bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022–08–21
25 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues.
  2. Spatiotemporal single-cell regulatory atlas reveals neural crest lineage diversification and cellular function during tooth morphogenesis.
  3. Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses.
  4. Multiscale light-sheet organoid imaging framework.
  5. Endocytosis in the axon initial segment maintains neuronal polarity.
  6. Spatial profiling of chromatin accessibility in mouse and human tissues.
  7. Post-translational control of beige fat biogenesis by PRDM16 stabilization.
  8. Carbon source availability drives nutrient utilization in CD8+ T cells.
  9. Piperazine-derived lipid nanoparticles deliver mRNA to immune cells in vivo.
  10. ABCA1 is an extracellular phospholipid translocase.
  11. MYB orchestrates T cell exhaustion and response to checkpoint inhibition.
  12. Scent of a human: The mosquito olfactory system defies dogma to ensure attraction to humans.
  13. The mitochondrial calcium uniporter engages UCP1 to form a thermoporter that promotes thermogenesis.
  14. Rapid evolution of mutation rate and spectrum in response to environmental and population-genetic challenges.
  15. Circular EZH2-encoded EZH2-92aa mediates immune evasion in glioblastoma via inhibition of surface NKG2D ligands.
  16. Integrated multi-omics reveals cellular and molecular interactions governing the invasive niche of basal cell carcinoma.
  17. Succinate uptake by T cells suppresses their effector function via inhibition of mitochondrial glucose oxidation.
  18. TBK1-mTOR Signaling Attenuates Obesity-Linked Hyperglycemia and Insulin Resistance.
  19. High-dimensional investigation of the cerebrospinal fluid to explore and monitor CNS immune responses.
  20. MicroRNA-regulated B cells in obesity.
  21. Scientists isolate the genes that shape the human pelvis.
  22. The evolving role of tissue-resident memory T cells in infections and cancer.
  23. RNA-Editing Enzyme ADAR1 p150 Isoform Is Critical for Germinal Center B Cell Response.
  24. Intrinsic cell rheology drives junction maturation.
  25. Centriole signaling restricts hepatocyte ploidy to maintain liver integrity.
  1. Nat Commun. 2022 Aug 16. 13(1): 4827
    A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues.
    Dominik Saul, Robyn Laura Kosinsky, Elizabeth J Atkinson, Madison L Doolittle, Xu Zhang, Nathan K LeBrasseur, Robert J Pignolo, Paul D Robbins, Laura J Niedernhofer, Yuji Ikeno, Diana Jurk, João F Passos, LaTonya J Hickson, Ailing Xue, David G Monroe, Tamara Tchkonia, James L Kirkland, Joshua N Farr, Sundeep Khosla.
      Although cellular senescence drives multiple age-related co-morbidities through the senescence-associated secretory phenotype, in vivo senescent cell identification remains challenging. Here, we generate a gene set (SenMayo) and validate its enrichment in bone biopsies from two aged human cohorts. We further demonstrate reductions in SenMayo in bone following genetic clearance of senescent cells in mice and in adipose tissue from humans following pharmacological senescent cell clearance. We next use SenMayo to identify senescent hematopoietic or mesenchymal cells at the single cell level from human and murine bone marrow/bone scRNA-seq data. Thus, SenMayo identifies senescent cells across tissues and species with high fidelity. Using this senescence panel, we are able to characterize senescent cells at the single cell level and identify key intercellular signaling pathways. SenMayo also represents a potentially clinically applicable panel for monitoring senescent cell burden with aging and other conditions as well as in studies of senolytic drugs.
    DOI:  https://doi.org/10.1038/s41467-022-32552-1
  2. Nat Commun. 2022 Aug 16. 13(1): 4803
    Spatiotemporal single-cell regulatory atlas reveals neural crest lineage diversification and cellular function during tooth morphogenesis.
    Junjun Jing, Jifan Feng, Yuan Yuan, Tingwei Guo, Jie Lei, Fei Pei, Thach-Vu Ho, Yang Chai.
      Cranial neural crest cells are an evolutionary innovation of vertebrates for craniofacial development and function, yet the mechanisms that govern the cell fate decisions of postmigratory cranial neural crest cells remain largely unknown. Using the mouse molar as a model, we perform single-cell transcriptome profiling to interrogate the cell fate diversification of postmigratory cranial neural crest cells. We reveal the landscape of transcriptional heterogeneity and define the specific cellular domains during the progression of cranial neural crest cell-derived dental lineage diversification, and find that each domain makes a specific contribution to distinct molar mesenchymal tissues. Furthermore, IGF signaling-mediated cell-cell interaction between the cellular domains highlights the pivotal role of autonomous regulation of the dental mesenchyme. Importantly, we reveal cell-type-specific gene regulatory networks in the dental mesenchyme and show that Foxp4 is indispensable for the differentiation of periodontal ligament. Our single-cell atlas provides comprehensive mechanistic insight into the cell fate diversification process of the cranial neural crest cell-derived odontogenic populations.
    DOI:  https://doi.org/10.1038/s41467-022-32490-y
  3. Nat Commun. 2022 Aug 15. 13(1): 4728
    Chimeric GPCRs mimic distinct signaling pathways and modulate microglia responses.
    Rouven Schulz, Medina Korkut-Demirbaş, Alessandro Venturino, Gloria Colombo, Sandra Siegert.
      G protein-coupled receptors (GPCRs) regulate processes ranging from immune responses to neuronal signaling. However, ligands for many GPCRs remain unknown, suffer from off-target effects or have poor bioavailability. Additionally, dissecting cell type-specific responses is challenging when the same GPCR is expressed on different cells within a tissue. Here, we overcome these limitations by engineering DREADD-based GPCR chimeras that bind clozapine-N-oxide and mimic a GPCR-of-interest. We show that chimeric DREADD-β2AR triggers responses comparable to β2AR on second messenger and kinase activity, post-translational modifications, and protein-protein interactions. Moreover, we successfully recapitulate β2AR-mediated filopodia formation in microglia, an immune cell capable of driving central nervous system inflammation. When dissecting microglial inflammation, we included two additional DREADD-based chimeras mimicking microglia-enriched GPR65 and GPR109A. DREADD-β2AR and DREADD-GPR65 modulate the inflammatory response with high similarity to endogenous β2AR, while DREADD-GPR109A shows no impact. Our DREADD-based approach allows investigation of cell type-dependent pathways without known endogenous ligands.
    DOI:  https://doi.org/10.1038/s41467-022-32390-1
  4. Nat Commun. 2022 Aug 18. 13(1): 4864
    Multiscale light-sheet organoid imaging framework.
    Gustavo de Medeiros, Raphael Ortiz, Petr Strnad, Andrea Boni, Franziska Moos, Nicole Repina, Ludivine Challet Meylan, Francisca Maurer, Prisca Liberali.
      Organoids provide an accessible in vitro system to mimic the dynamics of tissue regeneration and development. However, long-term live-imaging of organoids remains challenging. Here we present an experimental and image-processing framework capable of turning long-term light-sheet imaging of intestinal organoids into digital organoids. The framework combines specific imaging optimization combined with data processing via deep learning techniques to segment single organoids, their lumen, cells and nuclei in 3D over long periods of time. By linking lineage trees with corresponding 3D segmentation meshes for each organoid, the extracted information is visualized using a web-based "Digital Organoid Viewer" tool allowing combined understanding of the multivariate and multiscale data. We also show backtracking of cells of interest, providing detailed information about their history within entire organoid contexts. Furthermore, we show cytokinesis failure of regenerative cells and that these cells never reside in the intestinal crypt, hinting at a tissue scale control on cellular fidelity.
    DOI:  https://doi.org/10.1038/s41467-022-32465-z
  5. Nature. 2022 Aug 17.
    Endocytosis in the axon initial segment maintains neuronal polarity.
    Kelsie Eichel, Takeshi Uenaka, Vivek Belapurkar, Rui Lu, Shouqiang Cheng, Joseph S Pak, Caitlin A Taylor, Thomas C Südhof, Robert Malenka, Marius Wernig, Engin Özkan, David Perrais, Kang Shen.
      Neurons are highly polarized cells that face the fundamental challenge of compartmentalizing a vast and diverse repertoire of proteins in order to function properly1. The axon initial segment (AIS) is a specialized domain that separates a neuron's morphologically, biochemically and functionally distinct axon and dendrite compartments2,3. How the AIS maintains polarity between these compartments is not fully understood. Here we find that in Caenorhabditis elegans, mouse, rat and human neurons, dendritically and axonally polarized transmembrane proteins are recognized by endocytic machinery in the AIS, robustly endocytosed and targeted to late endosomes for degradation. Forcing receptor interaction with the AIS master organizer, ankyrinG, antagonizes receptor endocytosis in the AIS, causes receptor accumulation in the AIS, and leads to polarity deficits with subsequent morphological and behavioural defects. Therefore, endocytic removal of polarized receptors that diffuse into the AIS serves as a membrane-clearance mechanism that is likely to work in conjunction with the known AIS diffusion-barrier mechanism to maintain neuronal polarity on the plasma membrane. Our results reveal a conserved endocytic clearance mechanism in the AIS to maintain neuronal polarity by reinforcing axonal and dendritic compartment membrane boundaries.
    DOI:  https://doi.org/10.1038/s41586-022-05074-5
  6. Nature. 2022 Aug 17.
    Spatial profiling of chromatin accessibility in mouse and human tissues.
    Yanxiang Deng, Marek Bartosovic, Sai Ma, Di Zhang, Petra Kukanja, Yang Xiao, Graham Su, Yang Liu, Xiaoyu Qin, Gorazd B Rosoklija, Andrew J Dwork, J John Mann, Mina L Xu, Stephanie Halene, Joseph E Craft, Kam W Leong, Maura Boldrini, Gonçalo Castelo-Branco, Rong Fan.
      Cellular function in tissue is dependent on the local environment, requiring new methods for spatial mapping of biomolecules and cells in the tissue context1. The emergence of spatial transcriptomics has enabled genome-scale gene expression mapping2-5, but the ability to capture spatial epigenetic information of tissue at the cellular level and genome scale is lacking. Here we describe a method for spatially resolved chromatin accessibility profiling of tissue sections using next-generation sequencing (spatial-ATAC-seq) by combining in situ Tn5 transposition chemistry6 and microfluidic deterministic barcoding5. Profiling mouse embryos using spatial-ATAC-seq delineated tissue-region-specific epigenetic landscapes and identified gene regulators involved in the development of the central nervous system. Mapping the accessible genome in the mouse and human brain revealed the intricate arealization of brain regions. Applying spatial-ATAC-seq to tonsil tissue resolved the spatially distinct organization of immune cell types and states in lymphoid follicles and extrafollicular zones. This technology progresses spatial biology by enabling spatially resolved chromatin accessibility profiling to improve our understanding of cell identity, cell state and cell fate decision in relation to epigenetic underpinnings in development and disease.
    DOI:  https://doi.org/10.1038/s41586-022-05094-1
  7. Nature. 2022 Aug 17.
    Post-translational control of beige fat biogenesis by PRDM16 stabilization.
    Qiang Wang, Huixia Li, Kazuki Tajima, Anthony R P Verkerke, Zachary H Taxin, Zhishuai Hou, Joanne B Cole, Fei Li, Jake Wong, Ichitaro Abe, Rachana N Pradhan, Tadashi Yamamuro, Takeshi Yoneshiro, Joel N Hirschhorn, Shingo Kajimura.
      Compelling evidence shows that brown and beige adipose tissue are protective against metabolic diseases1,2. PR domain-containing 16 (PRDM16) is a dominant activator of the biogenesis of beige adipocytes by forming a complex with transcriptional and epigenetic factors and is therefore an attractive target for improving metabolic health3-8. However, a lack of knowledge surrounding the regulation of PRDM16 protein expression hampered us from selectively targeting this transcriptional pathway. Here we identify CUL2-APPBP2 as the ubiquitin E3 ligase that determines PRDM16 protein stability by catalysing its polyubiquitination. Inhibition of CUL2-APPBP2 sufficiently extended the half-life of PRDM16 protein and promoted beige adipocyte biogenesis. By contrast, elevated CUL2-APPBP2 expression was found in aged adipose tissues and repressed adipocyte thermogenesis by degrading PRDM16 protein. Importantly, extended PRDM16 protein stability by adipocyte-specific deletion of CUL2-APPBP2 counteracted diet-induced obesity, glucose intolerance, insulin resistance and dyslipidaemia in mice. These results offer a cell-autonomous route to selectively activate the PRDM16 pathway in adipose tissues.
    DOI:  https://doi.org/10.1038/s41586-022-05067-4
  8. Cell Metab. 2022 Aug 11. pii: S1550-4131(22)00311-4. [Epub ahead of print]
    Carbon source availability drives nutrient utilization in CD8+ T cells.
    Irem Kaymak, Katarzyna M Luda, Lauren R Duimstra, Eric H Ma, Joseph Longo, Michael S Dahabieh, Brandon Faubert, Brandon M Oswald, McLane J Watson, Susan M Kitchen-Goosen, Lisa M DeCamp, Shelby E Compton, Zhen Fu, Ralph J DeBerardinis, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.
      How environmental nutrient availability impacts T cell metabolism and function remains poorly understood. Here, we report that the presence of physiologic carbon sources (PCSs) in cell culture medium broadly impacts glucose utilization by CD8+ T cells, independent of transcriptional changes in metabolic reprogramming. The presence of PCSs reduced glucose contribution to the TCA cycle and increased effector function of CD8+ T cells, with lactate directly fueling the TCA cycle. In fact, CD8+ T cells responding to Listeria infection preferentially consumed lactate over glucose as a TCA cycle substrate in vitro, with lactate enhancing T cell bioenergetic and biosynthetic capacity. Inhibiting lactate-dependent metabolism in CD8+ T cells by silencing lactate dehydrogenase A (Ldha) impaired both T cell metabolic homeostasis and proliferative expansion in vivo. Together, our data indicate that carbon source availability shapes T cell glucose metabolism and identifies lactate as a bioenergetic and biosynthetic fuel for CD8+ effector T cells.
    Keywords:  (13)C tracing; T cells; TCA cycle; immunometabolism; lactate; metabolic programming; metabolomics
    DOI:  https://doi.org/10.1016/j.cmet.2022.07.012
  9. Nat Commun. 2022 Aug 15. 13(1): 4766
    Piperazine-derived lipid nanoparticles deliver mRNA to immune cells in vivo.
    Huanzhen Ni, Marine Z C Hatit, Kun Zhao, David Loughrey, Melissa P Lokugamage, Hannah E Peck, Ada Del Cid, Abinaya Muralidharan, YongTae Kim, Philip J Santangelo, James E Dahlman.
      In humans, lipid nanoparticles (LNPs) have safely delivered therapeutic RNA to hepatocytes after systemic administration and to antigen-presenting cells after intramuscular injection. However, systemic RNA delivery to non-hepatocytes remains challenging, especially without targeting ligands such as antibodies, peptides, or aptamers. Here we report that piperazine-containing ionizable lipids (Pi-Lipids) preferentially deliver mRNA to immune cells in vivo without targeting ligands. After synthesizing and characterizing Pi-Lipids, we use high-throughput DNA barcoding to quantify how 65 chemically distinct LNPs functionally delivered mRNA (i.e., mRNA translated into functional, gene-editing protein) in 14 cell types directly in vivo. By analyzing the relationships between lipid structure and cellular targeting, we identify lipid traits that increase delivery in vivo. In addition, we characterize Pi-A10, an LNP that preferentially delivers mRNA to the liver and splenic immune cells at the clinically relevant dose of 0.3 mg/kg. These data demonstrate that high-throughput in vivo studies can identify nanoparticles with natural non-hepatocyte tropism and support the hypothesis that lipids with bioactive small-molecule motifs can deliver mRNA in vivo.
    DOI:  https://doi.org/10.1038/s41467-022-32281-5
  10. Nat Commun. 2022 Aug 16. 13(1): 4812
    ABCA1 is an extracellular phospholipid translocase.
    Jere P Segrest, Chongren Tang, Hyun D Song, Martin K Jones, W Sean Davidson, Stephen G Aller, Jay W Heinecke.
      Production of high density lipoprotein (HDL) requires ATP-binding cassette transporter A1 (ABCA1) to drive phospholipid (PL) from the plasma membrane into extracellular apolipoprotein A-I. Here, we use simulations to show that domains of ABCA1 within the plasma membrane remove PL from the membrane's outer leaflet. In our simulations, after the lipid diffuses into the interior of ABCA1's outward-open cavity, PL extracted by the gateway passes through a ring-shaped domain, the annulus orifice, which forms the base of an elongated hydrophobic tunnel in the transporter's extracellular domain. Engineered mutations in the gateway and annulus strongly inhibit lipid export by ABCA1 without affecting cell-surface expression levels. Our finding that ABCA1 extracts lipid from the outer face of the plasma membrane and forces it through its gateway and annulus into an elongated hydrophobic tunnel contrasts with the alternating access model, which proposes that ABCA1 flops PL substrate from the inner leaflet to the outer leaflet of the membrane. Consistent with our model, ABCA1 lacks the charged amino acid residues in the transmembrane domain found in the floppase members of the ABC transporter family.
    DOI:  https://doi.org/10.1038/s41467-022-32437-3
  11. Nature. 2022 Aug 17.
    MYB orchestrates T cell exhaustion and response to checkpoint inhibition.
    Carlson Tsui, Lorenz Kretschmer, Svenja Rapelius, Sarah S Gabriel, David Chisanga, Konrad Knöpper, Daniel T Utzschneider, Simone Nüssing, Yang Liao, Teisha Mason, Santiago Valle Torres, Stephen A Wilcox, Krystian Kanev, Sebastian Jarosch, Justin Leube, Stephen L Nutt, Dietmar Zehn, Ian A Parish, Wolfgang Kastenmüller, Wei Shi, Veit R Buchholz, Axel Kallies.
      CD8+ T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality-which is referred to as T cell exhaustion1,2-is maintained by precursors of exhausted T (TPEX) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1- exhausted effector T cells3-6. Here we show that the long-term proliferative potential, multipotency and repopulation capacity of exhausted T cells during chronic infection are selectively preserved in a small population of transcriptionally distinct CD62L+ TPEX cells. The transcription factor MYB is not only essential for the development of CD62L+ TPEX cells and maintenance of the antiviral CD8+ T cell response, but also induces functional exhaustion and thereby prevents lethal immunopathology. Furthermore, the proliferative burst in response to PD-1 checkpoint inhibition originates exclusively from CD62L+ TPEX cells and depends on MYB. Our findings identify CD62L+ TPEX cells as a stem-like population that is central to the maintenance of long-term antiviral immunity and responsiveness to immunotherapy. Moreover, they show that MYB is a transcriptional orchestrator of two fundamental aspects of exhausted T cell responses: the downregulation of effector function and the long-term preservation of self-renewal capacity.
    DOI:  https://doi.org/10.1038/s41586-022-05105-1
  12. Cell. 2022 Aug 18. pii: S0092-8674(22)00921-7. [Epub ahead of print]185(17): 3079-3081
    Scent of a human: The mosquito olfactory system defies dogma to ensure attraction to humans.
    Colleen N McLaughlin, Liqun Luo.
      Mosquitoes are strongly attracted to humans, and their bites not only cause intense itch but can beget severe diseases. In this issue of Cell, Herre et al. reveal that non-canonical olfactory circuit organization and coding likely endow mosquitoes with a robust ability to locate human hosts.
    DOI:  https://doi.org/10.1016/j.cell.2022.07.018
  13. Cell Metab. 2022 Aug 11. pii: S1550-4131(22)00310-2. [Epub ahead of print]
    The mitochondrial calcium uniporter engages UCP1 to form a thermoporter that promotes thermogenesis.
    Kaili Xue, Dongmei Wu, Yushuang Wang, Yiheng Zhao, Hongyu Shen, Jingfei Yao, Xun Huang, Xinmeng Li, Zhao Zhou, Zihao Wang, Yifu Qiu.
      Uncoupling protein 1 (UCP1)-mediated adaptive thermogenesis protects mammals against hypothermia and metabolic dysregulation. Whether and how mitochondrial calcium regulates this process remains unclear. Here, we show that mitochondrial calcium uniporter (MCU) recruits UCP1 through essential MCU regulator (EMRE) to form an MCU-EMRE-UCP1 complex upon adrenergic stimulation. This complex formation increases mitochondrial calcium uptake to accelerate the tricarboxylic acid cycle and supply more protons that promote uncoupled respiration, functioning as a thermogenic uniporter. Mitochondrial calcium uptake 1 (MICU1) negatively regulates thermogenesis probably through inhibiting thermogenic uniporter formation. Accordingly, the deletion of Mcu or Emre in brown adipocytes markedly impairs thermogenesis and exacerbates obesity and metabolic dysfunction. Remarkably, the enhanced assembly of the thermogenic uniporter via Micu1 knockout or expressing linked EMRE-UCP1 results in opposite phenotypes. Thus, we have uncovered a "thermoporter" that provides a driving force for the UCP1 operation in thermogenesis, which could be leveraged to combat obesity and associated metabolic disorders.
    Keywords:  UCP1; brown adipose tissue; metabolic dysfunction; mitochondrial calcium uniporter; obesity; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2022.07.011
  14. Nat Commun. 2022 Aug 13. 13(1): 4752
    Rapid evolution of mutation rate and spectrum in response to environmental and population-genetic challenges.
    Wen Wei, Wei-Chin Ho, Megan G Behringer, Samuel F Miller, George Bcharah, Michael Lynch.
      Ecological and demographic factors can significantly shape the evolution of microbial populations both directly and indirectly, as when changes in the effective population size affect the efficiency of natural selection on the mutation rate. However, it remains unclear how rapidly the mutation-rate responds evolutionarily to the entanglement of ecological and population-genetic factors over time. Here, we directly assess the mutation rate and spectrum of Escherichia coli clones isolated from populations evolving in response to 1000 days of different transfer volumes and resource-replenishment intervals. The evolution of mutation rates proceeded rapidly in response to demographic and/or environmental changes, with substantial bidirectional shifts observed as early as 59 generations. These results highlight the remarkable rapidity by which mutation rates are shaped in asexual lineages in response to environmental and population-genetic forces, and are broadly consistent with the drift-barrier hypothesis for the evolution of mutation rates, while also highlighting situations in which mutator genotypes may be promoted by positive selection.
    DOI:  https://doi.org/10.1038/s41467-022-32353-6
  15. Nat Commun. 2022 Aug 15. 13(1): 4795
    Circular EZH2-encoded EZH2-92aa mediates immune evasion in glioblastoma via inhibition of surface NKG2D ligands.
    Jian Zhong, Xuesong Yang, Junju Chen, Kejun He, Xinya Gao, Xujia Wu, Maolei Zhang, Huangkai Zhou, Feizhe Xiao, Lele An, Xiuxing Wang, Yu Shi, Nu Zhang.
      Glioblastoma (GBM) is a highly aggressive primary brain tumour and is resistant to nearly all available treatments, including natural killer (NK) cell immunotherapy. However, the factors mediating NK cell evasion in GBM remain largely unclear. Here, we report that EZH2-92aa, a protein encoded by circular EZH2, is overexpressed in GBM and induces the immune evasion of GBM stem cells (GSCs) from NK cells. Positively regulated by DEAD-box helicase 3 (DDX3), EZH2-92aa directly binds the major histocompatibility complex class I polypeptide-related sequence A/B (MICA/B) promoters and represses their transcription; it also indirectly represses UL16-binding protein (ULBP) transcription by stabilizing EZH2. The downregulation of NK group 2D ligands (NKG2DLs, including MICA/B and ULBPs) in GSCs mediates NK cell resistance. Moreover, stable EZH2-92aa knockdown enhances NK cell-mediated GSC eradication in vitro and in vivo and synergizes with anti-PD1 therapy. Our results highlight the immunosuppressive function of EZH2-92aa in inhibiting the NK cell response in GBM and the clinical potential of targeting EZH2-92aa for NK-cell-directed immune therapy.
    DOI:  https://doi.org/10.1038/s41467-022-32311-2
  16. Nat Commun. 2022 Aug 20. 13(1): 4897
    Integrated multi-omics reveals cellular and molecular interactions governing the invasive niche of basal cell carcinoma.
    Laura Yerly, Christine Pich-Bavastro, Jeremy Di Domizio, Tania Wyss, Stéphanie Tissot-Renaud, Michael Cangkrama, Michel Gilliet, Sabine Werner, François Kuonen.
      Tumors invade the surrounding tissues to progress, but the heterogeneity of cell types at the tumor-stroma interface and the complexity of their potential interactions hampered mechanistic insight required for efficient therapeutic targeting. Here, combining single-cell and spatial transcriptomics on human basal cell carcinomas, we define the cellular contributors of tumor progression. In the invasive niche, tumor cells exhibit a collective migration phenotype, characterized by the expression of cell-cell junction complexes. In physical proximity, we identify cancer-associated fibroblasts with extracellular matrix-remodeling features. Tumor cells strongly express the cytokine Activin A, and increased Activin A-induced gene signature is found in adjacent cancer-associated fibroblast subpopulations. Altogether, our data identify the cell populations and their transcriptional reprogramming contributing to the spatial organization of the basal cell carcinoma invasive niche. They also demonstrate the power of integrated spatial and single-cell multi-omics to decipher cancer-specific invasive properties and develop targeted therapies.
    DOI:  https://doi.org/10.1038/s41467-022-32670-w
  17. Cell Rep. 2022 Aug 16. pii: S2211-1247(22)01010-5. [Epub ahead of print]40(7): 111193
    Succinate uptake by T cells suppresses their effector function via inhibition of mitochondrial glucose oxidation.
    Nancy Gudgeon, Haydn Munford, Emma L Bishop, James Hill, Taylor Fulton-Ward, David Bending, Jennie Roberts, Daniel A Tennant, Sarah Dimeloe.
      Succinate dehydrogenase (SDH) loss-of-function mutations drive succinate accumulation in tumor microenvironments, for example in the neuroendocrine tumors pheochromocytoma (PC) and paraganglioma (PG). Control of innate immune cell activity by succinate is described, but effects on T cells have not been interrogated. Here we report that exposure of human CD4+ and CD8+ T cells to tumor-associated succinate concentrations suppresses degranulation and cytokine secretion, including of the key anti-tumor cytokine interferon-γ (IFN-γ). Mechanistically, this is associated with succinate uptake-partly via the monocarboxylate transporter 1 (MCT1)-inhibition of succinyl coenzyme A synthetase activity and impaired glucose flux through the tricarboxylic acid cycle. Consistently, pharmacological and genetic interventions restoring glucose oxidation rescue T cell function. Tumor RNA-sequencing data from patients with PC and PG reveal profound suppression of IFN-γ-induced genes in SDH-deficient tumors compared with those with other mutations, supporting a role for succinate in modulating the anti-tumor immune response in vivo.
    Keywords:  CP: immunology; CP: metabolism; T cell; metabolism; metabolite; succinate; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2022.111193
  18. Diabetes. 2022 Aug 19. pii: db220256. [Epub ahead of print]
    TBK1-mTOR Signaling Attenuates Obesity-Linked Hyperglycemia and Insulin Resistance.
    Cagri Bodur, Dubek Kazyken, Kezhen Huang, Aaron Seth Tooley, Kae Won Cho, Tammy M Barnes, Carey N Lumeng, Martin G Myers, Diane C Fingar.
      The innate immune kinase TBK1 (TANK-binding kinase 1) responds to microbial-derived signals to initiate responses against viral and bacterial pathogens. More recent work implicates TBK1 in metabolism and tumorigenesis. The kinase mTOR (mechanistic target of rapamycin) integrates diverse environmental cues to control fundamental cellular processes. Our prior work demonstrated in cells that TBK1 phosphorylates mTOR (on S2159) to increase mTORC1 and mTORC2 catalytic activity and signaling. Here we investigate a role for TBK1-mTOR signaling in control of glucose metabolism in vivo. We find that diet induced obese (DIO) but not lean mice bearing a whole-body "TBK1 resistant" Mtor S2159A knockin allele (MtorA/A) display exacerbated hyperglycemia and systemic insulin resistance with no change in energy balance. Mechanistically, Mtor S2159A knockin in DIO mice reduces mTORC1 and mTORC2 signaling in response to insulin and innate immune agonists, reduces anti-inflammatory gene expression in adipose tissue, and blunts anti-inflammatory macrophage M2 polarization, phenotypes shared by mice with tissue-specific inactivation of TBK1 or mTOR complexes. Tissues from DIO mice display elevated TBK1 activity and mTOR S2159 phosphorylation relative to lean mice. We propose a model whereby obesity-associated signals increase TBK1 activity and mTOR phosphorylation, which boosts mTORC1 and mTORC2 signaling in parallel to the insulin pathway, thereby attenuating insulin resistance to improve glycemic control during diet-induced obesity.
    DOI:  https://doi.org/10.2337/db22-0256
  19. Genome Med. 2022 Aug 17. 14(1): 94
    High-dimensional investigation of the cerebrospinal fluid to explore and monitor CNS immune responses.
    Michael Heming, Anna-Lena Börsch, Heinz Wiendl, Gerd Meyer Zu Hörste.
      The cerebrospinal fluid (CSF) features a unique immune cell composition and is in constant contact with the brain borders, thus permitting insights into the brain to diagnose and monitor diseases. Recently, the meninges, which are filled with CSF, were identified as a neuroimmunological interface, highlighting the potential of exploring central nervous system (CNS) immunity by studying CNS border compartments. Here, we summarize how single-cell transcriptomics of such border compartments advance our understanding of neurological diseases, the challenges that remain, and what opportunities novel multi-omic methods offer. Single-cell transcriptomics studies have detected cytotoxic CD4+ T cells and clonally expanded T and B cells in the CSF in the autoimmune disease multiple sclerosis; clonally expanded pathogenic CD8+ T cells were found in the CSF and in the brain adjacent to β-amyloid plaques of dementia patients; in patients with brain metastases, CD8+ T cell clonotypes were shared between the brain parenchyma and the CSF and persisted after therapy. We also outline how novel multi-omic approaches permit the simultaneous measurements of gene expression, chromatin accessibility, and protein in the same cells, which remain to be explored in the CSF. This calls for multicenter initiatives to create single-cell atlases, posing challenges in integrating patients and modalities across centers. While high-dimensional analyses of CSF cells are challenging, they hold potential for personalized medicine by better resolving heterogeneous diseases and stratifying patients.
    Keywords:  Alzheimer’s disease; Brain metastases; COVID-19; Cerebrospinal fluid; Multiple sclerosis; Parkinson’s disease; Single-cell atlas; Single-cell transcriptomics
    DOI:  https://doi.org/10.1186/s13073-022-01097-9
  20. Immunometabolism (Cobham). 2022 Jul;4(3): e00005
    MicroRNA-regulated B cells in obesity.
    Alyssa J Matz, Lili Qu, Keaton Karlinsey, Beiyan Zhou.
      Obesity is a prevalent health risk by inducing chronic, low-grade inflammation and insulin resistance, in part from adipose tissue inflammation perpetuated by activated B cells and other resident immune cells. However, regulatory mechanisms controlling B-cell actions in adipose tissue remain poorly understood, limiting therapeutic innovations. MicroRNAs are potent regulators of immune cell dynamics through fine-tuning a network of downstream genes in multiple signaling pathways. In particular, miR-150 is crucial to B-cell development and suppresses obesity-associated inflammation via regulating adipose tissue B-cell function. Herein, we review the effect of microRNAs on B-cell development, activation, and function and highlight miR-150-regulated B-cell actions during obesity which modulate systemic inflammation and insulin resistance. In this way, we hope to promote translational discoveries that mitigate obesity-induced health risks by targeting microRNA-regulated B-cell actions.
    Keywords:  B cell; adipose tissue; microRNA; obesity
    DOI:  https://doi.org/10.1097/IN9.0000000000000005
  21. Science. 2022 Aug 19. 377(6608): 802
    Scientists isolate the genes that shape the human pelvis.
    Michael Price.
      Embryonic tissue samples reveal how pelvis shape-primed for bipedalism-comes to life.
    DOI:  https://doi.org/10.1126/science.ade4426
  22. Sci Adv. 2022 Aug 19. 8(33): eabo5871
    The evolving role of tissue-resident memory T cells in infections and cancer.
    Sasitorn Yenyuwadee, Jose Luis Sanchez-Trincado Lopez, Rushil Shah, Pamela C Rosato, Vassiliki A Boussiotis.
      Resident memory T cells (TRM) form a distinct type of T memory cells that stably resides in tissues. TRM form an integral part of the immune sensing network and have the ability to control local immune homeostasis and participate in immune responses mediated by pathogens, cancer, and possibly autoantigens during autoimmunity. TRM express residence gene signatures, functional properties of both memory and effector cells, and remarkable plasticity. TRM have a well-established role in pathogen immunity, whereas their role in antitumor immune responses and immunotherapy is currently evolving. As TRM form the most abundant T memory cell population in nonlymphoid tissues, they are attractive targets for therapeutic exploitation. Here, we provide a concise review of the development and physiological role of CD8+ TRM, their involvement in diseases, and their potential therapeutic exploitation.
    DOI:  https://doi.org/10.1126/sciadv.abo5871
  23. J Immunol. 2022 Aug 17. pii: ji2200149. [Epub ahead of print]
    RNA-Editing Enzyme ADAR1 p150 Isoform Is Critical for Germinal Center B Cell Response.
    Yuxing Li, Gui-Xin Ruan, Wenjing Chen, Hengjun Huang, Rui Zhang, Jing Wang, Yan Li, Shengli Xu, Xijun Ou.
      Adenosine deaminase acting on RNA (ADAR)1 is the principal enzyme for adenosine-to-inosine editing, an RNA modification-avoiding cytosolic nucleic acid sensor's activation triggered by endogenous dsRNAs. Two ADAR1 isoforms exist in mammals, a longer IFN-inducible and mainly cytoplasm-localized p150 isoform and a shorter constitutively expressed and primarily nucleus-localized p110 isoform. Studies of ADAR1 mutant mice have demonstrated that ADAR1 is essential for multiple physiological processes, including embryonic development, innate immune response, and B and T lymphocyte development. However, it remained unknown whether ADAR1 plays a role in the humoral immune response. In this study, we conditionally delete Adar1 in activated B cells and show that ADAR1-deficient mice have a defective T cell-dependent Ab response and diminished germinal center (GC) B cells. Using various double mutant mice concurrently deficient in ADAR1 and different downstream dsRNA sensors, we demonstrate that ADAR1 regulates the GC response by preventing hyperactivation of the melanoma differentiation-associated protein 5 (MDA5) but not the protein kinase R or RNase L pathway. We also show that p150 is exclusively responsible for ADAR1's function in the GC response, and the p110 isoform cannot substitute for the p150's role, even when p110 is constitutively expressed in the cytoplasm. We further demonstrated that the dsRNA-binding but not the RNA-editing activity is required for ADAR1's function in the GC response. Thus, our data suggest that the ADAR1 p150 isoform plays a crucial role in regulating the GC B cell response.
    DOI:  https://doi.org/10.4049/jimmunol.2200149
  24. Nat Commun. 2022 Aug 17. 13(1): 4832
    Intrinsic cell rheology drives junction maturation.
    K Sri-Ranjan, J L Sanchez-Alonso, P Swiatlowska, S Rothery, P Novak, S Gerlach, D Koeninger, B Hoffmann, R Merkel, M M Stevens, S X Sun, J Gorelik, Vania M M Braga.
      A fundamental property of higher eukaryotes that underpins their evolutionary success is stable cell-cell cohesion. Yet, how intrinsic cell rheology and stiffness contributes to junction stabilization and maturation is poorly understood. We demonstrate that localized modulation of cell rheology governs the transition of a slack, undulated cell-cell contact (weak adhesion) to a mature, straight junction (optimal adhesion). Cell pairs confined on different geometries have heterogeneous elasticity maps and control their own intrinsic rheology co-ordinately. More compliant cell pairs grown on circles have slack contacts, while stiffer triangular cell pairs favour straight junctions with flanking contractile thin bundles. Counter-intuitively, straighter cell-cell contacts have reduced receptor density and less dynamic junctional actin, suggesting an unusual adaptive mechano-response to stabilize cell-cell adhesion. Our modelling informs that slack junctions arise from failure of circular cell pairs to increase their own intrinsic stiffness and resist the pressures from the neighbouring cell. The inability to form a straight junction can be reversed by increasing mechanical stress artificially on stiffer substrates. Our data inform on the minimal intrinsic rheology to generate a mature junction and provide a springboard towards understanding elements governing tissue-level mechanics.
    DOI:  https://doi.org/10.1038/s41467-022-32102-9
  25. Genes Dev. 2022 Aug 18.
    Centriole signaling restricts hepatocyte ploidy to maintain liver integrity.
    Valentina C Sladky, Hanan Akbari, Daniel Tapias-Gomez, Lauren T Evans, Chelsea G Drown, Margaret A Strong, Gina M LoMastro, Tatianna Larman, Andrew J Holland.
      Hepatocyte polyploidization is a tightly controlled process that is initiated at weaning and increases with age. The proliferation of polyploid hepatocytes in vivo is restricted by the PIDDosome-P53 axis, but how this pathway is triggered remains unclear. Given that increased hepatocyte ploidy protects against malignant transformation, the evolutionary driver that sets the upper limit for hepatocyte ploidy remains unknown. Here we show that hepatocytes accumulate centrioles during cycles of polyploidization in vivo. The presence of excess mature centrioles containing ANKRD26 was required to activate the PIDDosome in polyploid cells. As a result, mice lacking centrioles in the liver or ANKRD26 exhibited increased hepatocyte ploidy. Under normal homeostatic conditions, this increase in liver ploidy did not impact organ function. However, in response to chronic liver injury, blocking centriole-mediated ploidy control leads to a massive increase in hepatocyte polyploidization, severe liver damage, and impaired liver function. These results show that hyperpolyploidization sensitizes the liver to injury, posing a trade-off for the cancer-protective effect of increased hepatocyte ploidy. Our results may have important implications for unscheduled polyploidization that frequently occurs in human patients with chronic liver disease.
    Keywords:  ANKRD26; PIDDosome; TP53; centrioles; distal appendage; liver; polyploidy
    DOI:  https://doi.org/10.1101/gad.349727.122
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