomed News
on Metabolites in pathological microenvironments and immunometabolism
Issue of 2024‒06‒16
fifteen papers selected by
Erika Mariana Palmieri, NIH/NCI Laboratory of Cancer ImmunoMetabolism
  1. Electron transport chain inhibition increases cellular dependence on purine transport and salvage.
  2. Metabolic inflexibility promotes mitochondrial health during liver regeneration.
  3. MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.
  4. Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer.
  5. The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity.
  6. Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.
  7. Coenzyme A biosynthesis: mechanisms of regulation, function and disease.
  8. Reactive oxygen species regulation by NCF1 governs ferroptosis susceptibility of Kupffer cells to MASH.
  9. Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes.
  10. ASS1 metabolically contributes to the nuclear and cytosolic p53-mediated DNA damage response.
  11. Mitochondria from osteolineage cells regulate myeloid cell-mediated bone resorption.
  12. Neutrophil glucose flux as a therapeutic target in antiphospholipid syndrome.
  13. In vivo editing of lung stem cells for durable gene correction in mice.
  14. Phytate metabolism is mediated by microbial cross-feeding in the gut microbiota.
  15. IL-12 induces a B cell-intrinsic IL-12/IFNγ feed-forward loop promoting extrafollicular B cell responses.
  1. Cell Metab. 2024 Jun 07. pii: S1550-4131(24)00190-6. [Epub ahead of print]
    Electron transport chain inhibition increases cellular dependence on purine transport and salvage.
    Zheng Wu, Divya Bezwada, Feng Cai, Robert C Harris, Bookyung Ko, Varun Sondhi, Chunxiao Pan, Hieu S Vu, Phong T Nguyen, Brandon Faubert, Ling Cai, Hongli Chen, Misty Martin-Sandoval, Duyen Do, Wen Gu, Yuanyuan Zhang, Yuannyu Zhang, Bailey Brooks, Sherwin Kelekar, Lauren G Zacharias, K Celeste Oaxaca, Joao S Patricio, Thomas P Mathews, Javier Garcia-Bermudez, Min Ni, Ralph J DeBerardinis.
      Mitochondria house many metabolic pathways required for homeostasis and growth. To explore how human cells respond to mitochondrial dysfunction, we performed metabolomics in fibroblasts from patients with various mitochondrial disorders and cancer cells with electron transport chain (ETC) blockade. These analyses revealed extensive perturbations in purine metabolism, and stable isotope tracing demonstrated that ETC defects suppress de novo purine synthesis while enhancing purine salvage. In human lung cancer, tumors with markers of low oxidative mitochondrial metabolism exhibit enhanced expression of the salvage enzyme hypoxanthine phosphoribosyl transferase 1 (HPRT1) and high levels of the HPRT1 product inosine monophosphate. Mechanistically, ETC blockade activates the pentose phosphate pathway, providing phosphoribosyl diphosphate to drive purine salvage supplied by uptake of extracellular bases. Blocking HPRT1 sensitizes cancer cells to ETC inhibition. These findings demonstrate how cells remodel purine metabolism upon ETC blockade and uncover a new metabolic vulnerability in tumors with low respiration.
    Keywords:  HPRT1; NAD(+):NADH ratio; electron transport chain; metabolomics; purine metabolism; stable isotopes
    DOI:  https://doi.org/10.1016/j.cmet.2024.05.014
  2. Science. 2024 Jun 14. 384(6701): eadj4301
    Metabolic inflexibility promotes mitochondrial health during liver regeneration.
    Xun Wang, Cameron J Menezes, Yuemeng Jia, Yi Xiao, Siva Sai Krishna Venigalla, Feng Cai, Meng-Hsiung Hsieh, Wen Gu, Liming Du, Jessica Sudderth, Dohun Kim, Spencer D Shelton, Claire B Llamas, Yu-Hsuan Lin, Min Zhu, Salma Merchant, Divya Bezwada, Sherwin Kelekar, Lauren G Zacharias, Thomas P Mathews, Gerta Hoxhaj, R Max Wynn, Uttam K Tambar, Ralph J DeBerardinis, Hao Zhu, Prashant Mishra.
      Mitochondria are critical for proper organ function and mechanisms to promote mitochondrial health during regeneration would benefit tissue homeostasis. We report that during liver regeneration, proliferation is suppressed in electron transport chain (ETC)-dysfunctional hepatocytes due to an inability to generate acetyl-CoA from peripheral fatty acids through mitochondrial β-oxidation. Alternative modes for acetyl-CoA production from pyruvate or acetate are suppressed in the setting of ETC dysfunction. This metabolic inflexibility forces a dependence on ETC-functional mitochondria and restoring acetyl-CoA production from pyruvate is sufficient to allow ETC-dysfunctional hepatocytes to proliferate. We propose that metabolic inflexibility within hepatocytes can be advantageous by limiting the expansion of ETC-dysfunctional cells.
    DOI:  https://doi.org/10.1126/science.adj4301
  3. Cell. 2024 Jun 05. pii: S0092-8674(24)00526-9. [Epub ahead of print]
    MTFP1 controls mitochondrial fusion to regulate inner membrane quality control and maintain mtDNA levels.
    Luis Carlos Tábara, Stephen P Burr, Michele Frison, Suvagata R Chowdhury, Vincent Paupe, Yu Nie, Mark Johnson, Jara Villar-Azpillaga, Filipa Viegas, Mayuko Segawa, Hanish Anand, Kasparas Petkevicius, Patrick F Chinnery, Julien Prudent.
      Mitochondrial dynamics play a critical role in cell fate decisions and in controlling mtDNA levels and distribution. However, the molecular mechanisms linking mitochondrial membrane remodeling and quality control to mtDNA copy number (CN) regulation remain elusive. Here, we demonstrate that the inner mitochondrial membrane (IMM) protein mitochondrial fission process 1 (MTFP1) negatively regulates IMM fusion. Moreover, manipulation of mitochondrial fusion through the regulation of MTFP1 levels results in mtDNA CN modulation. Mechanistically, we found that MTFP1 inhibits mitochondrial fusion to isolate and exclude damaged IMM subdomains from the rest of the network. Subsequently, peripheral fission ensures their segregation into small MTFP1-enriched mitochondria (SMEM) that are targeted for degradation in an autophagic-dependent manner. Remarkably, MTFP1-dependent IMM quality control is essential for basal nucleoid recycling and therefore to maintain adequate mtDNA levels within the cell.
    Keywords:  IMM quality control; IMM remodeling; MTFP1; autophagy; fission and fusion; mitochondria; mitochondrial dynamics; mitophagy; mtDNA
    DOI:  https://doi.org/10.1016/j.cell.2024.05.017
  4. Nat Metab. 2024 Jun 14.
    Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer.
    Hyun Min Lee, Nefertiti Muhammad, Elizabeth L Lieu, Feng Cai, Jiawei Mu, Yun-Sok Ha, Guoshen Cao, Chamey Suchors, Kenneth Joves, Constantinos Chronis, Kailong Li, Gregory S Ducker, Kellen Olszewski, Ling Cai, Derek B Allison, Sara E Bachert, William R Ewing, Harvey Wong, Hyosun Seo, Isaac Y Kim, Brandon Faubert, James Kim, Jiyeon Kim.
      Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine-glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT). LKB1 loss, in collaboration with KEAP1 loss, activated SHMT through inactivation of the salt-induced kinase (SIK)-NRF2 axis and satisfied the increased demand for one-carbon units necessary for antioxidant defence. Chemical and genetic SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor enhanced the in vivo therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing oxidative stress) in KEAP1-mutant KL tumours. The data reveal how this highly aggressive molecular subtype of NSCLC fulfills their metabolic requirements and provides insight into therapeutic strategies.
    DOI:  https://doi.org/10.1038/s42255-024-01066-z
  5. Nat Commun. 2024 Jun 08. 15(1): 4915
    The TAS1R2 G-protein-coupled receptor is an ambient glucose sensor in skeletal muscle that regulates NAD homeostasis and mitochondrial capacity.
    Joan Serrano, Jordan Boyd, Ian S Brown, Carter Mason, Kathleen R Smith, Katalin Karolyi, Santosh K Maurya, Nishita N Meshram, Vanida Serna, Grace M Link, Stephen J Gardell, George A Kyriazis.
      The bioavailability of nicotinamide adenine dinucleotide (NAD) is vital for skeletal muscle health, yet the mechanisms or signals regulating NAD homeostasis remain unclear. Here, we uncover a pathway connecting peripheral glucose sensing to the modulation of muscle NAD through TAS1R2, the sugar-sensing G protein-coupled receptor (GPCR) initially identified in taste perception. Muscle TAS1R2 receptor stimulation by glucose and other agonists induces ERK1/2-dependent phosphorylation and activation of poly(ADP-ribose) polymerase1 (PARP1), a major NAD consumer in skeletal muscle. Consequently, muscle-specific deletion of TAS1R2 (mKO) in male mice suppresses PARP1 activity, elevating NAD levels and enhancing mitochondrial capacity and running endurance. Plasma glucose levels negatively correlate with muscle NAD, and TAS1R2 receptor deficiency enhances NAD responses across the glycemic range, implicating TAS1R2 as a peripheral energy surveyor. These findings underscore the role of GPCR signaling in NAD regulation and propose TAS1R2 as a potential therapeutic target for maintaining muscle health.
    DOI:  https://doi.org/10.1038/s41467-024-49100-8
  6. Nature. 2024 Jun 12.
    Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.
    Jackie E Bader, Melissa M Wolf, Gian Luca Lupica-Tondo, Matthew Z Madden, Bradley I Reinfeld, Emily N Arner, Emma S Hathaway, KayLee K Steiner, Gabriel A Needle, Zaid Hatem, Madelyn D Landis, Eden E Faneuff, Amondrea Blackman, Elysa M Wolf, Matthew A Cottam, Xiang Ye, Madison E Bates, Kyra Smart, Wenjun Wang, Laura V Pinheiro, Anthos Christofides, DuPreez Smith, Vassiliki A Boussiotis, Scott M Haake, Kathryn E Beckermann, Kathryn E Wellen, Cynthia A Reinhart-King, C Henrique Serezani, Cheng-Han Lee, Christa Aubrey, Heidi Chen, W Kimryn Rathmell, Alyssa H Hasty, Jeffrey C Rathmell.
      Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can in some cases enhance survival3-5 and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells6-8. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-19-12. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8+ T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity.
    DOI:  https://doi.org/10.1038/s41586-024-07529-3
  7. Nat Metab. 2024 Jun 13.
    Coenzyme A biosynthesis: mechanisms of regulation, function and disease.
    Samuel A Barritt, Sarah E DuBois-Coyne, Christian C Dibble.
      The tricarboxylic acid cycle, nutrient oxidation, histone acetylation and synthesis of lipids, glycans and haem all require the cofactor coenzyme A (CoA). Although the sources and regulation of the acyl groups carried by CoA for these processes are heavily studied, a key underlying question is less often considered: how is production of CoA itself controlled? Here, we discuss the many cellular roles of CoA and the regulatory mechanisms that govern its biosynthesis from cysteine, ATP and the essential nutrient pantothenate (vitamin B5), or from salvaged precursors in mammals. Metabolite feedback and signalling mechanisms involving acetyl-CoA, other acyl-CoAs, acyl-carnitines, MYC, p53, PPARα, PINK1 and insulin- and growth factor-stimulated PI3K-AKT signalling regulate the vitamin B5 transporter SLC5A6/SMVT and CoA biosynthesis enzymes PANK1, PANK2, PANK3, PANK4 and COASY. We also discuss methods for measuring CoA-related metabolites, compounds that target CoA biosynthesis and diseases caused by mutations in pathway enzymes including types of cataracts, cardiomyopathy and neurodegeneration (PKAN and COPAN).
    DOI:  https://doi.org/10.1038/s42255-024-01059-y
  8. Cell Metab. 2024 Jun 04. pii: S1550-4131(24)00184-0. [Epub ahead of print]
    Reactive oxygen species regulation by NCF1 governs ferroptosis susceptibility of Kupffer cells to MASH.
    Jing Zhang, Yu Wang, Meiyang Fan, Yanglong Guan, Wentao Zhang, Fumeng Huang, Zhengqiang Zhang, Xiaomeng Li, Bingyu Yuan, Wenbin Liu, Manman Geng, Xiaowei Li, Jing Xu, Congshan Jiang, Wenjuan Zhao, Feng Ye, Wenhua Zhu, Liesu Meng, Shemin Lu, Rikard Holmdahl.
      Impaired self-renewal of Kupffer cells (KCs) leads to inflammation in metabolic dysfunction-associated steatohepatitis (MASH). Here, we identify neutrophil cytosolic factor 1 (NCF1) as a critical regulator of iron homeostasis in KCs. NCF1 is upregulated in liver macrophages and dendritic cells in humans with metabolic dysfunction-associated steatotic liver disease and in MASH mice. Macrophage NCF1, but not dendritic cell NCF1, triggers KC iron overload, ferroptosis, and monocyte-derived macrophage infiltration, thus aggravating MASH progression. Mechanistically, elevated oxidized phospholipids induced by macrophage NCF1 promote Toll-like receptor (TLR4)-dependent hepatocyte hepcidin production, leading to increased KC iron deposition and subsequent KC ferroptosis. Importantly, the human low-functional polymorphic variant NCF190H alleviates KC ferroptosis and MASH in mice. In conclusion, macrophage NCF1 impairs iron homeostasis in KCs by oxidizing phospholipids, triggering hepatocyte hepcidin release and KC ferroptosis in MASH, highlighting NCF1 as a therapeutic target for improving KC fate and limiting MASH progression.
    Keywords:  Kupffer cells; NCF1; ferroptosis; hepatocytes; iron deposition; lipid peroxidation; macrophages; metabolic dysfunction-associated steatohepatitis; oxidized phospholipids; reactive oxygen species
    DOI:  https://doi.org/10.1016/j.cmet.2024.05.008
  9. Nat Metab. 2024 Jun 13.
    Characterization of genetic variants of GIPR reveals a contribution of β-arrestin to metabolic phenotypes.
    Hüsün S Kizilkaya, Kimmie V Sørensen, Jakob S Madsen, Peter Lindquist, Jonathan D Douros, Jette Bork-Jensen, Alessandro Berghella, Peter A Gerlach, Lærke S Gasbjerg, Jacek Mokrosiński, Stephanie A Mowery, Patrick J Knerr, Brian Finan, Jonathan E Campbell, David A D'Alessio, Diego Perez-Tilve, Felix Faas, Signe Mathiasen, Jørgen Rungby, Henrik T Sørensen, Allan Vaag, Jens S Nielsen, Jens-Christian Holm, Jeannet Lauenborg, Peter Damm, Oluf Pedersen, Allan Linneberg, Bolette Hartmann, Jens J Holst, Torben Hansen, Shane C Wright, Volker M Lauschke, Niels Grarup, Alexander S Hauser, Mette M Rosenkilde.
      Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR-GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of β-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and β-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and β-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a β-arrestin dependency and genetic ablation of β-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of β-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.
    DOI:  https://doi.org/10.1038/s42255-024-01061-4
  10. Nat Metab. 2024 Jun 10.
    ASS1 metabolically contributes to the nuclear and cytosolic p53-mediated DNA damage response.
    Lisha Qiu Jin Lim, Lital Adler, Emma Hajaj, Leandro R Soria, Rotem Ben-Tov Perry, Naama Darzi, Ruchama Brody, Noa Furth, Michal Lichtenstein, Elizabeta Bab-Dinitz, Ziv Porat, Tevie Melman, Alexander Brandis, Yael Aylon, Shifra Ben-Dor, Irit Orr, Amir Pri-Or, Rony Seger, Yoav Shaul, Eytan Ruppin, Moshe Oren, Minervo Perez, Jordan Meier, Nicola Brunetti-Pierri, Efrat Shema, Igor Ulitsky, Ayelet Erez, Sergey Malitsky, Maxim Itkin.
      Downregulation of the urea cycle enzyme argininosuccinate synthase (ASS1) in multiple tumors is associated with a poor prognosis partly because of the metabolic diversion of cytosolic aspartate for pyrimidine synthesis, supporting proliferation and mutagenesis owing to nucleotide imbalance. Here, we find that prolonged loss of ASS1 promotes DNA damage in colon cancer cells and fibroblasts from subjects with citrullinemia type I. Following acute induction of DNA damage with doxorubicin, ASS1 expression is elevated in the cytosol and the nucleus with at least a partial dependency on p53; ASS1 metabolically restrains cell cycle progression in the cytosol by restricting nucleotide synthesis. In the nucleus, ASS1 and ASL generate fumarate for the succination of SMARCC1, destabilizing the chromatin-remodeling complex SMARCC1-SNF5 to decrease gene transcription, specifically in a subset of the p53-regulated cell cycle genes. Thus, following DNA damage, ASS1 is part of the p53 network that pauses cell cycle progression, enabling genome maintenance and survival. Loss of ASS1 contributes to DNA damage and promotes cell cycle progression, likely contributing to cancer mutagenesis and, hence, adaptability potential.
    DOI:  https://doi.org/10.1038/s42255-024-01060-5
  11. Nat Commun. 2024 Jun 14. 15(1): 5094
    Mitochondria from osteolineage cells regulate myeloid cell-mediated bone resorption.
    Peng Ding, Chuan Gao, Jian Zhou, Jialun Mei, Gan Li, Delin Liu, Hao Li, Peng Liao, Meng Yao, Bingqi Wang, Yafei Lu, Xiaoyuan Peng, Chenyi Jiang, Jimin Yin, Yigang Huang, Minghao Zheng, Youshui Gao, Changqing Zhang, Junjie Gao.
      Interactions between osteolineage cells and myeloid cells play important roles in maintaining skeletal homeostasis. Herein, we find that osteolineage cells transfer mitochondria to myeloid cells. Impairment of the transfer of mitochondria by deleting MIRO1 in osteolineage cells leads to increased myeloid cell commitment toward osteoclastic lineage cells and promotes bone resorption. In detail, impaired mitochondrial transfer from osteolineage cells alters glutathione metabolism and protects osteoclastic lineage cells from ferroptosis, thus promoting osteoclast activities. Furthermore, mitochondrial transfer from osteolineage cells to myeloid cells is involved in the regulation of glucocorticoid-induced osteoporosis, and glutathione depletion alleviates the progression of glucocorticoid-induced osteoporosis. These findings reveal an unappreciated mechanism underlying the interaction between osteolineage cells and myeloid cells to regulate skeletal metabolic homeostasis and provide insights into glucocorticoid-induced osteoporosis progression.
    DOI:  https://doi.org/10.1038/s41467-024-49159-3
  12. J Clin Invest. 2024 Jun 13. pii: e169893. [Epub ahead of print]
    Neutrophil glucose flux as a therapeutic target in antiphospholipid syndrome.
    Ajay Tambralli, Alyssa Harbaugh, Somanathapura K NaveenKumar, Megan D Radyk, Christine E Rysenga, Kaitlyn Sabb, Julia M Hurley, Gautam J Sule, Srilakshmi Yalavarthi, Shanea K Estes, Claire Hoy, Tristin Smith, Cyrus Sarosh, Jacqueline A Madison, Jordan K Schaefer, Suman L Sood, Yu Zuo, Amr H Sawalha, Costas A Lyssiotis, Jason S Knight.
      Neutrophil hyperactivity and neutrophil extracellular trap release (NETosis) appear to play important roles in the pathogenesis of the thromboinflammatory autoimmune disease known as antiphospholipid syndrome (APS). The understanding of neutrophil metabolism has advanced tremendously in the past decade, and accumulating evidence suggests that a variety of metabolic pathways guide neutrophil activities in health and disease. Our previous work characterizing the transcriptome of APS neutrophils revealed that genes related to glycolysis, glycogenolysis, and the pentose phosphate pathway (PPP) were significantly upregulated. Here, we found that APS patient neutrophils used glycolysis more avidly than healthy control neutrophils, especially when the neutrophils were from APS patients with a history of microvascular disease. In vitro, inhibiting either glycolysis or the PPP tempered phorbol myristate acetate- and APS IgG-induced NETosis, but not NETosis triggered by a calcium ionophore. In mice, inhibiting either glycolysis or the PPP reduced neutrophil reactive oxygen species production and suppressed APS IgG-induced NETosis ex vivo. When APS-associated thrombosis was evaluated in mice, inhibiting either glycolysis or the PPP markedly suppressed thrombosis and circulating NET remnants. In summary, these data identify a potential role for restraining neutrophil glucose flux in the treatment of APS.
    Keywords:  Autoimmune diseases; Autoimmunity; Glucose metabolism; Neutrophils
    DOI:  https://doi.org/10.1172/JCI169893
  13. Science. 2024 Jun 14. 384(6701): 1196-1202
    In vivo editing of lung stem cells for durable gene correction in mice.
    Yehui Sun, Sumanta Chatterjee, Xizhen Lian, Zachary Traylor, Sandhya R Sattiraju, Yufen Xiao, Sean A Dilliard, Yun-Chieh Sung, Minjeong Kim, Sang M Lee, Stephen Moore, Xu Wang, Di Zhang, Shiying Wu, Pratima Basak, Jialu Wang, Jing Liu, Rachel J Mann, David F LePage, Weihong Jiang, Shadaan Abid, Mirko Hennig, Anna Martinez, Brandon A Wustman, David J Lockhart, Raksha Jain, Ronald A Conlon, Mitchell L Drumm, Craig A Hodges, Daniel J Siegwart.
      In vivo genome correction holds promise for generating durable disease cures; yet, effective stem cell editing remains challenging. In this work, we demonstrate that optimized lung-targeting lipid nanoparticles (LNPs) enable high levels of genome editing in stem cells, yielding durable responses. Intravenously administered gene-editing LNPs in activatable tdTomato mice achieved >70% lung stem cell editing, sustaining tdTomato expression in >80% of lung epithelial cells for 660 days. Addressing cystic fibrosis (CF), NG-ABE8e messenger RNA (mRNA)-sgR553X LNPs mediated >95% cystic fibrosis transmembrane conductance regulator (CFTR) DNA correction, restored CFTR function in primary patient-derived bronchial epithelial cells equivalent to Trikafta for F508del, corrected intestinal organoids and corrected R553X nonsense mutations in 50% of lung stem cells in CF mice. These findings introduce LNP-enabled tissue stem cell editing for disease-modifying genome correction.
    DOI:  https://doi.org/10.1126/science.adk9428
  14. Nat Microbiol. 2024 Jun 10.
    Phytate metabolism is mediated by microbial cross-feeding in the gut microbiota.
    Willem M De Vos, Minh Nguyen Trung, Mark Davids, Guizhen Liu, Melany Rios-Morales, Henning Jessen, Dorothea Fiedler, Max Nieuwdorp, Thi Phuong Nam Bui.
      Dietary intake of phytate has various reported health benefits. Previous work showed that the gut microbiota can convert phytate to short-chain fatty acids (SCFAs), but the microbial species and metabolic pathway are unclear. Here we identified Mitsuokella jalaludinii as an efficient phytate degrader, which works synergistically with Anaerostipes rhamnosivorans to produce the SCFA propionate. Analysis of published human gut taxonomic profiles revealed that Mitsuokella spp., in particular M. jalaludinii, are prevalent in human gut microbiomes. NMR spectroscopy using 13C-isotope labelling, metabolomic and transcriptomic analyses identified a complete phytate degradation pathway in M. jalaludinii, including production of the intermediate Ins(2)P/myo-inositol. The major end product, 3-hydroxypropionate, was converted into propionate via a synergistic interaction with Anaerostipes rhamnosivorans both in vitro and in mice. Upon [13C6]phytate administration, various 13C-labelled components were detected in mouse caecum in contrast with the absence of [13C6] InsPs or [13C6]myo-inositol in plasma. Caco-2 cells incubated with co-culture supernatants exhibited improved intestinal barrier integrity. These results suggest that the microbiome plays a major role in the metabolism of this phytochemical and that its fermentation to propionate by M. jalaludinii and A. rhamnosivorans may contribute to phytate-driven health benefits.
    DOI:  https://doi.org/10.1038/s41564-024-01698-7
  15. Nat Immunol. 2024 Jun 11.
    IL-12 induces a B cell-intrinsic IL-12/IFNγ feed-forward loop promoting extrafollicular B cell responses.
    Rebecca A Elsner, Shuchi Smita, Mark J Shlomchik.
      While some infections elicit germinal centers, others produce only extrafollicular responses. The mechanisms controlling these dichotomous fates are poorly understood. We identify IL-12 as a cytokine switch, acting directly on B cells to promote extrafollicular and suppress germinal center responses. IL-12 initiates a B cell-intrinsic feed-forward loop between IL-12 and IFNγ, amplifying IFNγ production, which promotes proliferation and plasmablast differentiation from mouse and human B cells, in synergy with IL-12. IL-12 sustains the expression of a portion of IFNγ-inducible genes. Together, they also induce unique gene changes, reflecting both IFNγ amplification and cooperative effects between both cytokines. In vivo, cells lacking both IL-12 and IFNγ receptors are more impaired in plasmablast production than those lacking either receptor alone. Further, B cell-derived IL-12 enhances both plasmablast responses and T helper 1 cell commitment. Thus, B cell-derived IL-12, acting on T and B cells, determines the immune response mode, with implications for vaccines, pathogen protection and autoimmunity.
    DOI:  https://doi.org/10.1038/s41590-024-01858-1
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