bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023‒03‒26
47 papers selected by
Fawaz Alzaïd
Sorbonne Université
  1. The patenting versus publishing dilemma.
  2. FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation.
  3. Epigenetic state determines the in vivo efficacy of STING agonist therapy.
  4. Microbiome checkpoint.
  5. Single-cell and spatial transcriptomics during human organogenesis.
  6. Embrace compassion.
  7. Benchmarking integration of single-cell differential expression.
  8. Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion.
  9. A defect in mitochondrial protein translation influences mitonuclear communication in the heart.
  10. Dual genetic tracing reveals a unique fibroblast subpopulation modulating cardiac fibrosis.
  11. Modulating bone marrow niches.
  12. Epigenetic dosage identifies two major and functionally distinct β cell subtypes.
  13. Structural basis of mitochondrial membrane bending by the I-II-III2-IV2 supercomplex.
  14. Mitochondrial damage activates the NLRP10 inflammasome.
  15. Genomic Analysis of Foxp3 Function in Regulatory T Cells.
  16. Rescue of astrocyte activity by the calcium sensor STIM1 restores long-term synaptic plasticity in female mice modelling Alzheimer's disease.
  17. Building on the Past, Meeting the Moment.
  18. Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation.
  19. Antigen discrimination by T cells relies on size-constrained microvillar contact.
  20. Molecular and metabolic heterogeneity of astrocytes and microglia.
  21. Human T cell generation is restored in CD3δ severe combined immunodeficiency through adenine base editing.
  22. Thymidine nucleotide metabolism controls human telomere length.
  23. Androgens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination.
  24. Systems Immunology: Origins.
  25. How autoreactive thymocytes differentiate into regulatory versus effector CD4+ T cells after avoiding clonal deletion.
  26. Saturated fatty acids dampen the immunogenicity of cancer by suppressing STING.
  27. A Small Molecule RIG-I Agonist Serves as an Adjuvant to Induce Broad Multifaceted Influenza Virus Vaccine Immunity.
  28. Single-cell transcriptomics uncovers a non-autonomous Tbx1-dependent genetic program controlling cardiac neural crest cell development.
  29. Systems Approaches for Studying Immunity.
  30. Aiolos represses CD4+ T cell cytotoxic programming via reciprocal regulation of TFH transcription factors and IL-2 sensitivity.
  31. The rhythmic coupling of Egr-1 and Cidea regulates age-related metabolic dysfunction in the liver of male mice.
  32. CCR3 plays a role in murine age-related cognitive changes and T-cell infiltration into the brain.
  33. Memory T cells possess an innate-like function in local protection from mucosal infection.
  34. Single-cell profiling identifies a novel human polyclonal unconventional T cell lineage.
  35. N-cadherin cleavage: A critical function that induces diabetic retinopathy fibrosis via regulation of β-catenin translocation.
  36. Acute liver steatosis translationally controls the epigenetic regulator MIER1 to promote liver regeneration in a study with male mice.
  37. Blocking dPerk in the intestine suppresses neurodegeneration in a Drosophila model of Parkinson's disease.
  38. Interoperable slide microscopy viewer and annotation tool for imaging data science and computational pathology.
  39. Insights into receptor structure and dynamics at the surface of living cells.
  40. Translating from mouse to man to better understand immune-mediated inflammatory diseases.
  41. Toward a comprehensive catalog of regulatory elements.
  42. Bats play host to a horde of nasty viruses - can studying their immunity help stop pandemics?
  43. Fate-mapping antibodies to study sinful immune dynamics.
  44. Loss of fatty acid degradation by astrocytic mitochondria triggers neuroinflammation and neurodegeneration.
  45. SLC25A46 promotes mitochondrial fission and mediates resistance to lipotoxic stress in INS-1E insulin secreting cells.
  46. Bacteriophage antidefense genes that neutralize TIR and STING immune responses.
  47. A unifying statistical framework to discover disease genes from GWASs.
  1. Nat Commun. 2023 Mar 21. 14(1): 1562
    The patenting versus publishing dilemma.
      
    DOI:  https://doi.org/10.1038/s41467-023-37243-z
  2. Nat Commun. 2023 Mar 23. 14(1): 1625
    FTD-tau S320F mutation stabilizes local structure and allosterically promotes amyloid motif-dependent aggregation.
    Dailu Chen, Sofia Bali, Ruhar Singh, Aleksandra Wosztyl, Vishruth Mullapudi, Jaime Vaquer-Alicea, Parvathy Jayan, Shamiram Melhem, Harro Seelaar, John C van Swieten, Marc I Diamond, Lukasz A Joachimiak.
      Amyloid deposition of the microtubule-associated protein tau is associated with neurodegenerative diseases. In frontotemporal dementia with abnormal tau (FTD-tau), missense mutations in tau enhance its aggregation propensity. Here we describe the structural mechanism for how an FTD-tau S320F mutation drives spontaneous aggregation, integrating data from in vitro, in silico and cellular experiments. We find that S320F stabilizes a local hydrophobic cluster which allosterically exposes the 306VQIVYK311 amyloid motif; identify a suppressor mutation that destabilizes S320F-based hydrophobic clustering reversing the phenotype in vitro and in cells; and computationally engineer spontaneously aggregating tau sequences through optimizing nonpolar clusters surrounding the S320 position. We uncover a mechanism for regulating tau aggregation which balances local nonpolar contacts with long-range interactions that sequester amyloid motifs. Understanding this process may permit control of tau aggregation into structural polymorphs to aid the design of reagents targeting disease-specific tau conformations.
    DOI:  https://doi.org/10.1038/s41467-023-37274-6
  3. Nat Commun. 2023 Mar 22. 14(1): 1573
    Epigenetic state determines the in vivo efficacy of STING agonist therapy.
    Rana Falahat, Anders Berglund, Patricio Perez-Villarroel, Ryan M Putney, Imene Hamaidi, Sungjune Kim, Shari Pilon-Thomas, Glen N Barber, James J Mulé.
      While STING-activating agents have shown limited efficacy in early-phase clinical trials, multiple lines of evidence suggest the importance of tumor cell-intrinsic STING function in mediating antitumor immune responses. Although STING signaling is impaired in human melanoma, its restoration through epigenetic reprogramming can augment its antigenicity and T cell recognition. In this study, we show that reversal of methylation silencing of STING in murine melanoma cell lines using a clinically available DNA methylation inhibitor can improve agonist-induced STING activation and type-I IFN induction, which, in tumor-bearing mice, can induce tumor regression through a CD8+ T cell-dependent immune response. These findings not only provide mechanistic insight into how STING signaling dysfunction in tumor cells can contribute to impaired responses to STING agonist therapy, but also suggest that pharmacological restoration of STING signaling through epigenetic reprogramming might improve the therapeutic efficacy of STING agonists.
    DOI:  https://doi.org/10.1038/s41467-023-37217-1
  4. Nat Immunol. 2023 Mar 23.
    Microbiome checkpoint.
    Nicholas J Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-023-01486-1
  5. Nat Cell Biol. 2023 Mar 22.
    Single-cell and spatial transcriptomics during human organogenesis.
      
    DOI:  https://doi.org/10.1038/s41556-023-01113-z
  6. Science. 2023 Mar 24. 379(6638): 1266
    Embrace compassion.
    Jessica Larsen.
      
    DOI:  https://doi.org/10.1126/science.adh8519
  7. Nat Commun. 2023 Mar 21. 14(1): 1570
    Benchmarking integration of single-cell differential expression.
    Hai C T Nguyen, Bukyung Baik, Sora Yoon, Taesung Park, Dougu Nam.
      Integration of single-cell RNA sequencing data between different samples has been a major challenge for analyzing cell populations. However, strategies to integrate differential expression analysis of single-cell data remain underinvestigated. Here, we benchmark 46 workflows for differential expression analysis of single-cell data with multiple batches. We show that batch effects, sequencing depth and data sparsity substantially impact their performances. Notably, we find that the use of batch-corrected data rarely improves the analysis for sparse data, whereas batch covariate modeling improves the analysis for substantial batch effects. We show that for low depth data, single-cell techniques based on zero-inflation model deteriorate the performance, whereas the analysis of uncorrected data using limmatrend, Wilcoxon test and fixed effects model performs well. We suggest several high-performance methods under different conditions based on various simulation and real data analyses. Additionally, we demonstrate that differential expression analysis for a specific cell type outperforms that of large-scale bulk sample data in prioritizing disease-related genes.
    DOI:  https://doi.org/10.1038/s41467-023-37126-3
  8. Mol Cell. 2023 Mar 15. pii: S1097-2765(23)00153-3. [Epub ahead of print]
    Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion.
    Elena Battistello, Kimberlee A Hixon, Dawn E Comstock, Clayton K Collings, Xufeng Chen, Javier Rodriguez Hernaez, Soobeom Lee, Kasey S Cervantes, Madeline M Hinkley, Konstantinos Ntatsoulis, Annamaria Cesarano, Kathryn Hockemeyer, W Nicholas Haining, Matthew T Witkowski, Jun Qi, Aristotelis Tsirigos, Fabiana Perna, Iannis Aifantis, Cigall Kadoch.
      Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.
    Keywords:  ATP-dependent chromatin remodeling; CRISPR screening; CUT&Tag; HNF1B; PROTACs; SWI/SNF; T cells; immunotherapy; small-molecule inhibitors; transcription factors
    DOI:  https://doi.org/10.1016/j.molcel.2023.02.026
  9. Nat Commun. 2023 Mar 22. 14(1): 1595
    A defect in mitochondrial protein translation influences mitonuclear communication in the heart.
    Feng Gao, Tian Liang, Yao Wei Lu, Xuyang Fu, Xiaoxuan Dong, Linbin Pu, Tingting Hong, Yuxia Zhou, Yu Zhang, Ning Liu, Feng Zhang, Jianming Liu, Andrea P Malizia, Hong Yu, Wei Zhu, Douglas B Cowan, Hong Chen, Xinyang Hu, John D Mably, Jian'an Wang, Da-Zhi Wang, Jinghai Chen.
      The regulation of the informational flow from the mitochondria to the nucleus (mitonuclear communication) is not fully characterized in the heart. We have determined that mitochondrial ribosomal protein S5 (MRPS5/uS5m) can regulate cardiac function and key pathways to coordinate this process during cardiac stress. We demonstrate that loss of Mrps5 in the developing heart leads to cardiac defects and embryonic lethality while postnatal loss induces cardiac hypertrophy and heart failure. The structure and function of mitochondria is disrupted in Mrps5 mutant cardiomyocytes, impairing mitochondrial protein translation and OXPHOS. We identify Klf15 as a Mrps5 downstream target and demonstrate that exogenous Klf15 is able to rescue the overt defects and re-balance the cardiac metabolome. We further show that Mrps5 represses Klf15 expression through c-myc, together with the metabolite L-phenylalanine. This critical role for Mrps5 in cardiac metabolism and mitonuclear communication highlights its potential as a target for heart failure therapies.
    DOI:  https://doi.org/10.1038/s41467-023-37291-5
  10. Nat Genet. 2023 Mar 23.
    Dual genetic tracing reveals a unique fibroblast subpopulation modulating cardiac fibrosis.
    Maoying Han, Zixin Liu, Lei Liu, Xiuzhen Huang, Haixiao Wang, Wenjuan Pu, Enci Wang, Xiuxiu Liu, Yan Li, Lingjuan He, Xufeng Li, Jiayu Wu, Lin Qiu, Ruling Shen, Qing-Dong Wang, Yong Ji, Reza Ardehali, Qiang Shu, Kathy O Lui, Lixin Wang, Bin Zhou.
      After severe heart injury, fibroblasts are activated and proliferate excessively to form scarring, leading to decreased cardiac function and eventually heart failure. It is unknown, however, whether cardiac fibroblasts are heterogeneous with respect to their degree of activation, proliferation and function during cardiac fibrosis. Here, using dual recombinase-mediated genetic lineage tracing, we find that endocardium-derived fibroblasts preferentially proliferate and expand in response to pressure overload. Fibroblast-specific proliferation tracing revealed highly regional expansion of activated fibroblasts after injury, whose pattern mirrors that of endocardium-derived fibroblast distribution in the heart. Specific ablation of endocardium-derived fibroblasts alleviates cardiac fibrosis and reduces the decline of heart function after pressure overload injury. Mechanistically, Wnt signaling promotes activation and expansion of endocardium-derived fibroblasts during cardiac remodeling. Our study identifies endocardium-derived fibroblasts as a key fibroblast subpopulation accounting for severe cardiac fibrosis after pressure overload injury and as a potential therapeutic target against cardiac fibrosis.
    DOI:  https://doi.org/10.1038/s41588-023-01337-7
  11. Nat Immunol. 2023 Mar 23.
    Modulating bone marrow niches.
    Laurie A Dempsey.
      
    DOI:  https://doi.org/10.1038/s41590-023-01487-0
  12. Cell Metab. 2023 Mar 16. pii: S1550-4131(23)00086-4. [Epub ahead of print]
    Epigenetic dosage identifies two major and functionally distinct β cell subtypes.
    Erez Dror, Luca Fagnocchi, Vanessa Wegert, Stefanos Apostle, Brooke Grimaldi, Tim Gruber, Ilaria Panzeri, Steffen Heyne, Kira Daniela Höffler, Victor Kreiner, Reagan Ching, Tess Tsai-Hsiu Lu, Ayush Semwal, Ben Johnson, Parijat Senapati, Adelheid Lempradl, Dustin Schones, Axel Imhof, Hui Shen, John Andrew Pospisilik.
      The mechanisms that specify and stabilize cell subtypes remain poorly understood. Here, we identify two major subtypes of pancreatic β cells based on histone mark heterogeneity (βHI and βLO). βHI cells exhibit ∼4-fold higher levels of H3K27me3, distinct chromatin organization and compaction, and a specific transcriptional pattern. βHI and βLO cells also differ in size, morphology, cytosolic and nuclear ultrastructure, epigenomes, cell surface marker expression, and function, and can be FACS separated into CD24+ and CD24- fractions. Functionally, βHI cells have increased mitochondrial mass, activity, and insulin secretion in vivo and ex vivo. Partial loss of function indicates that H3K27me3 dosage regulates βHI/βLO ratio in vivo, suggesting that control of β cell subtype identity and ratio is at least partially uncoupled. Both subtypes are conserved in humans, with βHI cells enriched in humans with type 2 diabetes. Thus, epigenetic dosage is a novel regulator of cell subtype specification and identifies two functionally distinct β cell subtypes.
    Keywords:  H3K27me3; beta cells; bivalent genes; cell heterogeneity; chromatin organization; epigenetics; insulin; pancreatic islet; single cell
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.008
  13. Nature. 2023 Mar 22.
    Structural basis of mitochondrial membrane bending by the I-II-III2-IV2 supercomplex.
    Alexander Mühleip, Rasmus Kock Flygaard, Rozbeh Baradaran, Outi Haapanen, Thomas Gruhl, Victor Tobiasson, Amandine Maréchal, Vivek Sharma, Alexey Amunts.
      Mitochondrial energy conversion requires an intricate architecture of the inner mitochondrial membrane1. Here we show that a supercomplex containing all four respiratory chain components contributes to membrane curvature induction in ciliates. We report cryo-electron microscopy and cryo-tomography structures of the supercomplex that comprises 150 different proteins and 311 bound lipids, forming a stable 5.8-MDa assembly. Owing to subunit acquisition and extension, complex I associates with a complex IV dimer, generating a wedge-shaped gap that serves as a binding site for complex II. Together with a tilted complex III dimer association, it results in a curved membrane region. Using molecular dynamics simulations, we demonstrate that the divergent supercomplex actively contributes to the membrane curvature induction and tubulation of cristae. Our findings highlight how the evolution of protein subunits of respiratory complexes has led to the I-II-III2-IV2 supercomplex that contributes to the shaping of the bioenergetic membrane, thereby enabling its functional specialization.
    DOI:  https://doi.org/10.1038/s41586-023-05817-y
  14. Nat Immunol. 2023 Mar 20.
    Mitochondrial damage activates the NLRP10 inflammasome.
    Tomasz Próchnicki, Matilde B Vasconcelos, Kim S Robinson, Matthew S J Mangan, Dennis De Graaf, Kateryna Shkarina, Marta Lovotti, Lena Standke, Romina Kaiser, Rainer Stahl, Fraser G Duthie, Maximilian Rothe, Kateryna Antonova, Lea-Marie Jenster, Zhi Heng Lau, Sarah Rösing, Nora Mirza, Clarissa Gottschild, Dagmar Wachten, Claudia Günther, Thomas A Kufer, Florian I Schmidt, Franklin L Zhong, Eicke Latz.
      Upon detecting pathogens or cell stress, several NOD-like receptors (NLRs) form inflammasome complexes with the adapter ASC and caspase-1, inducing gasdermin D (GSDMD)-dependent cell death and maturation and release of IL-1β and IL-18. The triggers and activation mechanisms of several inflammasome-forming sensors are not well understood. Here we show that mitochondrial damage activates the NLRP10 inflammasome, leading to ASC speck formation and caspase-1-dependent cytokine release. While the AIM2 inflammasome can also sense mitochondrial demise by detecting mitochondrial DNA (mtDNA) in the cytosol, NLRP10 monitors mitochondrial integrity in an mtDNA-independent manner, suggesting the recognition of distinct molecular entities displayed by the damaged organelles. NLRP10 is highly expressed in differentiated human keratinocytes, in which it can also assemble an inflammasome. Our study shows that this inflammasome surveils mitochondrial integrity. These findings might also lead to a better understanding of mitochondria-linked inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41590-023-01451-y
  15. J Immunol. 2023 Apr 01. 210(7): 880-887
    Genomic Analysis of Foxp3 Function in Regulatory T Cells.
    Gabriel A Dolsten, Yuri Pritykin.
      Regulatory T (Treg) cells are critical for tolerance to self-antigens and for preventing autoimmunity. Foxp3 has been identified as a Treg cell lineage-defining transcription factor controlling Treg cell differentiation and function. In this article, we review the current mechanistic and systemic understanding of Foxp3 function enabled by experimental and computational advances in high-throughput genomics.
    DOI:  https://doi.org/10.4049/jimmunol.2200864
  16. Nat Commun. 2023 Mar 22. 14(1): 1590
    Rescue of astrocyte activity by the calcium sensor STIM1 restores long-term synaptic plasticity in female mice modelling Alzheimer's disease.
    Annamaria Lia, Gabriele Sansevero, Angela Chiavegato, Miriana Sbrissa, Diana Pendin, Letizia Mariotti, Tullio Pozzan, Nicoletta Berardi, Giorgio Carmignoto, Cristina Fasolato, Micaela Zonta.
      Calcium dynamics in astrocytes represent a fundamental signal that through gliotransmitter release regulates synaptic plasticity and behaviour. Here we present a longitudinal study in the PS2APP mouse model of Alzheimer's disease (AD) linking astrocyte Ca2+ hypoactivity to memory loss. At the onset of plaque deposition, somatosensory cortical astrocytes of AD female mice exhibit a drastic reduction of Ca2+ signaling, closely associated with decreased endoplasmic reticulum Ca2+ concentration and reduced expression of the Ca2+ sensor STIM1. In parallel, astrocyte-dependent long-term synaptic plasticity declines in the somatosensory circuitry, anticipating specific tactile memory loss. Notably, we show that both astrocyte Ca2+ signaling and long-term synaptic plasticity are fully recovered by selective STIM1 overexpression in astrocytes. Our data unveil astrocyte Ca2+ hypoactivity in neocortical astrocytes as a functional hallmark of early AD stages and indicate astrocytic STIM1 as a target to rescue memory deficits.
    DOI:  https://doi.org/10.1038/s41467-023-37240-2
  17. J Immunol. 2023 Apr 01. 210(7): 849-854
    Building on the Past, Meeting the Moment.
    Gary A Koretzky.
      
    DOI:  https://doi.org/10.4049/jimmunol.2390003
  18. Nat Immunol. 2023 Mar 20.
    Epithelial Nlrp10 inflammasome mediates protection against intestinal autoinflammation.
    Danping Zheng, Gayatree Mohapatra, Lara Kern, Yiming He, Merav D Shmueli, Rafael Valdés-Mas, Aleksandra A Kolodziejczyk, Tomasz Próchnicki, Matilde B Vasconcelos, Lena Schorr, Franziska Hertel, Ye Seul Lee, Miguel Camacho Rufino, Emmanuelle Ceddaha, Sandy Shimshy, Ryan James Hodgetts, Mally Dori-Bachash, Christian Kleimeyer, Kim Goldenberg, Melina Heinemann, Noa Stettner, Alon Harmelin, Hagit Shapiro, Jens Puschhof, Minhu Chen, Richard A Flavell, Eicke Latz, Yifat Merbl, Suhaib K Abdeen, Eran Elinav.
      Unlike other nucleotide oligomerization domain-like receptors, Nlrp10 lacks a canonical leucine-rich repeat domain, suggesting that it is incapable of signal sensing and inflammasome formation. Here we show that mouse Nlrp10 is expressed in distal colonic intestinal epithelial cells (IECs) and modulated by the intestinal microbiome. In vitro, Nlrp10 forms an Apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC)-dependent, m-3M3FBS-activated, polyinosinic:polycytidylic acid-modulated inflammasome driving interleukin-1β and interleukin-18 secretion. In vivo, Nlrp10 signaling is dispensable during steady state but becomes functional during autoinflammation in antagonizing mucosal damage. Importantly, whole-body or conditional IEC Nlrp10 depletion leads to reduced IEC caspase-1 activation, coupled with enhanced susceptibility to dextran sodium sulfate-induced colitis, mediated by altered inflammatory and healing programs. Collectively, understanding Nlrp10 inflammasome-dependent and independent activity, regulation and possible human relevance might facilitate the development of new innate immune anti-inflammatory interventions.
    DOI:  https://doi.org/10.1038/s41590-023-01450-z
  19. Nat Commun. 2023 Mar 23. 14(1): 1611
    Antigen discrimination by T cells relies on size-constrained microvillar contact.
    Edward Jenkins, Markus Körbel, Caitlin O'Brien-Ball, James McColl, Kevin Y Chen, Mateusz Kotowski, Jane Humphrey, Anna H Lippert, Heather Brouwer, Ana Mafalda Santos, Steven F Lee, Simon J Davis, David Klenerman.
      T cells use finger-like protrusions called 'microvilli' to interrogate their targets, but why they do so is unknown. To form contacts, T cells must overcome the highly charged, barrier-like layer of large molecules forming a target cell's glycocalyx. Here, T cells are observed to use microvilli to breach a model glycocalyx barrier, forming numerous small (<0.5 μm diameter) contacts each of which is stabilized by the small adhesive protein CD2 expressed by the T cell, and excludes large proteins including CD45, allowing sensitive, antigen dependent TCR signaling. In the absence of the glycocalyx or when microvillar contact-size is increased by enhancing CD2 expression, strong signaling occurs that is no longer antigen dependent. Our observations suggest that, modulated by the opposing effects of the target cell glycocalyx and small adhesive proteins, the use of microvilli equips T cells with the ability to effect discriminatory receptor signaling.
    DOI:  https://doi.org/10.1038/s41467-023-36855-9
  20. Cell Metab. 2023 Mar 17. pii: S1550-4131(23)00084-0. [Epub ahead of print]
    Molecular and metabolic heterogeneity of astrocytes and microglia.
    Philip Hasel, William H Aisenberg, F Chris Bennett, Shane A Liddelow.
      Astrocytes and microglia are central players in a myriad of processes in the healthy and diseased brain, ranging from metabolism to immunity. The crosstalk between these two cell types contributes to pathology in many if not all neuroinflammatory and neurodegenerative diseases. Recent advancements in integrative multimodal sequencing techniques have begun to highlight how heterogeneous both cell types are and the importance of metabolism to their regulation. We discuss here the transcriptomic, metabolic, and functional heterogeneity of astrocytes and microglia and highlight their interaction in health and disease.
    DOI:  https://doi.org/10.1016/j.cmet.2023.03.006
  21. Cell. 2023 Mar 15. pii: S0092-8674(23)00170-8. [Epub ahead of print]
    Human T cell generation is restored in CD3δ severe combined immunodeficiency through adenine base editing.
    Grace E McAuley, Gloria Yiu, Patrick C Chang, Gregory A Newby, Beatriz Campo-Fernandez, Sorel T Fitz-Gibbon, Xiaomeng Wu, Sung-Hae L Kang, Amber Garibay, Jeffrey Butler, Valentina Christian, Ryan L Wong, Kelcee A Everette, Anthony Azzun, Hila Gelfer, Christopher S Seet, Aru Narendran, Luis Murguia-Favela, Zulema Romero, Nicola Wright, David R Liu, Gay M Crooks, Donald B Kohn.
      CD3δ SCID is a devastating inborn error of immunity caused by mutations in CD3D, encoding the invariant CD3δ chain of the CD3/TCR complex necessary for normal thymopoiesis. We demonstrate an adenine base editing (ABE) strategy to restore CD3δ in autologous hematopoietic stem and progenitor cells (HSPCs). Delivery of mRNA encoding a laboratory-evolved ABE and guide RNA into a CD3δ SCID patient's HSPCs resulted in a 71.2% ± 7.85% (n = 3) correction of the pathogenic mutation. Edited HSPCs differentiated in artificial thymic organoids produced mature T cells exhibiting diverse TCR repertoires and TCR-dependent functions. Edited human HSPCs transplanted into immunodeficient mice showed 88% reversion of the CD3D defect in human CD34+ cells isolated from mouse bone marrow after 16 weeks, indicating correction of long-term repopulating HSCs. These findings demonstrate the preclinical efficacy of ABE in HSPCs for the treatment of CD3δ SCID, providing a foundation for the development of a one-time treatment for CD3δ SCID patients.
    Keywords:  CD3D severe combined immune deficiency; CITE-seq; artificial thymic organoid; base editing; hematopoietic stem and progenitor cells
    DOI:  https://doi.org/10.1016/j.cell.2023.02.027
  22. Nat Genet. 2023 Mar 23.
    Thymidine nucleotide metabolism controls human telomere length.
    William Mannherz, Suneet Agarwal.
      Telomere length in humans is associated with lifespan and severe diseases, yet the genetic determinants of telomere length remain incompletely defined. Here we performed genome-wide CRISPR-Cas9 functional telomere length screening and identified thymidine (dT) nucleotide metabolism as a limiting factor in human telomere maintenance. Targeted genetic disruption using CRISPR-Cas9 revealed multiple telomere length control points across the thymidine nucleotide metabolism pathway: decreasing dT nucleotide salvage via deletion of the gene encoding nuclear thymidine kinase (TK1) or de novo production by knockout of the thymidylate synthase gene (TYMS) decreased telomere length, whereas inactivation of the deoxynucleoside triphosphohydrolase-encoding gene SAMHD1 lengthened telomeres. Remarkably, supplementation with dT alone drove robust telomere elongation by telomerase in cells, and thymidine triphosphate stimulated telomerase activity in a substrate-independent manner in vitro. In induced pluripotent stem cells derived from patients with genetic telomere biology disorders, dT supplementation or inhibition of SAMHD1 promoted telomere restoration. Our results demonstrate a critical role of thymidine metabolism in controlling human telomerase and telomere length, which may be therapeutically actionable in patients with fatal degenerative diseases.
    DOI:  https://doi.org/10.1038/s41588-023-01339-5
  23. Nat Commun. 2023 Mar 22. 14(1): 1592
    Androgens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination.
    Amina Zahaf, Abdelmoumen Kassoussi, Tom Hutteau-Hamel, Amine Mellouk, Corentine Marie, Lida Zoupi, Foteini Tsouki, Claudia Mattern, Pierre Bobé, Michael Schumacher, Anna Williams, Carlos Parras, Elisabeth Traiffort.
      Neuroprotective, anti-inflammatory, and remyelinating properties of androgens are well-characterized in demyelinated male mice and men suffering from multiple sclerosis. However, androgen effects mediated by the androgen receptor (AR), have been only poorly studied in females who make low androgen levels. Here, we show a predominant microglial AR expression in demyelinated lesions from female mice and women with multiple sclerosis, but virtually undetectable AR expression in lesions from male animals and men with multiple sclerosis. In female mice, androgens and estrogens act in a synergistic way while androgens drive microglia response towards regeneration. Transcriptomic comparisons of demyelinated mouse spinal cords indicate that, regardless of the sex, androgens up-regulate genes related to neuronal function integrity and myelin production. Depending on the sex, androgens down-regulate genes related to the immune system in females and lipid catabolism in males. Thus, androgens are required for proper myelin regeneration in females and therapeutic approaches of demyelinating diseases need to consider male-female differences.
    DOI:  https://doi.org/10.1038/s41467-023-36846-w
  24. J Immunol. 2023 Apr 01. 210(7): 845-847
    Systems Immunology: Origins.
    Mark M Davis.
      
    DOI:  https://doi.org/10.4049/jimmunol.2200631
  25. Nat Immunol. 2023 Mar 23.
    How autoreactive thymocytes differentiate into regulatory versus effector CD4+ T cells after avoiding clonal deletion.
    Xuguang Tai, Alyssa Indart, Mirelle Rojano, Jie Guo, Nicolai Apenes, Tejas Kadakia, Marco Craveiro, Amala Alag, Ruth Etzensperger, Mohamed Elsherif Badr, Flora Zhang, Zhongmei Zhang, Jie Mu, Terry Guinter, Assiatu Crossman, Larry Granger, Susan Sharrow, Xuyu Zhou, Alfred Singer.
      Thymocytes bearing autoreactive T cell receptors (TCRs) are agonist-signaled by TCR/co-stimulatory molecules to either undergo clonal deletion or to differentiate into specialized regulatory T (Treg) or effector T (Teff) CD4+ cells. How these different fates are achieved during development remains poorly understood. We now document that deletion and differentiation are agonist-signaled at different times during thymic selection and that Treg and Teff cells both arise after clonal deletion as alternative lineage fates of agonist-signaled CD4+CD25+ precursors. Disruption of agonist signaling induces CD4+CD25+ precursors to initiate Foxp3 expression and become Treg cells, whereas persistent agonist signaling induces CD4+CD25+ precursors to become IL-2+ Teff cells. Notably, we discovered that transforming growth factor-β induces Foxp3 expression and promotes Treg cell development by disrupting weaker agonist signals and that Foxp3 expression is not induced by IL-2 except under non-physiological in vivo conditions. Thus, TCR signaling disruption versus persistence is a general mechanism of lineage fate determination in the thymus that directs development of agonist-signaled autoreactive thymocytes.
    DOI:  https://doi.org/10.1038/s41590-023-01469-2
  26. Cell Rep. 2023 Mar 22. pii: S2211-1247(23)00314-5. [Epub ahead of print]42(4): 112303
    Saturated fatty acids dampen the immunogenicity of cancer by suppressing STING.
    Blake R Heath, Wang Gong, Hülya F Taner, Luke Broses, Kohei Okuyama, Wanqing Cheng, Max Jin, Zackary R Fitzsimonds, Andriana Manousidaki, Yuesong Wu, Shaoping Zhang, Haitao Wen, Steven B Chinn, Eric Bartee, Yuying Xie, James J Moon, Yu Leo Lei.
      Oncogenes destabilize STING in epithelial cell-derived cancer cells, such as head and neck squamous cell carcinomas (HNSCCs), to promote immune escape. Despite the abundance of tumor-infiltrating myeloid cells, HNSCC presents notable resistance to STING stimulation. Here, we show how saturated fatty acids in the microenvironment dampen tumor response to STING stimulation. Using single-cell analysis, we found that obesity creates an IFN-I-deprived tumor microenvironment with a massive expansion of suppressive myeloid cell clusters and contraction of effector T cells. Saturated fatty acids, but not unsaturated fatty acids, potently inhibit the STING-IFN-I pathway in HNSCC cells. Myeloid cells from obese mice show dampened responses to STING stimulation and are more suppressive of T cell activation. In agreement, obese hosts exhibited increased tumor burden and lower responsiveness to STING agonist. As a mechanism, saturated fatty acids induce the expression of NLRC3, depletion of which results in a T cell inflamed tumor microenvironment and IFN-I-dependent tumor control.
    Keywords:  CP: Cancer; CP: Immunology; NLRC3; STING; head and neck cancer; immunogenicity; innate immunity; metabolism; obesity; saturated fatty acids; type-I interferon
    DOI:  https://doi.org/10.1016/j.celrep.2023.112303
  27. J Immunol. 2023 03 20. pii: ji2300026. [Epub ahead of print]
    A Small Molecule RIG-I Agonist Serves as an Adjuvant to Induce Broad Multifaceted Influenza Virus Vaccine Immunity.
    Emily A Hemann, Megan L Knoll, Courtney R Wilkins, Caroline Subra, Richard Green, Adolfo García-Sastre, Paul G Thomas, Lydie Trautmann, Renee C Ireton, Yueh-Ming Loo, Michael Gale.
      Retinoic acid-inducible gene I (RIG-I) is essential for activating host cell innate immunity to regulate the immune response against many RNA viruses. We previously identified that a small molecule compound, KIN1148, led to the activation of IFN regulatory factor 3 (IRF3) and served to enhance protection against influenza A virus (IAV) A/California/04/2009 infection. We have now determined direct binding of KIN1148 to RIG-I to drive expression of IFN regulatory factor 3 and NF-κB target genes, including specific immunomodulatory cytokines and chemokines. Intriguingly, KIN1148 does not lead to ATPase activity or compete with ATP for binding but activates RIG-I to induce antiviral gene expression programs distinct from type I IFN treatment. When administered in combination with a vaccine against IAV, KIN1148 induces both neutralizing Ab and IAV-specific T cell responses compared with vaccination alone, which induces comparatively poor responses. This robust KIN1148-adjuvanted immune response protects mice from lethal A/California/04/2009 and H5N1 IAV challenge. Importantly, KIN1148 also augments human CD8+ T cell activation. Thus, we have identified a small molecule RIG-I agonist that serves as an effective adjuvant in inducing noncanonical RIG-I activation for induction of innate immune programs that enhance adaptive immune protection of antiviral vaccination.
    DOI:  https://doi.org/10.4049/jimmunol.2300026
  28. Nat Commun. 2023 Mar 21. 14(1): 1551
    Single-cell transcriptomics uncovers a non-autonomous Tbx1-dependent genetic program controlling cardiac neural crest cell development.
    Christopher De Bono, Yang Liu, Alexander Ferrena, Aneesa Valentine, Deyou Zheng, Bernice E Morrow.
      Disruption of cardiac neural crest cells (CNCCs) results in congenital heart disease, yet we do not understand the cell fate dynamics as these cells differentiate to vascular smooth muscle cells. Here we performed single-cell RNA-sequencing of NCCs from the pharyngeal apparatus with the heart in control mouse embryos and when Tbx1, the gene for 22q11.2 deletion syndrome, is inactivated. We uncover three dynamic transitions of pharyngeal NCCs expressing Tbx2 and Tbx3 through differentiated CNCCs expressing cardiac transcription factors with smooth muscle genes. These transitions are altered non-autonomously by loss of Tbx1. Further, inactivation of Tbx2 and Tbx3 in early CNCCs results in aortic arch branching defects due to failed smooth muscle differentiation. Loss of Tbx1 interrupts mesoderm to CNCC cell-cell communication with upregulation and premature activation of BMP signaling and reduced MAPK signaling, as well as alteration of other signaling, and failed dynamic transitions of CNCCs leading to disruption of aortic arch artery formation and cardiac outflow tract septation.
    DOI:  https://doi.org/10.1038/s41467-023-37015-9
  29. J Immunol. 2023 Apr 01. 210(7): 843-844
    Systems Approaches for Studying Immunity.
    Golnaz Vahedi, Eugene M Oltz.
      
    DOI:  https://doi.org/10.4049/jimmunol.2300097
  30. Nat Commun. 2023 Mar 24. 14(1): 1652
    Aiolos represses CD4+ T cell cytotoxic programming via reciprocal regulation of TFH transcription factors and IL-2 sensitivity.
    Kaitlin A Read, Devin M Jones, Srijana Pokhrel, Emily D S Hales, Aditi Varkey, Jasmine A Tuazon, Caprice D Eisele, Omar Abdouni, Abbey Saadey, Melissa R Leonard, Robert T Warren, Michael D Powell, Jeremy M Boss, Emily A Hemann, Jacob S Yount, Gang Xin, Hazem E Ghoneim, Chan-Wang J Lio, Aharon G Freud, Patrick L Collins, Kenneth J Oestreich.
      During intracellular infection, T follicular helper (TFH) and T helper 1 (TH1) cells promote humoral and cell-mediated responses, respectively. Another subset, CD4-cytotoxic T lymphocytes (CD4-CTLs), eliminate infected cells via functions typically associated with CD8+ T cells. The mechanisms underlying differentiation of these populations are incompletely understood. Here, we identify the transcription factor Aiolos as a reciprocal regulator of TFH and CD4-CTL programming. We find that Aiolos deficiency results in downregulation of key TFH transcription factors, and consequently reduced TFH differentiation and antibody production, during influenza virus infection. Conversely, CD4-CTL programming is elevated, including enhanced Eomes and cytolytic molecule expression. We further demonstrate that Aiolos deficiency allows for enhanced IL-2 sensitivity and increased STAT5 association with CD4-CTL gene targets, including Eomes, effector molecules, and IL2Ra. Thus, our collective findings identify Aiolos as a pivotal regulator of CD4-CTL and TFH programming and highlight its potential as a target for manipulating CD4+ T cell responses.
    DOI:  https://doi.org/10.1038/s41467-023-37420-0
  31. Nat Commun. 2023 Mar 24. 14(1): 1634
    The rhythmic coupling of Egr-1 and Cidea regulates age-related metabolic dysfunction in the liver of male mice.
    Jing Wu, Dandan Bu, Haiquan Wang, Di Shen, Danyang Chong, Tongyu Zhang, Weiwei Tao, Mengfei Zhao, Yue Zhao, Lei Fang, Peng Li, Bin Xue, Chao-Jun Li.
      The liver lipid metabolism of older individuals canbecome impaired and the circadian rhythm of genes involved in lipid metabolism is also disturbed. Although the link between metabolism and circadian rhythms is already recognized, how these processes are decoupled in liver during aging is still largely unknown. Here, we show that the circadian rhythm for the transcription factor Egr-1 expression is shifted forward with age in male mice. Egr-1 deletion accelerates liver age-related metabolic dysfunction, which associates with increased triglyceride accumulation, disruption of the opposite rhythmic coupling of Egr-1 and Cidea (Cell Death Inducing DFFA Like Effector A) at the transcriptional level and large lipid droplet formation. Importantly, adjustment of the central clock with light via a 4-hour forward shift in 6-month-old mice, leads to recovery the rhythm shift of Egr-1 during aging and largely ameliorated liver metabolic dysfunction. All our collected data suggest that liver Egr-1 might integrate the central and peripheral rhythms and regulate metabolic homeostasis in the liver.
    DOI:  https://doi.org/10.1038/s41467-023-36775-8
  32. Commun Biol. 2023 03 18. 6(1): 292
    CCR3 plays a role in murine age-related cognitive changes and T-cell infiltration into the brain.
    Sanket V Rege, Arnaud Teichert, Juliet Masumi, Onkar S Dhande, Reema Harish, Brett W Higgins, Yesenia Lopez, Lily Akrapongpisak, Hannah Hackbart, Sofia Caryotakis, Dino P Leone, Balazs Szoke, Jonas Hannestad, Karoly Nikolich, Steven P Braithwaite, S Sakura Minami.
      Targeting immune-mediated, age-related, biology has the potential to be a transformative therapeutic strategy. However, the redundant nature of the multiple cytokines that change with aging requires identification of a master downstream regulator to successfully exert therapeutic efficacy. Here, we discovered CCR3 as a prime candidate, and inhibition of CCR3 has pro-cognitive benefits in mice, but these benefits are not driven by an obvious direct action on central nervous system (CNS)-resident cells. Instead, CCR3-expressing T cells in the periphery that are modulated in aging inhibit infiltration of these T cells across the blood-brain barrier and reduce neuroinflammation. The axis of CCR3-expressing T cells influencing crosstalk from periphery to brain provides a therapeutically tractable link. These findings indicate the broad therapeutic potential of CCR3 inhibition in a spectrum of neuroinflammatory diseases of aging.
    DOI:  https://doi.org/10.1038/s42003-023-04665-w
  33. J Clin Invest. 2023 Mar 23. pii: e162800. [Epub ahead of print]
    Memory T cells possess an innate-like function in local protection from mucosal infection.
    Tanvi Arkatkar, Veronica A Davé, Irene Cruz Talavera, Jessica B Graham, Jessica L Swarts, Sean M Hughes, Timothy A Bell, Pablo Hock, Joe Farrington, Ginger D Shaw, Anna C Kirby, Michael Fialkow, Meei-Li Huang, Keith R Jerome, Martin T Ferris, Florian Hladik, Joshua T Schiffer, Martin Prlic, Jennifer M Lund.
      Mucosal infections pose a significant global health burden. Antigen-specific tissue resident T cells are critical to maintaining barrier immunity. Previous studies in the context of systemic infection suggest that memory CD8 T cells may also provide innate-like protection against antigenically unrelated pathogens independent of TCR engagement. Whether "bystander T cell activation" is also an important defense mechanism in the mucosa is poorly understood. Here, we investigated if innate-like memory CD8 T cells could protect against a model mucosal virus infection, herpes simplex virus 2 (HSV-2). We found that immunization with an irrelevant antigen delayed disease progression from lethal HSV-2 challenge, suggesting that memory CD8 T cells may mediate protection despite the lack of antigen-specificity. Upon HSV-2 infection, we observed an early infiltration, rather than substantial local proliferation, of antigen-non-specific CD8 T cells, which became bystander-activated only within the infected mucosal tissue. Critically, we show that bystander-activated CD8 T cells are sufficient to reduce early viral burden after HSV-2 infection. Finally, local cytokine cues within the tissue microenvironment after infection were sufficient for bystander activation of mucosal tissue memory CD8 T cells from mice and humans. Altogether, our findings suggest that local bystander-activation of CD8 memory T cells contribute a fast and effective innate-like response to infection in mucosal tissue.
    Keywords:  Immunology; Infectious disease; T cells
    DOI:  https://doi.org/10.1172/JCI162800
  34. J Exp Med. 2023 Jun 05. pii: e20220942. [Epub ahead of print]220(6):
    Single-cell profiling identifies a novel human polyclonal unconventional T cell lineage.
    Lore Billiet, Laurenz De Cock, Guillem Sanchez Sanchez, Rupert L Mayer, Glenn Goetgeluk, Stijn De Munter, Melissa Pille, Joline Ingels, Hanne Jansen, Karin Weening, Eva Pascal, Killian Raes, Sarah Bonte, Tessa Kerre, Niels Vandamme, Ruth Seurinck, Jana Roels, Marieke Lavaert, Filip Van Nieuwerburgh, Georges Leclercq, Tom Taghon, Francis Impens, Björn Menten, David Vermijlen, Bart Vandekerckhove.
      In the human thymus, a CD10+ PD-1+ TCRαβ+ differentiation pathway diverges from the conventional single positive T cell lineages at the early double-positive stage. Here, we identify the progeny of this unconventional lineage in antigen-inexperienced blood. These unconventional T cells (UTCs) in thymus and blood share a transcriptomic profile, characterized by hallmark transcription factors (i.e., ZNF683 and IKZF2), and a polyclonal TCR repertoire with autoreactive features, exhibiting a bias toward early TCRα chain rearrangements. Single-cell RNA sequencing confirms a common developmental trajectory between the thymic and blood UTCs and clearly delineates this unconventional lineage in blood. Besides MME+ recent thymic emigrants, effector-like clusters are identified in this heterogeneous lineage. Expression of Helios and KIR and a decreased CD8β expression are characteristics of this lineage. This UTC lineage could be identified in adult blood and intestinal tissues. In summary, our data provide a comprehensive characterization of the polyclonal unconventional lineage in antigen-inexperienced blood and identify the adult progeny.
    DOI:  https://doi.org/10.1084/jem.20220942
  35. FASEB J. 2023 Apr;37(4): e22878
    N-cadherin cleavage: A critical function that induces diabetic retinopathy fibrosis via regulation of β-catenin translocation.
    Wei Xiang, Longhui Li, Fuyan Hong, Yongcheng Zeng, Jin Zhang, Jinye Xie, Gang Shen, Jinhong Wang, Zhenzhen Fang, Weiwei Qi, Xia Yang, Guoquan Gao, Ti Zhou.
      Retinal fibrosis is a severe pathological change in the late stage of diabetic retinopathy and is also the leading cause of blindness. We have previously revealed that N-cadherin was significantly increased in type 1 and type 2 diabetic mice retinas and the fibrovascular membranes from proliferative diabetic retinopathy (PDR) patients. However, whether N-cadherin directly induces retinal fibrosis in DR and the related mechanism is unknown. Here, we investigated the pathogenic role of N-cadherin in mediating retinal fibrosis and further explored the relevant therapeutic targets. We found that the level of N-cadherin was significantly increased in PDR patients and STZ-induced diabetic mice and positively correlated with the fibrotic molecules Connective Tissue Growth Factor (CTGF) and fibronectin (FN). Moreover, intravitreal injection of N-cadherin adenovirus significantly increased the expression of FN and CTGF in normal mice retinas. Mechanistically, overexpression of N-cadherin promotes N-cadherin cleavage, and N-cadherin cleavage can further induce translocation of non-p-β-catenin in the nucleus and upregulation of fibrotic molecules. Furthermore, we found a novel N-cadherin cleavage inhibitor, pigment epithelial-derived factor (PEDF), which ameliorated the N-cadherin cleavage and subsequent retinal fibrosis in diabetic mice. Thus, our findings provide novel evidence that elevated N-cadherin level not only acts as a classic EMT maker but also plays a causative role in diabetic retinal fibrosis, and targeting N-cadherin cleavage may provide a strategy to inhibit retinal fibrosis in DR patients.
    Keywords:  CTF2; N-cadherin cleavage; connective tissue growth factor (CTGF); diabetic retinopathy (DR); retinal fibrosis; β-Catenin
    DOI:  https://doi.org/10.1096/fj.202201664RR
  36. Nat Commun. 2023 Mar 18. 14(1): 1521
    Acute liver steatosis translationally controls the epigenetic regulator MIER1 to promote liver regeneration in a study with male mice.
    Yanhao Chen, Lanlan Chen, Xiaoshan Wu, Yongxu Zhao, Yuchen Wang, Dacheng Jiang, Xiaojian Liu, Tingting Zhou, Shuang Li, Yuda Wei, Yan Liu, Cheng Hu, Ben Zhou, Jun Qin, Hao Ying, Qiurong Ding.
      The early phase lipid accumulation is essential for liver regeneration. However, whether this acute lipid accumulation can serve as signals to direct liver regeneration rather than simply providing building blocks for cell proliferation remains unclear. Through in vivo CRISPR screening, we identify MIER1 (mesoderm induction early response 1) as a key epigenetic regulator that bridges the acute lipid accumulation and cell cycle gene expression during liver regeneration in male animals. Physiologically, liver acute lipid accumulation induces the phosphorylation of EIF2S1(eukaryotic translation initiation factor 2), which consequently attenuated Mier1 translation. MIER1 downregulation in turn promotes cell cycle gene expression and regeneration through chromatin remodeling. Importantly, the lipids-EIF2S1-MIER1 pathway is impaired in animals with chronic liver steatosis; whereas MIER1 depletion significantly improves regeneration in these animals. Taken together, our studies identify an epigenetic mechanism by which the early phase lipid redistribution from adipose tissue to liver during regeneration impacts hepatocyte proliferation, and suggest a potential strategy to boost liver regeneration.
    DOI:  https://doi.org/10.1038/s41467-023-37247-9
  37. Cell Death Dis. 2023 Mar 22. 14(3): 206
    Blocking dPerk in the intestine suppresses neurodegeneration in a Drosophila model of Parkinson's disease.
    Rebeka Popovic, Amrita Mukherjee, Nuno Santos Leal, Lydia Morris, Yizhou Yu, Samantha H Y Loh, L Miguel Martins.
      Parkinson's disease (PD) is characterised by selective death of dopaminergic (DA) neurons in the midbrain and motor function impairment. Gastrointestinal issues often precede motor deficits in PD, indicating that the gut-brain axis is involved in the pathogenesis of this disease. The features of PD include both mitochondrial dysfunction and activation of the unfolded protein response (UPR) in the endoplasmic reticulum (ER). PINK1 is a mitochondrial kinase involved in the recycling of defective mitochondria, and PINK1 mutations cause early-onset PD. Like PD patients, pink1 mutant Drosophila show degeneration of DA neurons and intestinal dysfunction. These mutant flies also lack vital proteins due to sustained activation of the kinase R-like endoplasmic reticulum kinase (dPerk), a kinase that induces the UPR. Here, we investigated the role of dPerk in intestinal dysfunction. We showed that intestinal expression of dPerk impairs mitochondrial function, induces cell death, and decreases lifespan. We found that suppressing dPerk in the intestine of pink1-mutant flies rescues intestinal cell death and is neuroprotective. We conclude that in a fly model of PD, blocking gut-brain transmission of UPR-mediated toxicity, is neuroprotective.
    DOI:  https://doi.org/10.1038/s41419-023-05729-9
  38. Nat Commun. 2023 Mar 22. 14(1): 1572
    Interoperable slide microscopy viewer and annotation tool for imaging data science and computational pathology.
    Chris Gorman, Davide Punzo, Igor Octaviano, Steven Pieper, William J R Longabaugh, David A Clunie, Ron Kikinis, Andrey Y Fedorov, Markus D Herrmann.
      The exchange of large and complex slide microscopy imaging data in biomedical research and pathology practice is impeded by a lack of data standardization and interoperability, which is detrimental to the reproducibility of scientific findings and clinical integration of technological innovations. We introduce Slim, an open-source, web-based slide microscopy viewer that implements the internationally accepted Digital Imaging and Communications in Medicine (DICOM) standard to achieve interoperability with a multitude of existing medical imaging systems. We showcase the capabilities of Slim as the slide microscopy viewer of the NCI Imaging Data Commons and demonstrate how the viewer enables interactive visualization of traditional brightfield microscopy and highly-multiplexed immunofluorescence microscopy images from The Cancer Genome Atlas and Human Tissue Atlas Network, respectively, using standard DICOMweb services. We further show how Slim enables the collection of standardized image annotations for the development or validation of machine learning models and the visual interpretation of model inference results in the form of segmentation masks, spatial heat maps, or image-derived measurements.
    DOI:  https://doi.org/10.1038/s41467-023-37224-2
  39. Nat Commun. 2023 Mar 22. 14(1): 1596
    Insights into receptor structure and dynamics at the surface of living cells.
    Frederik Steiert, Peter Schultz, Siegfried Höfinger, Thomas D Müller, Petra Schwille, Thomas Weidemann.
      Evaluating protein structures in living cells remains a challenge. Here, we investigate Interleukin-4 receptor alpha (IL-4Rα) into which the non-canonical amino acid bicyclo[6.1.0]nonyne-lysine (BCNK) is incorporated by genetic code expansion. Bioorthogonal click labeling is performed with tetrazine-conjugated dyes. To quantify the reaction yield in situ, we develop brightness-calibrated ratiometric imaging, a protocol where fluorescent signals in confocal multi-color images are ascribed to local concentrations. Screening receptor mutants bearing BCNK in the extracellular domain uncovered site-specific variations of both click efficiency and Interleukin-4 binding affinity, indicating subtle well-defined structural perturbations. Molecular dynamics and continuum electrostatics calculations suggest solvent polarization to determine site-specific variations of BCNK reactivity. Strikingly, signatures of differential click efficiency, measured for IL-4Rα in ligand-bound and free form, mirror sub-angstrom deformations of the protein backbone at corresponding locations. Thus, click efficiency by itself represents a remarkably informative readout linked to protein structure and dynamics in the native plasma membrane.
    DOI:  https://doi.org/10.1038/s41467-023-37284-4
  40. Cell Rep Med. 2023 Mar 21. pii: S2666-3791(23)00089-7. [Epub ahead of print]4(3): 100983
    Translating from mouse to man to better understand immune-mediated inflammatory diseases.
    Dominik Aschenbrenner, Richard M Siegel.
      Lilja et al.1 explore single-cell transcriptomes across multiple organs of mice with collagen-induced arthritis. They apply network analysis to prioritize functional pathways that support or suppress inflammation and integrate findings with tissue transcriptomics in human immune-mediated inflammatory diseases.
    DOI:  https://doi.org/10.1016/j.xcrm.2023.100983
  41. Hum Genet. 2023 Mar 19.
    Toward a comprehensive catalog of regulatory elements.
    Kaili Fan, Edith Pfister, Zhiping Weng.
      Regulatory elements are the genomic regions that interact with transcription factors to control cell-type-specific gene expression in different cellular environments. A precise and complete catalog of functional elements encoded by the human genome is key to understanding mammalian gene regulation. Here, we review the current state of regulatory element annotation. We first provide an overview of assays for characterizing functional elements, including genome, epigenome, transcriptome, three-dimensional chromatin interaction, and functional validation assays. We then discuss computational methods for defining regulatory elements, including peak-calling and other statistical modeling methods. Finally, we introduce several high-quality lists of regulatory element annotations and suggest potential future directions.
    DOI:  https://doi.org/10.1007/s00439-023-02519-3
  42. Nature. 2023 Mar;615(7953): 576-579
    Bats play host to a horde of nasty viruses - can studying their immunity help stop pandemics?
    Smriti Mallapaty.
      
    Keywords:  Animal behaviour; Immunology; SARS-CoV-2
    DOI:  https://doi.org/10.1038/d41586-023-00791-x
  43. Nat Immunol. 2023 Mar 23.
    Fate-mapping antibodies to study sinful immune dynamics.
    Joshua J C McGrath, Patrick C Wilson.
      
    DOI:  https://doi.org/10.1038/s41590-023-01467-4
  44. Nat Metab. 2023 Mar 23.
    Loss of fatty acid degradation by astrocytic mitochondria triggers neuroinflammation and neurodegeneration.
    Yashi Mi, Guoyuan Qi, Francesca Vitali, Yuan Shang, Adam C Raikes, Tian Wang, Yan Jin, Roberta D Brinton, Haiwei Gu, Fei Yin.
      Astrocytes provide key neuronal support, and their phenotypic transformation is implicated in neurodegenerative diseases. Metabolically, astrocytes possess low mitochondrial oxidative phosphorylation (OxPhos) activity, but its pathophysiological role in neurodegeneration remains unclear. Here, we show that the brain critically depends on astrocytic OxPhos to degrade fatty acids (FAs) and maintain lipid homeostasis. Aberrant astrocytic OxPhos induces lipid droplet (LD) accumulation followed by neurodegeneration that recapitulates key features of Alzheimer's disease (AD), including synaptic loss, neuroinflammation, demyelination and cognitive impairment. Mechanistically, when FA load overwhelms astrocytic OxPhos capacity, elevated acetyl-CoA levels induce astrocyte reactivity by enhancing STAT3 acetylation and activation. Intercellularly, lipid-laden reactive astrocytes stimulate neuronal FA oxidation and oxidative stress, activate microglia through IL-3 signalling, and inhibit the biosynthesis of FAs and phospholipids required for myelin replenishment. Along with LD accumulation and impaired FA degradation manifested in an AD mouse model, we reveal a lipid-centric, AD-resembling mechanism by which astrocytic mitochondrial dysfunction progressively induces neuroinflammation and neurodegeneration.
    DOI:  https://doi.org/10.1038/s42255-023-00756-4
  45. J Cell Sci. 2023 Mar 21. pii: jcs.260049. [Epub ahead of print]
    SLC25A46 promotes mitochondrial fission and mediates resistance to lipotoxic stress in INS-1E insulin secreting cells.
    Jaime Santo-Domingo, Steve Lassueur, Antonio Núñez Galindo, Pilar Alvarez-Illera, Silvia Romero-Sanz, Elena Caldero-Escudero, Sergio de la Fuente, Loïc Dayon, Andreas Wiederkehr.
      Glucose sensing in pancreatic beta-cells depends on oxidative phosphorylation and mitochondria-derived signals that promote insulin secretion. Using mass spectrometry-based phosphoproteomics to search for down-stream effectors of glucose dependent signal transduction in INS-1E insulinoma cells, we identified the outer mitochondrial membrane protein SLC25A46. Under resting glucose concentrations, SLC25A46 was phosphorylated on a pair of threonine residues (T44/T45) and was dephosphorylated in response to glucose-induced calcium signals. Overexpression of SLC25A46 in INS-1E cells caused complete mitochondrial fragmentation, resulting in a mild mitochondrial defect associated with lowered glucose-induced insulin secretion. In contrast, inactivation of the SLC25A46 gene resulted in dramatic mitochondrial hyperfusion but without affecting respiratory activity or insulin secretion. Consequently, SLC25A46 is not essential for metabolism-secretion coupling under normal nutrient conditions. Importantly, insulin secreting cells lacking SLC25A46 had an exacerbated sensitivity to lipotoxic conditions undergoing massive apoptosis when exposed to palmitate. Therefore, in addition to its role in mitochondrial dynamics, SLC25A46 plays a role in preventing mitochondria-induced apoptosis in INS-E cells exposed to nutrient stress. By protecting mitochondria, SLC25A46 may help to maintain beta-cell mass essential for blood glucose control.
    Keywords:  Beta-cell; Mitochondria; Mitochondrial dynamics
    DOI:  https://doi.org/10.1242/jcs.260049
  46. Cell Rep. 2023 Mar 22. pii: S2211-1247(23)00316-9. [Epub ahead of print]42(4): 112305
    Bacteriophage antidefense genes that neutralize TIR and STING immune responses.
    Peiyin Ho, Yibu Chen, Subarna Biswas, Ethan Canfield, Alireza Abdolvahabi, Douglas E Feldman.
      Programmed cell suicide of infected bacteria, known as abortive infection (Abi), serves as an immune defense strategy to prevent the propagation of bacteriophage viruses. Many Abi systems utilize bespoke cyclic nucleotide immune messengers generated upon infection to mobilize cognate death effectors. Here, we identify a family of bacteriophage nucleotidyltransferases (NTases) that synthesize competitor cyclic dinucleotide (CDN) ligands and inhibit TIR NADase effectors activated via a linked STING CDN sensor domain (TIR-STING). Through a functional screen of NTase-adjacent phage genes, we uncover candidate inhibitors of cell suicide induced by heterologous expression of tonically active TIR-STING. Among these, we demonstrate that a virus MazG-like nucleotide pyrophosphohydrolase, Atd1, depletes the starvation alarmone (p)ppGpp, revealing a potential role for the alarmone-activated host toxin MazF as an executioner of TIR-driven Abi. Phage NTases and counterdefenses like Atd1 preserve host viability to ensure virus propagation and represent tools to modulate TIR and STING immune responses.
    Keywords:  CP: Immunology; CP: Microbiology
    DOI:  https://doi.org/10.1016/j.celrep.2023.112305
  47. Cell Genom. 2023 Mar 08. 3(3): 100264
    A unifying statistical framework to discover disease genes from GWASs.
    Justin N J McManus, Robert J Lovelett, Daniel Lowengrub, Sarah Christensen.
      Genome-wide association studies (GWASs) identify genomic loci associated with complex traits, but it remains a challenge to identify the genes affected by causal genetic variants in these loci. Attempts to solve this challenge are frustrated by a number of compounding problems. Here, we show how to combine solutions to these problems into a unified mathematical framework. From this synthesis, it becomes possible to compute the probability that each gene in the genome is affected by a causal variant, given a particular trait, without making assumptions about the relevant cell types or tissues. We validate each component of the framework individually and in combination. When applied to large GWASs of human disease, the resulting paradigm can rediscover the majority of well-known disease genes. Moreover, it establishes human genetics support for many genes previously implicated only by clinical or preclinical evidence, and it uncovers a plethora of novel disease genes with compelling biological rationale.
    Keywords:  DNase I hypersensitive sites; causal genes; drug discovery; enhancers; functional genomics; genome-wide association study; linkage disequilibrium; statistical fine-mapping
    DOI:  https://doi.org/10.1016/j.xgen.2023.100264
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