bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2023–02–05
57 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. The value of applied science.
  2. HERV1-env Induces Unfolded Protein Response Activation in Autoimmune Liver Disease: A Potential Mechanism for Regulatory T Cell Dysfunction.
  3. Dendritic cell--biased precursors support early human thymopoiesis.
  4. Host-microbe co-metabolism via MCAD generates circulating metabolites including hippuric acid.
  5. Enhancing CAR-T cell functionality in a patient-specific manner.
  6. AMPK-dependent phosphorylation of the GATOR2 component WDR24 suppresses glucose-mediated mTORC1 activation.
  7. Phosphoinositide acyl chain saturation drives CD8+ effector T cell signaling and function.
  8. Adipose-specific deletion of the cation channel TRPM7 inhibits TAK1 kinase-dependent inflammation and obesity in male mice.
  9. Top Reads.
  10. B1 SINE-binding ZFP266 impedes mouse iPSC generation through suppression of chromatin opening mediated by reprogramming factors.
  11. Distributed harmonic patterns of structure-function dependence orchestrate human consciousness.
  12. Cardiolipin coordinates inflammatory metabolic reprogramming through regulation of Complex II disassembly and degradation.
  13. Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure.
  14. Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea in diabetes.
  15. Age-dependent nuclear lipid droplet deposition is a cellular hallmark of aging in Caenorhabditis elegans.
  16. Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer.
  17. Increased levels of endogenous retroviruses trigger fibroinflammation and play a role in kidney disease development.
  18. Integrative in situ mapping of single-cell transcriptional states and tissue histopathology in a mouse model of Alzheimer's disease.
  19. FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism in C. elegans.
  20. Epigenetic signals that direct cell type-specific interferon beta response in mouse cells.
  21. A spatiotemporal complexity architecture of human brain activity.
  22. Glycolysis regulates KRAS plasma membrane localization and function through defined glycosphingolipids.
  23. Germline T cell receptor exchange results in physiological T cell development and function.
  24. Estimation of cell lineages in tumors from spatial transcriptomics data.
  25. A split ribozyme that links detection of a native RNA to orthogonal protein outputs.
  26. Biologically informed deep learning to query gene programs in single-cell atlases.
  27. FTO-dependent m6A modification of Plpp3 in circSCMH1-regulated vascular repair and functional recovery following stroke.
  28. Dogma-defying bacteria package DNA in unusual ways.
  29. Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy.
  30. The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system.
  31. CD8 T cells are forever.
  32. Endothelial cell-derived oxysterol ablation attenuates experimental autoimmune encephalomyelitis.
  33. Lipid-induced transcriptomic changes in blood link to lipid metabolism and allergic response.
  34. Next-Generation Morphometry for pathomics-data mining in histopathology.
  35. Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria.
  36. Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata.
  37. Sharing GWAS summary statistics results in more citations.
  38. Actin-driven chromosome clustering facilitates fast and complete chromosome capture in mammalian oocytes.
  39. Distinctive transcriptomic and epigenomic signatures of bone marrow-derived myeloid cells and microglia in CNS autoimmunity.
  40. RNA disruption is a widespread phenomenon associated with stress-induced cell death in tumour cells.
  41. Neutrophil CEACAM1 determines susceptibility to NETosis by regulating the S1PR2/S1PR3 axis in liver transplantation.
  42. Phagocytosis in the retina promotes local insulin production in the eye.
  43. When IL-17 gets on your nerves.
  44. A two-faced selectivity solution to target SMARCA2 for cancer therapy.
  45. How quickly does COVID immunity fade? What scientists know.
  46. A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation resulting in pro-metastatic NF-κB signaling.
  47. Spermine enhances antiviral and anticancer responses by stabilizing DNA binding with the DNA sensor cGAS.
  48. CCPG1 recognizes ER luminal proteins for selective ER-phagy.
  49. Human-specific genetics: new tools to explore the molecular and cellular basis of human evolution.
  50. Atlas of plasma NMR biomarkers for health and disease in 118,461 individuals from the UK Biobank.
  51. Unlocking life-threatening COVID-19 through two types of inborn errors of type I IFNs.
  52. Influence of circadian clocks on adaptive immunity and vaccination responses.
  53. The function and evolution of a genetic switch controlling sexually dimorphic eye differentiation in honeybees.
  54. G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma.
  55. Immunologic prediction of long COVID.
  56. Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress.
  57. RNA binding protein DDX5 restricts RORγt+ Treg suppressor function to promote intestine inflammation.
  1. Nat Commun. 2023 Feb 03. 14(1): 587
    The value of applied science.
      
    DOI:  https://doi.org/10.1038/s41467-023-36307-4
  2. J Immunol. 2023 Feb 01. pii: ji2100186. [Epub ahead of print]
    HERV1-env Induces Unfolded Protein Response Activation in Autoimmune Liver Disease: A Potential Mechanism for Regulatory T Cell Dysfunction.
    Kumar Subramanian, Saikat Paul, Andrew Libby, Jordan Patterson, Adam Arterbery, James Knight, Christopher Castaldi, Guilin Wang, Yaron Avitzur, Mercedes Martinez, Steve Lobritto, Yanhong Deng, Gan Geliang, Alexander Kroemer, Thomas Fishbein, Andrew Mason, Margarita Dominguez-Villar, Malaiyalam Mariappan, Udeme D Ekong.
      Regulatory T cells (Tregs) are not terminally differentiated but can acquire effector properties. Here we report an increased expression of human endogenous retrovirus 1 (HERV1-env) proteins in Tregs of patients with de novo autoimmune hepatitis and autoimmune hepatitis, which induces endoplasmic reticulum (ER) stress. HERV1-env-triggered ER stress activates all three branches (IRE1, ATF6, and PERK) of the unfolded protein response (UPR). Our coimmunoprecipitation studies show an interaction between HERV1-env proteins and the ATF6 branch of the UPR. The activated form of ATF6α activates the expression of RORC and STAT3 by binding to promoter sequences and induces IL-17A production. Silencing of HERV1-env results in recovery of Treg suppressive function. These findings identify ER stress and UPR activation as key factors driving Treg plasticity (species: human).
    DOI:  https://doi.org/10.4049/jimmunol.2100186
  3. Nat Immunol. 2023 Feb 03.
    Dendritic cell--biased precursors support early human thymopoiesis.
      
    DOI:  https://doi.org/10.1038/s41590-023-01421-4
  4. Nat Commun. 2023 Jan 31. 14(1): 512
    Host-microbe co-metabolism via MCAD generates circulating metabolites including hippuric acid.
    Kali M Pruss, Haoqing Chen, Yuanyuan Liu, William Van Treuren, Steven K Higginbottom, John B Jarman, Curt R Fischer, Justin Mak, Beverly Wong, Tina M Cowan, Michael A Fischbach, Justin L Sonnenburg, Dylan Dodd.
      The human gut microbiota produces dozens of small molecules that circulate in blood, accumulate to comparable levels as pharmaceutical drugs, and influence host physiology. Despite the importance of these metabolites to human health and disease, the origin of most microbially-produced molecules and their fate in the host remains largely unknown. Here, we uncover a host-microbe co-metabolic pathway for generation of hippuric acid, one of the most abundant organic acids in mammalian urine. Combining stable isotope tracing with bacterial and host genetics, we demonstrate reduction of phenylalanine to phenylpropionic acid by gut bacteria; the host re-oxidizes phenylpropionic acid involving medium-chain acyl-CoA dehydrogenase (MCAD). Generation of germ-free male and female MCAD-/- mice enabled gnotobiotic colonization combined with untargeted metabolomics to identify additional microbial metabolites processed by MCAD in host circulation. Our findings uncover a host-microbe pathway for the abundant, non-toxic phenylalanine metabolite hippurate and identify β-oxidation via MCAD as a novel mechanism by which mammals metabolize microbiota-derived metabolites.
    DOI:  https://doi.org/10.1038/s41467-023-36138-3
  5. Nat Commun. 2023 Jan 31. 14(1): 506
    Enhancing CAR-T cell functionality in a patient-specific manner.
    David K Y Zhang, Kwasi Adu-Berchie, Siddharth Iyer, Yutong Liu, Nicoletta Cieri, Joshua M Brockman, Donna Neuberg, Catherine J Wu, David J Mooney.
      Patient responses to autologous CD19 chimeric antigen receptor (CAR) T-cell therapies are limited by insufficient and inconsistent cellular functionality. Here, we show that controlling the precise level of stimulation during T-cell activation to accommodate individual differences in the donor cells will dictate the functional attributes of CAR-T cell products. The functionality of CAR-T cell products, consisting of a diverse set of blood samples derived from healthy donors, acute lymphoblastic leukemia (ALL), and chronic lymphocytic lymphoma (CLL) patient samples, representing a range of patient health status, is tested upon culturing on artificial antigen-presenting cell scaffolds to deliver T-cell stimulatory ligands (anti-CD3/anti-CD28) at highly defined densities. A clear relationship is observed between the dose of stimulation, the phenotype of the T-cell blood sample prior to T-cell activation, and the functionality of the resulting CAR-T cell products. We present a model, based on this dataset, that predicts the precise stimulation needed to manufacture a desired CAR-T cell product, given the input T-cell attributes in the initial blood sample. These findings demonstrate a simple approach to enhance CAR-T functionality by personalizing the level of stimulation during T-cell activation to enable flexible manufacturing of more consistent and potent CAR-T cells.
    DOI:  https://doi.org/10.1038/s41467-023-36126-7
  6. Nat Metab. 2023 Feb 02.
    AMPK-dependent phosphorylation of the GATOR2 component WDR24 suppresses glucose-mediated mTORC1 activation.
    Xiaoming Dai, Cong Jiang, Qiwei Jiang, Lan Fang, Haihong Yu, Jinhe Guo, Peiqiang Yan, Fangtao Chi, Tao Zhang, Hiroyuki Inuzuka, John M Asara, Ping Wang, Jianping Guo, Wenyi Wei.
      The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth in response to amino acid and glucose levels. However, how mTORC1 senses glucose availability to regulate various downstream signalling pathways remains largely elusive. Here we report that AMP-activated protein kinase (AMPK)-mediated phosphorylation of WDR24, a core component of the GATOR2 complex, has a role in the glucose-sensing capability of mTORC1. Mechanistically, glucose deprivation activates AMPK, which directly phosphorylates WDR24 on S155, subsequently disrupting the integrity of the GATOR2 complex to suppress mTORC1 activation. Phosphomimetic Wdr24S155D knock-in mice exhibit early embryonic lethality and reduced mTORC1 activity. On the other hand, compared to wild-type littermates, phospho-deficient Wdr24S155A knock-in mice are more resistant to fasting and display elevated mTORC1 activity. Our findings reveal that AMPK-mediated phosphorylation of WDR24 modulates glucose-induced mTORC1 activation, thereby providing a rationale for targeting AMPK-WDR24 signalling to fine-tune mTORC1 activation as a potential therapeutic means to combat human diseases with aberrant activation of mTORC1 signalling including cancer.
    DOI:  https://doi.org/10.1038/s42255-022-00732-4
  7. Nat Immunol. 2023 Feb 02.
    Phosphoinositide acyl chain saturation drives CD8+ effector T cell signaling and function.
    Joy Edwards-Hicks, Petya Apostolova, Joerg M Buescher, Hannes Maib, Michal A Stanczak, Mauro Corrado, Ramon I Klein Geltink, Maria Elena Maccari, Matteo Villa, Gustavo E Carrizo, David E Sanin, Francesc Baixauli, Beth Kelly, Jonathan D Curtis, Fabian Haessler, Annette Patterson, Cameron S Field, George Caputa, Ryan L Kyle, Melanie Soballa, Minsun Cha, Harry Paul, Jacob Martin, Katarzyna M Grzes, Lea Flachsmann, Michael Mitterer, Liang Zhao, Frances Winkler, David Ali Rafei-Shamsabadi, Frank Meiss, Bertram Bengsch, Robert Zeiser, Daniel J Puleston, David O'Sullivan, Edward J Pearce, Erika L Pearce.
      How lipidome changes support CD8+ effector T (Teff) cell differentiation is not well understood. Here we show that, although naive T cells are rich in polyunsaturated phosphoinositides (PIPn with 3-4 double bonds), Teff cells have unique PIPn marked by saturated fatty acyl chains (0-2 double bonds). PIPn are precursors for second messengers. Polyunsaturated phosphatidylinositol bisphosphate (PIP2) exclusively supported signaling immediately upon T cell antigen receptor activation. In late Teff cells, activity of phospholipase C-γ1, the enzyme that cleaves PIP2 into downstream mediators, waned, and saturated PIPn became essential for sustained signaling. Saturated PIP was more rapidly converted to PIP2 with subsequent recruitment of phospholipase C-γ1, and loss of saturated PIPn impaired Teff cell fitness and function, even in cells with abundant polyunsaturated PIPn. Glucose was the substrate for de novo PIPn synthesis, and was rapidly utilized for saturated PIP2 generation. Thus, separate PIPn pools with distinct acyl chain compositions and metabolic dependencies drive important signaling events to initiate and then sustain effector function during CD8+ T cell differentiation.
    DOI:  https://doi.org/10.1038/s41590-023-01419-y
  8. Nat Commun. 2023 Jan 30. 14(1): 491
    Adipose-specific deletion of the cation channel TRPM7 inhibits TAK1 kinase-dependent inflammation and obesity in male mice.
    Weiting Zhong, Mingming Ma, Jingwen Xie, Chengcui Huang, Xiaoyan Li, Min Gao.
      Chronic inflammation of white adipose tissue is a key link between obesity and the associated metabolic syndrome. Transient receptor potential melastatin-like 7 (TRPM7) is known to be related to inflammation; however, the role of TRPM7 in adipocyte phenotype and function in obesity remains unclear. Here, we observe that the activation of adipocyte TRPM7 plays an essential role in pro-inflammatory responses. Adult male mice are used in our experiments. Adipocyte-specific deficiency in TRPM7 attenuates the pro-inflammatory phenotype, improves glucose homeostasis, and suppresses weight gain in mice fed a high-fat diet. Mechanistically, the pro-inflammatory effect of TRPM7 is dependent on Ca2+ signaling. Ca2+ influx initiated by TRPM7 enhances transforming growth factor-β activated kinase 1 activation via the co-regulation of calcium/calmodulin-dependent protein kinase II and tumor necrosis factor receptor-associated factor 6, leading to exacerbated nuclear factor kappa B signaling. Additionally, obese mice treated with TRPM7 inhibitor are protected against obesity and insulin resistance. Our results demonstrate TRPM7 as a factor in the development of adipose inflammation that regulates insulin sensitivity in obesity.
    DOI:  https://doi.org/10.1038/s41467-023-36154-3
  9. J Immunol. 2023 Feb 15. 210(4): 357-358
    Top Reads.
      
    DOI:  https://doi.org/10.4049/jimmunol.2290028
  10. Nat Commun. 2023 Jan 30. 14(1): 488
    B1 SINE-binding ZFP266 impedes mouse iPSC generation through suppression of chromatin opening mediated by reprogramming factors.
    Daniel F Kaemena, Masahito Yoshihara, Meryam Beniazza, James Ashmore, Suling Zhao, Mårten Bertenstam, Victor Olariu, Shintaro Katayama, Keisuke Okita, Simon R Tomlinson, Kosuke Yusa, Keisuke Kaji.
      Induced pluripotent stem cell (iPSC) reprogramming is inefficient and understanding the molecular mechanisms underlying this inefficiency holds the key to successfully control cellular identity. Here, we report 24 reprogramming roadblock genes identified by CRISPR/Cas9-mediated genome-wide knockout (KO) screening. Of these, depletion of the predicted KRAB zinc finger protein (KRAB-ZFP) Zfp266 strongly and consistently enhances murine iPSC generation in several reprogramming settings, emerging as the most robust roadblock. We show that ZFP266 binds Short Interspersed Nuclear Elements (SINEs) adjacent to binding sites of pioneering factors, OCT4 (POU5F1), SOX2, and KLF4, and impedes chromatin opening. Replacing the KRAB co-suppressor with co-activator domains converts ZFP266 from an inhibitor to a potent facilitator of iPSC reprogramming. We propose that the SINE-KRAB-ZFP interaction is a critical regulator of chromatin accessibility at regulatory elements required for efficient cellular identity changes. In addition, this work serves as a resource to further illuminate molecular mechanisms hindering reprogramming.
    DOI:  https://doi.org/10.1038/s41467-023-36097-9
  11. Commun Biol. 2023 Jan 28. 6(1): 117
    Distributed harmonic patterns of structure-function dependence orchestrate human consciousness.
    Andrea I Luppi, Jakub Vohryzek, Morten L Kringelbach, Pedro A M Mediano, Michael M Craig, Ram Adapa, Robin L Carhart-Harris, Leor Roseman, Ioannis Pappas, Alexander R D Peattie, Anne E Manktelow, Barbara J Sahakian, Paola Finoia, Guy B Williams, Judith Allanson, John D Pickard, David K Menon, Selen Atasoy, Emmanuel A Stamatakis.
      A central question in neuroscience is how consciousness arises from the dynamic interplay of brain structure and function. Here we decompose functional MRI signals from pathological and pharmacologically-induced perturbations of consciousness into distributed patterns of structure-function dependence across scales: the harmonic modes of the human structural connectome. We show that structure-function coupling is a generalisable indicator of consciousness that is under bi-directional neuromodulatory control. We find increased structure-function coupling across scales during loss of consciousness, whether due to anaesthesia or brain injury, capable of discriminating between behaviourally indistinguishable sub-categories of brain-injured patients, tracking the presence of covert consciousness. The opposite harmonic signature characterises the altered state induced by LSD or ketamine, reflecting psychedelic-induced decoupling of brain function from structure and correlating with physiological and subjective scores. Overall, connectome harmonic decomposition reveals how neuromodulation and the network architecture of the human connectome jointly shape consciousness and distributed functional activation across scales.
    DOI:  https://doi.org/10.1038/s42003-023-04474-1
  12. Sci Adv. 2023 Feb 03. 9(5): eade8701
    Cardiolipin coordinates inflammatory metabolic reprogramming through regulation of Complex II disassembly and degradation.
    Mack B Reynolds, Hanna S Hong, Britton C Michmerhuizen, Anna-Lisa E Lawrence, Li Zhang, Jason S Knight, Costas A Lyssiotis, Basel H Abuaita, Mary X O'Riordan.
      Macrophage metabolic plasticity enables repurposing of electron transport from energy generation to inflammation and host defense. Altered respiratory complex II function has been implicated in cancer, diabetes, and inflammation, but regulatory mechanisms are incompletely understood. Here, we show that macrophage inflammatory activation triggers Complex II disassembly and succinate dehydrogenase subunit B loss through sequestration and selective mitophagy. Mitochondrial fission supported lipopolysaccharide-stimulated succinate dehydrogenase subunit B degradation but not sequestration. We hypothesized that this Complex II regulatory mechanism might be coordinated by the mitochondrial phospholipid cardiolipin. Cardiolipin synthase knockdown prevented lipopolysaccharide-induced metabolic remodeling and Complex II disassembly, sequestration, and degradation. Cardiolipin-depleted macrophages were defective in lipopolysaccharide-induced pro-inflammatory cytokine production, a phenotype partially rescued by Complex II inhibition. Thus, cardiolipin acts as a critical organizer of inflammatory metabolic remodeling.
    DOI:  https://doi.org/10.1126/sciadv.ade8701
  13. Nat Commun. 2023 Feb 02. 14(1): 558
    Genetic and pharmacologic inhibition of ALDH1A3 as a treatment of β-cell failure.
    Jinsook Son, Wen Du, Mark Esposito, Kaavian Shariati, Hongxu Ding, Yibin Kang, Domenico Accili.
      Type 2 diabetes (T2D) is associated with β-cell dedifferentiation. Aldehyde dehydrogenase 1 isoform A3 (ALHD1A3) is a marker of β-cell dedifferentiation and correlates with T2D progression. However, it is unknown whether ALDH1A3 activity contributes to β-cell failure, and whether the decrease of ALDH1A3-positive β-cells (A+) following pair-feeding of diabetic animals is due to β-cell restoration. To tackle these questions, we (i) investigated the fate of A+ cells during pair-feeding by lineage-tracing, (ii) somatically ablated ALDH1A3 in diabetic β-cells, and (iii) used a novel selective ALDH1A3 inhibitor to treat diabetes. Lineage tracing and functional characterization show that A+ cells can be reconverted to functional, mature β-cells. Genetic or pharmacological inhibition of ALDH1A3 in diabetic mice lowers glycemia and increases insulin secretion. Characterization of β-cells following ALDH1A3 inhibition shows reactivation of differentiation as well as regeneration pathways. We conclude that ALDH1A3 inhibition offers a therapeutic strategy against β-cell dysfunction in diabetes.
    DOI:  https://doi.org/10.1038/s41467-023-36315-4
  14. Sci Transl Med. 2023 Feb;15(681): eabq4126
    Cyb5r3-based mechanism and reversal of secondary failure to sulfonylurea in diabetes.
    Hitoshi Watanabe, Wen Du, Jinsook Son, Lina Sui, Shun-Ichiro Asahara, Irwin J Kurland, Taiyi Kuo, Takumi Kitamoto, Yasutaka Miyachi, Rafael de Cabo, Domenico Accili.
      Sulfonylureas (SUs) are effective and affordable antidiabetic drugs. However, chronic use leads to secondary failure, limiting their utilization. Here, we identify cytochrome b5 reductase 3 (Cyb5r3) down-regulation as a mechanism of secondary SU failure and successfully reverse it. Chronic exposure to SU lowered Cyb5r3 abundance and reduced islet glucose utilization in mice in vivo and in ex vivo murine islets. Cyb5r3 β cell-specific knockout mice phenocopied SU failure. Cyb5r3 engaged in a glucose-dependent interaction that stabilizes glucokinase (Gck) to maintain glucose utilization. Hence, Gck activators can circumvent Cyb5r3-dependent SU failure. A Cyb5r3 activator rescued secondary SU failure in mice in vivo and restored insulin secretion in ex vivo human islets. We conclude that Cyb5r3 is a key factor in the secondary failure to SU and a potential target for its prevention, which might rehabilitate SU use in diabetes.
    DOI:  https://doi.org/10.1126/scitranslmed.abq4126
  15. Aging Cell. 2023 Jan 31. e13788
    Age-dependent nuclear lipid droplet deposition is a cellular hallmark of aging in Caenorhabditis elegans.
    Konstantinos Palikaras, Meropi Mari, Christina Ploumi, Andrea Princz, George Filippidis, Nektarios Tavernarakis.
      Aging is the major risk factor for several life-threatening pathologies and impairs the function of multiple cellular compartments and organelles. Age-dependent deterioration of nuclear morphology is a common feature in evolutionarily divergent organisms. Lipid droplets have been shown to localize in most nuclear compartments, where they impinge on genome architecture and integrity. However, the significance of progressive nuclear lipid accumulation and its impact on organismal homeostasis remain obscure. Here, we implement non-linear imaging modalities to monitor and quantify age-dependent nuclear lipid deposition in Caenorhabditis elegans. We find that lipid droplets increasingly accumulate in the nuclear envelope, during aging. Longevity-promoting interventions, such as low insulin signaling and caloric restriction, abolish the rate of nuclear lipid accrual and decrease the size of lipid droplets. Suppression of lipotoxic lipid accumulation in hypodermal and intestinal nuclei is dependent on the transcription factor HLH-30/TFEB and the triglyceride lipase ATGL-1. HLH-30 regulates the expression of ATGL-1 to reduce nuclear lipid droplet abundance in response to lifespan-extending conditions. Notably, ATGL-1 localizes to the nuclear envelope and moderates lipid content in long-lived mutant nematodes during aging. Our findings indicate that the reduced ATGL-1 activity leads to excessive nuclear lipid accumulation, perturbing nuclear homeostasis and undermining organismal physiology, during aging.
    Keywords:  ATGL-1; HLH-30/TFEB; aging; lipid droplet; non-linear optical phenomena; nucleus
    DOI:  https://doi.org/10.1111/acel.13788
  16. Immunity. 2023 Jan 26. pii: S1074-7613(23)00020-1. [Epub ahead of print]
    Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer.
    Maria Zagorulya, Leon Yim, Duncan M Morgan, Austin Edwards, Elen Torres-Mejia, Noor Momin, Chloe V McCreery, Izabella L Zamora, Brendan L Horton, James G Fox, K Dane Wittrup, J Christopher Love, Stefani Spranger.
      Local environmental factors influence CD8+ T cell priming in lymph nodes (LNs). Here, we sought to understand how factors unique to the tumor-draining mediastinal LN (mLN) impact CD8+ T cell responses toward lung cancer. Type 1 conventional dendritic cells (DC1s) showed a mLN-specific failure to induce robust cytotoxic T cells responses. Using regulatory T (Treg) cell depletion strategies, we found that Treg cells suppressed DC1s in a spatially coordinated manner within tissue-specific microniches within the mLN. Treg cell suppression required MHC II-dependent contact between DC1s and Treg cells. Elevated levels of IFN-γ drove differentiation Treg cells into Th1-like effector Treg cells in the mLN. In patients with cancer, Treg cell Th1 polarization, but not CD8+/Treg cell ratios, correlated with poor responses to checkpoint blockade immunotherapy. Thus, IFN-γ in the mLN skews Treg cells to be Th1-like effector Treg cells, driving their close interaction with DC1s and subsequent suppression of cytotoxic T cell responses.
    Keywords:  T cell dysfunction; T cell priming; Th1-like effector regulatory T cells; anti-tumor immunity; cross-presenting dendritic cells; cytotoxic T cells; interferon-gamma; non-small cell lung cancer; regulatory T cells; tissue-specific immunity
    DOI:  https://doi.org/10.1016/j.immuni.2023.01.010
  17. Nat Commun. 2023 Feb 02. 14(1): 559
    Increased levels of endogenous retroviruses trigger fibroinflammation and play a role in kidney disease development.
    Poonam Dhillon, Kelly Ann Mulholland, Hailong Hu, Jihwan Park, Xin Sheng, Amin Abedini, Hongbo Liu, Allison Vassalotti, Junnan Wu, Katalin Susztak.
      Inflammation is a common feature of all forms of chronic kidney disease; however, the underlying mechanism remains poorly understood. Evolutionarily inherited endogenous retroviruses (ERVs) have the potential to trigger an immune reaction. Comprehensive RNA-sequencing of control and diseased kidneys from human and mouse disease models indicated higher expression of transposable elements (TEs) and ERVs in diseased kidneys. Loss of cytosine methylation causing epigenetic derepression likely contributes to an increase in ERV levels. Genetic deletion/pharmacological inhibition of DNA methyltransferase 1 (DNMT1) induces ERV expression. In cultured kidney tubule cells, ERVs elicit the activation of cytosolic nucleotide sensors such as RIG-I, MDA5, and STING. ERVs expressions in kidney tubules trigger RIG-I/STING, and cytokine expression, and correlate with the presence of immune cells. Genetic deletion of RIG-I or STING or treatment with reverse transcriptase inhibitor ameliorates kidney fibroinflammation. Our data indicate an important role of epigenetic derepression-induced ERV activation triggering renal fibroinflammation.
    DOI:  https://doi.org/10.1038/s41467-023-36212-w
  18. Nat Neurosci. 2023 Feb 02.
    Integrative in situ mapping of single-cell transcriptional states and tissue histopathology in a mouse model of Alzheimer's disease.
    Hu Zeng, Jiahao Huang, Haowen Zhou, William J Meilandt, Borislav Dejanovic, Yiming Zhou, Christopher J Bohlen, Seung-Hye Lee, Jingyi Ren, Albert Liu, Zefang Tang, Hao Sheng, Jia Liu, Morgan Sheng, Xiao Wang.
      Complex diseases are characterized by spatiotemporal cellular and molecular changes that may be difficult to comprehensively capture. However, understanding the spatiotemporal dynamics underlying pathology can shed light on disease mechanisms and progression. Here we introduce STARmap PLUS, a method that combines high-resolution spatial transcriptomics with protein detection in the same tissue section. As proof of principle, we analyze brain tissues of a mouse model of Alzheimer's disease at 8 and 13 months of age. Our approach provides a comprehensive cellular map of disease progression. It reveals a core-shell structure where disease-associated microglia (DAM) closely contact amyloid-β plaques, whereas disease-associated astrocyte-like (DAA-like) cells and oligodendrocyte precursor cells (OPCs) are enriched in the outer shells surrounding the plaque-DAM complex. Hyperphosphorylated tau emerges mainly in excitatory neurons in the CA1 region and correlates with the local enrichment of oligodendrocyte subtypes. The STARmap PLUS method bridges single-cell gene expression profiles with tissue histopathology at subcellular resolution, providing a tool to pinpoint the molecular and cellular changes underlying pathology.
    DOI:  https://doi.org/10.1038/s41593-022-01251-x
  19. Nat Commun. 2023 Feb 02. 14(1): 562
    FMO rewires metabolism to promote longevity through tryptophan and one carbon metabolism in C. elegans.
    Hyo Sub Choi, Ajay Bhat, Marshall B Howington, Megan L Schaller, Rebecca L Cox, Shijiao Huang, Safa Beydoun, Hillary A Miller, Angela M Tuckowski, Joy Mecano, Elizabeth S Dean, Lindy Jensen, Daniel A Beard, Charles R Evans, Scott F Leiser.
      Flavin containing monooxygenases (FMOs) are promiscuous enzymes known for metabolizing a wide range of exogenous compounds. In C. elegans, fmo-2 expression increases lifespan and healthspan downstream of multiple longevity-promoting pathways through an unknown mechanism. Here, we report that, beyond its classification as a xenobiotic enzyme, fmo-2 expression leads to rewiring of endogenous metabolism principally through changes in one carbon metabolism (OCM). These changes are likely relevant, as we find that genetically modifying OCM enzyme expression leads to alterations in longevity that interact with fmo-2 expression. Using computer modeling, we identify decreased methylation as the major OCM flux modified by FMO-2 that is sufficient to recapitulate its longevity benefits. We further find that tryptophan is decreased in multiple mammalian FMO overexpression models and is a validated substrate for FMO-2. Our resulting model connects a single enzyme to two previously unconnected key metabolic pathways and provides a framework for the metabolic interconnectivity of longevity-promoting pathways such as dietary restriction. FMOs are well-conserved enzymes that are also induced by lifespan-extending interventions in mice, supporting a conserved and important role in promoting health and longevity through metabolic remodeling.
    DOI:  https://doi.org/10.1038/s41467-023-36181-0
  20. Life Sci Alliance. 2023 Apr;pii: e202201823. [Epub ahead of print]6(4):
    Epigenetic signals that direct cell type-specific interferon beta response in mouse cells.
    Markus Muckenhuber, Isabelle Seufert, Katharina Müller-Ott, Jan-Philipp Mallm, Lara C Klett, Caroline Knotz, Jana Hechler, Nick Kepper, Fabian Erdel, Karsten Rippe.
      The antiviral response induced by type I interferon (IFN) via the JAK-STAT signaling cascade activates hundreds of IFN-stimulated genes (ISGs) across human and mouse tissues but varies between cell types. However, the links between the underlying epigenetic features and the ISG profile are not well understood. We mapped ISGs, binding sites of the STAT1 and STAT2 transcription factors, chromatin accessibility, and histone H3 lysine modification by acetylation (ac) and mono-/tri-methylation (me1, me3) in mouse embryonic stem cells and fibroblasts before and after IFNβ treatment. A large fraction of ISGs and STAT-binding sites was cell type specific with promoter binding of a STAT1/2 complex being a key driver of ISGs. Furthermore, STAT1/2 binding to putative enhancers induced ISGs as inferred from a chromatin co-accessibility analysis. STAT1/2 binding was dependent on the chromatin context and positively correlated with preexisting H3K4me1 and H3K27ac marks in an open chromatin state, whereas the presence of H3K27me3 had an inhibitory effect. Thus, chromatin features present before stimulation represent an additional regulatory layer for the cell type-specific antiviral response.
    DOI:  https://doi.org/10.26508/lsa.202201823
  21. Sci Adv. 2023 Feb 03. 9(5): eabq3851
    A spatiotemporal complexity architecture of human brain activity.
    Stephan Krohn, Nina von Schwanenflug, Leonhard Waschke, Amy Romanello, Martin Gell, Douglas D Garrett, Carsten Finke.
      The human brain operates in large-scale functional networks. These networks are an expression of temporally correlated activity across brain regions, but how global network properties relate to the neural dynamics of individual regions remains incompletely understood. Here, we show that the brain's network architecture is tightly linked to critical episodes of neural regularity, visible as spontaneous "complexity drops" in functional magnetic resonance imaging signals. These episodes closely explain functional connectivity strength between regions, subserve the propagation of neural activity patterns, and reflect interindividual differences in age and behavior. Furthermore, complexity drops define neural activity states that dynamically shape the connectivity strength, topological configuration, and hierarchy of brain networks and comprehensively explain known structure-function relationships within the brain. These findings delineate a principled complexity architecture of neural activity-a human "complexome" that underpins the brain's functional network organization.
    DOI:  https://doi.org/10.1126/sciadv.abq3851
  22. Nat Commun. 2023 Jan 28. 14(1): 465
    Glycolysis regulates KRAS plasma membrane localization and function through defined glycosphingolipids.
    Junchen Liu, Ransome van der Hoeven, Walaa E Kattan, Jeffrey T Chang, Dina Montufar-Solis, Wei Chen, Maurice Wong, Yong Zhou, Carlito B Lebrilla, John F Hancock.
      Oncogenic KRAS expression generates a metabolic dependency on aerobic glycolysis, known as the Warburg effect. We report an effect of increased glycolytic flux that feeds into glycosphingolipid biosynthesis and is directly linked to KRAS oncogenic function. High resolution imaging and genetic approaches show that a defined subset of outer leaflet glycosphingolipids, including GM3 and SM4, is required to maintain KRAS plasma membrane localization, with GM3 engaging in cross-bilayer coupling to maintain inner leaflet phosphatidylserine content. Thus, glycolysis is critical for KRAS plasma membrane localization and nanoscale spatial organization. Reciprocally oncogenic KRAS selectively upregulates cellular content of these same glycosphingolipids, whose depletion in turn abrogates KRAS oncogenesis in pancreatic cancer models. Our findings expand the role of the Warburg effect beyond ATP generation and biomass building to high-level regulation of KRAS function. The positive feedforward loop between oncogenic KRAS signaling and glycosphingolipid synthesis represents a vulnerability with therapeutic potential.
    DOI:  https://doi.org/10.1038/s41467-023-36128-5
  23. Nat Commun. 2023 Feb 01. 14(1): 528
    Germline T cell receptor exchange results in physiological T cell development and function.
    Meagan R Rollins, Jackson F Raynor, Ebony A Miller, Jonah Z Butler, Ellen J Spartz, Walker S Lahr, Yun You, Adam L Burrack, Branden S Moriarity, Beau R Webber, Ingunn M Stromnes.
      T cell receptor (TCR) transgenic mice represent an invaluable tool to study antigen-specific immune responses. In the pre-existing models, a monoclonal TCR is driven by a non-physiologic promoter and randomly integrated into the genome. Here, we create a highly efficient methodology to develop T cell receptor exchange (TRex) mice, in which TCRs, specific to the self/tumor antigen mesothelin (Msln), are integrated into the Trac locus, with concomitant Msln disruption to circumvent T cell tolerance. We show that high affinity TRex thymocytes undergo all sequential stages of maturation, express the exogenous TCR at DN4, require MHC class I for positive selection and undergo negative selection only when both Msln alleles are present. By comparison of TCRs with the same specificity but varying affinity, we show that Trac targeting improves functional sensitivity of a lower affinity TCR and confers resistance to T cell functional loss. By generating P14 TRex mice with the same specificity as the widely used LCMV-P14 TCR transgenic mouse, we demonstrate increased avidity of Trac-targeted TCRs over transgenic TCRs, while preserving physiologic T cell development. Together, our results support that the TRex methodology is an advanced tool to study physiological antigen-specific T cell behavior.
    DOI:  https://doi.org/10.1038/s41467-023-36180-1
  24. Nat Commun. 2023 Feb 02. 14(1): 568
    Estimation of cell lineages in tumors from spatial transcriptomics data.
    Beibei Ru, Jinlin Huang, Yu Zhang, Kenneth Aldape, Peng Jiang.
      Spatial transcriptomics (ST) technology through in situ capturing has enabled topographical gene expression profiling of tumor tissues. However, each capturing spot may contain diverse immune and malignant cells, with different cell densities across tissue regions. Cell type deconvolution in tumor ST data remains challenging for existing methods designed to decompose general ST or bulk tumor data. We develop the Spatial Cellular Estimator for Tumors (SpaCET) to infer cell identities from tumor ST data. SpaCET first estimates cancer cell abundance by integrating a gene pattern dictionary of copy number alterations and expression changes in common malignancies. A constrained regression model then calibrates local cell densities and determines immune and stromal cell lineage fractions. SpaCET provides higher accuracy than existing methods based on simulation and real ST data with matched double-blind histopathology annotations as ground truth. Further, coupling cell fractions with ligand-receptor coexpression analysis, SpaCET reveals how intercellular interactions at the tumor-immune interface promote cancer progression.
    DOI:  https://doi.org/10.1038/s41467-023-36062-6
  25. Nat Commun. 2023 Feb 01. 14(1): 543
    A split ribozyme that links detection of a native RNA to orthogonal protein outputs.
    Lauren Gambill, August Staubus, Kim Wai Mo, Andrea Ameruoso, James Chappell.
      Individual RNA remains a challenging signal to synthetically transduce into different types of cellular information. Here, we describe Ribozyme-ENabled Detection of RNA (RENDR), a plug-and-play strategy that uses cellular transcripts to template the assembly of split ribozymes, triggering splicing reactions that generate orthogonal protein outputs. To identify split ribozymes that require templating for splicing, we use laboratory evolution to evaluate the activities of different split variants of the Tetrahymena thermophila ribozyme. The best design delivers a 93-fold dynamic range of splicing with RENDR controlling fluorescent protein production in response to an RNA input. We further resolve a thermodynamic model to guide RENDR design, show how input signals can be transduced into diverse outputs, demonstrate portability across different bacteria, and use RENDR to detect antibiotic-resistant bacteria. This work shows how transcriptional signals can be monitored in situ and converted into different types of biochemical information using RNA synthetic biology.
    DOI:  https://doi.org/10.1038/s41467-023-36073-3
  26. Nat Cell Biol. 2023 Feb 02.
    Biologically informed deep learning to query gene programs in single-cell atlases.
    Mohammad Lotfollahi, Sergei Rybakov, Karin Hrovatin, Soroor Hediyeh-Zadeh, Carlos Talavera-López, Alexander V Misharin, Fabian J Theis.
      The increasing availability of large-scale single-cell atlases has enabled the detailed description of cell states. In parallel, advances in deep learning allow rapid analysis of newly generated query datasets by mapping them into reference atlases. However, existing data transformations learned to map query data are not easily explainable using biologically known concepts such as genes or pathways. Here we propose expiMap, a biologically informed deep-learning architecture that enables single-cell reference mapping. ExpiMap learns to map cells into biologically understandable components representing known 'gene programs'. The activity of each cell for a gene program is learned while simultaneously refining them and learning de novo programs. We show that expiMap compares favourably to existing methods while bringing an additional layer of interpretability to integrative single-cell analysis. Furthermore, we demonstrate its applicability to analyse single-cell perturbation responses in different tissues and species and resolve responses of patients who have coronavirus disease 2019 to different treatments across cell types.
    DOI:  https://doi.org/10.1038/s41556-022-01072-x
  27. Nat Commun. 2023 Jan 30. 14(1): 489
    FTO-dependent m6A modification of Plpp3 in circSCMH1-regulated vascular repair and functional recovery following stroke.
    Bin Li, Wen Xi, Ying Bai, Xue Liu, Yuan Zhang, Lu Li, Liang Bian, Chenchen Liu, Ying Tang, Ling Shen, Li Yang, Xiaochun Gu, Jian Xie, Zhongqiu Zhou, Yu Wang, Xiaoyu Yu, Jianhong Wang, Jie Chao, Bing Han, Honghong Yao.
      Vascular repair is considered a key restorative measure to improve long-term outcomes after ischemic stroke. N6-methyladenosine (m6A), the most prevalent internal modification in eukaryotic mRNAs, functionally mediates vascular repair. However, whether circular RNA SCMH1 (circSCMH1) promotes vascular repair by m6A methylation after stroke remains to be elucidated. Here, we identify the role of circSCMH1 in promoting vascular repair in peri-infarct cortex of male mice and male monkeys after photothrombotic (PT) stroke, and attenuating the ischemia-induced m6A methylation in peri-infarct cortex of male mice after PT stroke. Mechanically, circSCMH1 increased the translocation of ubiquitination-modified fat mass and obesity-associated protein (FTO) into nucleus of endothelial cells (ECs), leading to m6A demethylation of phospholipid phosphatase 3 (Plpp3) mRNA and subsequently the increase of Plpp3 expression in ECs. Our data demonstrate that circSCMH1 enhances vascular repair via FTO-regulated m6A methylation after stroke, providing insights into the mechanism of circSCMH1 in promoting stroke recovery.
    DOI:  https://doi.org/10.1038/s41467-023-36008-y
  28. Nature. 2023 Feb 03.
    Dogma-defying bacteria package DNA in unusual ways.
    Heidi Ledford.
      
    Keywords:  Cell biology; Microbiology
    DOI:  https://doi.org/10.1038/d41586-023-00334-4
  29. Nat Commun. 2023 Feb 02. 14(1): 86
    Deletion of SNX9 alleviates CD8 T cell exhaustion for effective cellular cancer immunotherapy.
    Marcel P Trefny, Nicole Kirchhammer, Priska Auf der Maur, Marina Natoli, Dominic Schmid, Markus Germann, Laura Fernandez Rodriguez, Petra Herzig, Jonas Lötscher, Maryam Akrami, Jane C Stinchcombe, Michal A Stanczak, Andreas Zingg, Melanie Buchi, Julien Roux, Romina Marone, Leyla Don, Didier Lardinois, Mark Wiese, Lukas T Jeker, Mohamed Bentires-Alj, Jérémie Rossy, Daniela S Thommen, Gillian M Griffiths, Heinz Läubli, Christoph Hess, Alfred Zippelius.
      Tumor-specific T cells are frequently exhausted by chronic antigenic stimulation. We here report on a human antigen-specific ex vivo model to explore new therapeutic options for T cell immunotherapies. T cells generated with this model resemble tumor-infiltrating exhausted T cells on a phenotypic and transcriptional level. Using a targeted pooled CRISPR-Cas9 screen and individual gene knockout validation experiments, we uncover sorting nexin-9 (SNX9) as a mediator of T cell exhaustion. Upon TCR/CD28 stimulation, deletion of SNX9 in CD8 T cells decreases PLCγ1, Ca2+, and NFATc2-mediated T cell signaling and reduces expression of NR4A1/3 and TOX. SNX9 knockout enhances memory differentiation and IFNγ secretion of adoptively transferred T cells and results in improved anti-tumor efficacy of human chimeric antigen receptor T cells in vivo. Our findings highlight that targeting SNX9 is a strategy to prevent T cell exhaustion and enhance anti-tumor immunity.
    DOI:  https://doi.org/10.1038/s41467-022-35583-w
  30. Nat Commun. 2023 Feb 02. 14(1): 560
    The AAA+ chaperone VCP disaggregates Tau fibrils and generates aggregate seeds in a cellular system.
    Itika Saha, Patricia Yuste-Checa, Miguel Da Silva Padilha, Qiang Guo, Roman Körner, Hauke Holthusen, Victoria A Trinkaus, Irina Dudanova, Rubén Fernández-Busnadiego, Wolfgang Baumeister, David W Sanders, Saurabh Gautam, Marc I Diamond, F Ulrich Hartl, Mark S Hipp.
      Amyloid-like aggregates of the microtubule-associated protein Tau are associated with several neurodegenerative disorders including Alzheimer's disease. The existence of cellular machinery for the removal of such aggregates has remained unclear, as specialized disaggregase chaperones are thought to be absent in mammalian cells. Here we show in cell culture and in neurons that the hexameric ATPase valosin-containing protein (VCP) is recruited to ubiquitylated Tau fibrils, resulting in their efficient disaggregation. Aggregate clearance depends on the functional cooperation of VCP with heat shock 70 kDa protein (Hsp70) and the ubiquitin-proteasome machinery. While inhibition of VCP activity stabilizes large Tau aggregates, disaggregation by VCP generates seeding-active Tau species as byproduct. These findings identify VCP as a core component of the machinery for the removal of neurodegenerative disease aggregates and suggest that its activity can be associated with enhanced aggregate spreading in tauopathies.
    DOI:  https://doi.org/10.1038/s41467-023-36058-2
  31. Sci Immunol. 2023 Feb 03. 8(80): eadg8279
    CD8 T cells are forever.
    Jonathan S Maltzman.
      Iterative acute stimulations can maintain CD8 T cells for longer than their organismal lifespan.
    DOI:  https://doi.org/10.1126/sciimmunol.adg8279
  32. EMBO Rep. 2023 Jan 30. e55328
    Endothelial cell-derived oxysterol ablation attenuates experimental autoimmune encephalomyelitis.
    Florian Ruiz, Benjamin Peter, Jessica Rebeaud, Solenne Vigne, Valentine Bressoud, Martin Roumain, Tania Wyss, Yannick Yersin, Ingrid Wagner, Mario Kreutzfeldt, Marisa Pimentel Mendes, Camille Kowalski, Gael Boivin, Leonard Roth, Markus Schwaninger, Doron Merkler, Giulio G Muccioli, Stephanie Hugues, Tatiana V Petrova, Caroline Pot.
      The vasculature is a key regulator of leukocyte trafficking into the central nervous system (CNS) during inflammatory diseases including multiple sclerosis (MS). However, the impact of endothelial-derived factors on CNS immune responses remains unknown. Bioactive lipids, in particular oxysterols downstream of Cholesterol-25-hydroxylase (Ch25h), promote neuroinflammation but their functions in the CNS are not well-understood. Using floxed-reporter Ch25h knock-in mice, we trace Ch25h expression to CNS endothelial cells (ECs) and myeloid cells and demonstrate that Ch25h ablation specifically from ECs attenuates experimental autoimmune encephalomyelitis (EAE). Mechanistically, inflamed Ch25h-deficient CNS ECs display altered lipid metabolism favoring polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) expansion, which suppresses encephalitogenic T lymphocyte proliferation. Additionally, endothelial Ch25h-deficiency combined with immature neutrophil mobilization into the blood circulation nearly completely protects mice from EAE. Our findings reveal a central role for CNS endothelial Ch25h in promoting neuroinflammation by inhibiting the expansion of immunosuppressive myeloid cell populations.
    Keywords:  cholesterol-25-hydroxylase; endothelial cells; experimental autoimmune encephalomyelitis; oxysterols; polymorphonuclear myeloid-derived suppressor cells
    DOI:  https://doi.org/10.15252/embr.202255328
  33. Nat Commun. 2023 Feb 01. 14(1): 544
    Lipid-induced transcriptomic changes in blood link to lipid metabolism and allergic response.
    BIOS consortium
      Immune cell function can be altered by lipids in circulation, a process potentially relevant to lipid-associated inflammatory diseases including atherosclerosis and rheumatoid arthritis. To gain further insight in the molecular changes involved, we here perform a transcriptome-wide association analysis of blood triglycerides, HDL cholesterol, and LDL cholesterol in 3229 individuals, followed by a systematic bidirectional Mendelian randomization analysis to assess the direction of effects and control for pleiotropy. Triglycerides are found to induce transcriptional changes in 55 genes and HDL cholesterol in 5 genes. The function and cell-specific expression pattern of these genes implies that triglycerides downregulate both cellular lipid metabolism and, unexpectedly, allergic response. Indeed, a Mendelian randomization approach based on GWAS summary statistics indicates that several of these genes, including interleukin-4 (IL4) and IgE receptors (FCER1A, MS4A2), affect the incidence of allergic diseases. Our findings highlight the interplay between triglycerides and immune cells in allergic disease.
    DOI:  https://doi.org/10.1038/s41467-022-35663-x
  34. Nat Commun. 2023 Jan 28. 14(1): 470
    Next-Generation Morphometry for pathomics-data mining in histopathology.
    David L Hölscher, Nassim Bouteldja, Mehdi Joodaki, Maria L Russo, Yu-Chia Lan, Alireza Vafaei Sadr, Mingbo Cheng, Vladimir Tesar, Saskia V Stillfried, Barbara M Klinkhammer, Jonathan Barratt, Jürgen Floege, Ian S D Roberts, Rosanna Coppo, Ivan G Costa, Roman D Bülow, Peter Boor.
      Pathology diagnostics relies on the assessment of morphology by trained experts, which remains subjective and qualitative. Here we developed a framework for large-scale histomorphometry (FLASH) performing deep learning-based semantic segmentation and subsequent large-scale extraction of interpretable, quantitative, morphometric features in non-tumour kidney histology. We use two internal and three external, multi-centre cohorts to analyse over 1000 kidney biopsies and nephrectomies. By associating morphometric features with clinical parameters, we confirm previous concepts and reveal unexpected relations. We show that the extracted features are independent predictors of long-term clinical outcomes in IgA-nephropathy. We introduce single-structure morphometric analysis by applying techniques from single-cell transcriptomics, identifying distinct glomerular populations and morphometric phenotypes along a trajectory of disease progression. Our study provides a concept for Next-generation Morphometry (NGM), enabling comprehensive quantitative pathology data mining, i.e., pathomics.
    DOI:  https://doi.org/10.1038/s41467-023-36173-0
  35. Cell. 2023 Feb 02. pii: S0092-8674(22)01581-1. [Epub ahead of print]186(3): 621-645.e33
    Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria.
    Jérémie Rosain, Anna-Lena Neehus, Jérémy Manry, Rui Yang, Jérémie Le Pen, Wassim Daher, Zhiyong Liu, Yi-Hao Chan, Natalia Tahuil, Özden Türel, Mathieu Bourgey, Masato Ogishi, Jean-Marc Doisne, Helena M Izquierdo, Takayoshi Shirasaki, Tom Le Voyer, Antoine Guérin, Paul Bastard, Marcela Moncada-Vélez, Ji Eun Han, Taushif Khan, Franck Rapaport, Seon-Hui Hong, Andrew Cheung, Kathrin Haake, Barbara C Mindt, Laura Pérez, Quentin Philippot, Danyel Lee, Peng Zhang, Darawan Rinchai, Fatima Al Ali, Manar Mahmoud Ahmad Ata, Mahbuba Rahman, Jessica N Peel, Søren Heissel, Henrik Molina, Yasemin Kendir-Demirkol, Rasheed Bailey, Shuxiang Zhao, Jonathan Bohlen, Mathieu Mancini, Yoann Seeleuthner, Marie Roelens, Lazaro Lorenzo, Camille Soudée, María Elvira Josefina Paz, María Laura González, Mohamed Jeljeli, Jean Soulier, Serge Romana, Anne-Sophie L'Honneur, Marie Materna, Rubén Martínez-Barricarte, Mathieu Pochon, Carmen Oleaga-Quintas, Alexandre Michev, Mélanie Migaud, Romain Lévy, Marie-Alexandra Alyanakian, Flore Rozenberg, Carys A Croft, Guillaume Vogt, Jean-François Emile, Laurent Kremer, Cindy S Ma, Jörg H Fritz, Stanley M Lemon, András N Spaan, Nicolas Manel, Laurent Abel, Margaret R MacDonald, Stéphanie Boisson-Dupuis, Nico Marr, Stuart G Tangye, James P Di Santo, Qian Zhang, Shen-Ying Zhang, Charles M Rice, Vivien Béziat, Nico Lachmann, David Langlais, Jean-Laurent Casanova, Philippe Gros, Jacinta Bustamante.
      Inborn errors of human IFN-γ-dependent macrophagic immunity underlie mycobacterial diseases, whereas inborn errors of IFN-α/β-dependent intrinsic immunity underlie viral diseases. Both types of IFNs induce the transcription factor IRF1. We describe unrelated children with inherited complete IRF1 deficiency and early-onset, multiple, life-threatening diseases caused by weakly virulent mycobacteria and related intramacrophagic pathogens. These children have no history of severe viral disease, despite exposure to many viruses, including SARS-CoV-2, which is life-threatening in individuals with impaired IFN-α/β immunity. In leukocytes or fibroblasts stimulated in vitro, IRF1-dependent responses to IFN-γ are, both quantitatively and qualitatively, much stronger than those to IFN-α/β. Moreover, IRF1-deficient mononuclear phagocytes do not control mycobacteria and related pathogens normally when stimulated with IFN-γ. By contrast, IFN-α/β-dependent intrinsic immunity to nine viruses, including SARS-CoV-2, is almost normal in IRF1-deficient fibroblasts. Human IRF1 is essential for IFN-γ-dependent macrophagic immunity to mycobacteria, but largely redundant for IFN-α/β-dependent antiviral immunity.
    Keywords:  IRF1; Mycobacterium; inborn errors of immunity; interferon-stimulated gene; interferon-γ; macrophages; viruses
    DOI:  https://doi.org/10.1016/j.cell.2022.12.038
  36. Nat Commun. 2023 Feb 01. 14(1): 542
    Evidence of a causal effect of genetic tendency to gain muscle mass on uterine leiomyomata.
    FinnGen
      Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1 A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.
    DOI:  https://doi.org/10.1038/s41467-023-35974-7
  37. Commun Biol. 2023 Jan 28. 6(1): 116
    Sharing GWAS summary statistics results in more citations.
    Guillermo Reales, Chris Wallace.
      
    DOI:  https://doi.org/10.1038/s42003-023-04497-8
  38. Nat Cell Biol. 2023 Feb 02.
    Actin-driven chromosome clustering facilitates fast and complete chromosome capture in mammalian oocytes.
    Katarina Harasimov, Julia Uraji, Eike Urs Mönnich, Zuzana Holubcová, Kay Elder, Martyn Blayney, Melina Schuh.
      Accurate chromosome segregation during meiosis is crucial for reproduction. Human and porcine oocytes transiently cluster their chromosomes before the onset of spindle assembly and subsequent chromosome segregation. The mechanism and function of chromosome clustering are unknown. Here we show that chromosome clustering is required to prevent chromosome losses in the long gap phase between nuclear envelope breakdown and the onset of spindle assembly, and to promote the rapid capture of all chromosomes by the acentrosomal spindle. The initial phase of chromosome clustering is driven by a dynamic network of Formin-2- and Spire-nucleated actin cables. The actin cables form in the disassembling nucleus and migrate towards the nuclear centre, moving the chromosomes centripetally by interacting with their arms and kinetochores as they migrate. A cage of stable microtubule loops drives the late stages of chromosome clustering. Together, our data establish a crucial role for chromosome clustering in accurate progression through meiosis.
    DOI:  https://doi.org/10.1038/s41556-022-01082-9
  39. Proc Natl Acad Sci U S A. 2023 Feb 07. 120(6): e2212696120
    Distinctive transcriptomic and epigenomic signatures of bone marrow-derived myeloid cells and microglia in CNS autoimmunity.
    Navid Manouchehri, Victor H Salinas, Rehana Z Hussain, Olaf Stüve.
      In the context of autoimmunity, myeloid cells of the central nervous system (CNS) constitute an ontogenically heterogeneous population that includes yolk sac-derived microglia and infiltrating bone marrow-derived cells (BMC). We previously identified a myeloid cell subset in the brain and spinal cord that expresses the surface markers CD88 and CD317 and is associated with the onset and persistence of clinical disease in the murine model of the human CNS autoimmune disorder, experimental autoimmune encephalomyelitis (EAE). We employed an experimental platform utilizing single-cell transcriptomic and epigenomic profiling of bone marrow-chimeric mice to categorically distinguish BMC from microglia during CNS autoimmunity. Analysis of gene expression and chromosomal accessibility identified CD88+CD317+ myeloid cells in the CNS of EAE mice as originating from BMC and microglia. Interestingly, each cell lineage exhibited overlapping and unique gene expression patterns and transcription factor motifs that allowed their segregation. Our observations will facilitate determining pathogenic contributions of BMC and microglia in CNS autoimmune disease. Ultimately, this agnostic characterization of myeloid cells will be required for devising disease stage-specific and tissue-specific interventions for CNS inflammatory and neurodegenerative disorders.
    Keywords:  experimental autoimmune encephalomyelitis; microglia; multiple sclerosis; myeloid cells; transcriptomics
    DOI:  https://doi.org/10.1073/pnas.2212696120
  40. Sci Rep. 2023 Jan 31. 13(1): 1711
    RNA disruption is a widespread phenomenon associated with stress-induced cell death in tumour cells.
    Phillipe Butler, Isabella Pascheto, Michayla Lizzi, Renée St-Onge, Carita Lanner, Baoqing Guo, Twinkle Masilamani, Laura B Pritzker, A Thomas Kovala, Amadeo M Parissenti.
      We have previously shown that neoadjuvant chemotherapy can induce the degradation of tumour ribosomal RNA (rRNA) in patients with advanced breast cancer, a phenomenon we termed "RNA disruption". Extensive tumour RNA disruption during chemotherapy was associated with a post-treatment pathological complete response and improved disease-free survival. The RNA disruption assay (RDA), which quantifies this phenomenon, is now being evaluated for its clinical utility in a large multinational clinical trial. However, it remains unclear if RNA disruption (i) is manifested across many tumour and non-tumour cell types, (ii) can occur in response to cell stress, and (iii) is associated with tumour cell death. In this study, we show that RNA disruption is induced by several mechanistically distinct chemotherapy agents and report that this phenomenon is observed in response to oxidative stress, endoplasmic reticulum (ER) stress, protein translation inhibition and nutrient/growth factor limitation. We further show that RNA disruption is dose- and time-dependent, and occurs in both tumourigenic and non-tumourigenic cell types. Northern blotting experiments suggest that the rRNA fragments generated during RNA disruption stem (at least in part) from the 28S rRNA. Moreover, we demonstrate that RNA disruption is reproducibly associated with three robust biomarkers of cell death: strongly reduced cell numbers, lost cell replicative capacity, and the generation of cells with a subG1 DNA content. Thus, our findings indicate that RNA disruption is a widespread phenomenon exhibited in mammalian cells under stress, and that high RNA disruption is associated with the onset of cell death.
    DOI:  https://doi.org/10.1038/s41598-023-28635-8
  41. J Clin Invest. 2023 Feb 01. pii: e162940. [Epub ahead of print]133(3):
    Neutrophil CEACAM1 determines susceptibility to NETosis by regulating the S1PR2/S1PR3 axis in liver transplantation.
    Hirofumi Hirao, Hidenobu Kojima, Kenneth J Dery, Kojiro Nakamura, Kentaro Kadono, Yuan Zhai, Douglas G Farmer, Fady M Kaldas, Jerzy W Kupiec-Weglinski.
      Neutrophils, the largest innate immune cell population in humans, are the primary proinflammatory sentinel in the ischemia-reperfusion injury (IRI) mechanism in orthotopic liver transplantation (OLT). Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1, CC1, or CD66a) is essential in neutrophil activation and serves as a checkpoint regulator of innate immune-driven IRI cascade in OLT. Although CC1 alternative splicing generates two functionally distinct short and long cytoplasmic isoforms, their role in neutrophil activation remains unknown. Here, we undertook molecular and functional studies to interrogate the significance of neutrophil CC1 signaling in mouse and human OLT recipients. In the experimental arm, we employed a mouse OLT model to document that ablation of recipient-derived neutrophil CC1-long (CC1-L) isotype aggravated hepatic IRI by promoting neutrophil extracellular traps (NETs). Notably, by regulating the S1P-S1PR2/S1PR3 axis, neutrophil CC1-L determined susceptibility to NET formation via autophagy signaling. In the clinical arm, liver grafts from 55 transplant patients selectively enriched for neutrophil CC1-L showed relative resistance to ischemia-reperfusion (IR) stress/tissue damage, improved hepatocellular function, and clinical outcomes. In conclusion, despite neutrophils being considered a principal villain in peritransplant tissue injury, their CC1-L isoform may serve as a regulator of IR stress resistance/NETosis in human and mouse OLT recipients.
    Keywords:  Hypoxia; Neutrophils; Organ transplantation; Transplantation
    DOI:  https://doi.org/10.1172/JCI162940
  42. Nat Metab. 2023 Feb 02.
    Phagocytosis in the retina promotes local insulin production in the eye.
    J Iker Etchegaray, Shannon Kelley, Kristen Penberthy, Laura Karvelyte, Yosuke Nagasaka, Sofia Gasperino, Soumen Paul, Vikram Seshadri, Michael Raymond, Ana Royo Marco, Jonathan Pinney, Marta Stremska, Brady Barron, Christopher Lucas, Nishikant Wase, Yong Fan, Emil Unanue, Bijoy Kundu, Tal Burstyn-Cohen, Justin Perry, Jayakrishna Ambati, Kodi S Ravichandran.
      The retina is highly metabolically active, relying on glucose uptake and aerobic glycolysis. Situated in close contact to photoreceptors, a key function of cells in the retinal pigment epithelium (RPE) is phagocytosis of damaged photoreceptor outer segments (POS). Here we identify RPE as a local source of insulin in the eye that is stimulated by POS phagocytosis. We show that Ins2 messenger RNA and insulin protein are produced by RPE cells and that this production correlates with RPE phagocytosis of POS. Genetic deletion of phagocytic receptors ('loss of function') reduces Ins2, whereas increasing the levels of the phagocytic receptor MerTK ('gain of function') increases Ins2 production in male mice. Contrary to pancreas-derived systemic insulin, RPE-derived local insulin is stimulated during starvation, which also increases RPE phagocytosis. Global or RPE-specific Ins2 gene deletion decreases retinal glucose uptake in starved male mice, dysregulates retinal physiology, causes defects in phototransduction and exacerbates photoreceptor loss in a mouse model of retinitis pigmentosa. Collectively, these data identify RPE cells as a phagocytosis-induced local source of insulin in the retina, with the potential to influence retinal physiology and disease.
    DOI:  https://doi.org/10.1038/s42255-022-00728-0
  43. Cell. 2023 Feb 02. pii: S0092-8674(22)01631-2. [Epub ahead of print]186(3): 466-468
    When IL-17 gets on your nerves.
    Iliyan D Iliev, Woan-Yu Lin, Sarah L Gaffen.
      Microbiota-induced IL-17 production mediates CNS processes and animal behavior. However, its role on the peripheral nervous system (PNS) remains largely unknown. Enamorado et al. demonstrate that commensal-specific Th17 cells are recalled following tissue injury to support local nerve regeneration, a process orchestrated by IL-17 signaling on peripheral neurons.
    DOI:  https://doi.org/10.1016/j.cell.2022.12.048
  44. Nat Commun. 2023 Jan 31. 14(1): 515
    A two-faced selectivity solution to target SMARCA2 for cancer therapy.
    John D Harling, Christopher P Tinworth.
      
    DOI:  https://doi.org/10.1038/s41467-023-36238-0
  45. Nature. 2023 Feb 02.
    How quickly does COVID immunity fade? What scientists know.
    Cassandra Willyard.
      
    Keywords:  Immunology; Infection; SARS-CoV-2; Vaccines
    DOI:  https://doi.org/10.1038/d41586-023-00124-y
  46. Nat Cancer. 2023 Feb 02.
    A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation resulting in pro-metastatic NF-κB signaling.
    Patricia Altea-Manzano, Ginevra Doglioni, Yawen Liu, Alejandro M Cuadros, Emma Nolan, Juan Fernández-García, Qi Wu, Mélanie Planque, Kathrin Julia Laue, Florencia Cidre-Aranaz, Xiao-Zheng Liu, Oskar Marin-Bejar, Joke Van Elsen, Ines Vermeire, Dorien Broekaert, Sofie Demeyer, Xander Spotbeen, Jakub Idkowiak, Aurélie Montagne, Margherita Demicco, H Furkan Alkan, Nick Rabas, Carla Riera-Domingo, François Richard, Tatjana Geukens, Maxim De Schepper, Sophia Leduc, Sigrid Hatse, Yentl Lambrechts, Emily Jane Kay, Sergio Lilla, Alisa Alekseenko, Vincent Geldhof, Bram Boeckx, Celia de la Calle Arregui, Giuseppe Floris, Johannes V Swinnen, Jean-Christophe Marine, Diether Lambrechts, Vicent Pelechano, Massimiliano Mazzone, Sara Zanivan, Jan Cools, Hans Wildiers, Véronique Baud, Thomas G P Grünewald, Uri Ben-David, Christine Desmedt, Ilaria Malanchi, Sarah-Maria Fendt.
      Metabolic rewiring is often considered an adaptive pressure limiting metastasis formation; however, some nutrients available at distant organs may inherently promote metastatic growth. We find that the lung and liver are lipid-rich environments. Moreover, we observe that pre-metastatic niche formation increases palmitate availability only in the lung, whereas a high-fat diet increases it in both organs. In line with this, targeting palmitate processing inhibits breast cancer-derived lung metastasis formation. Mechanistically, breast cancer cells use palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a-dependent manner. Concomitantly, lysine acetyltransferase 2a expression is promoted by palmitate, linking the available acetyl-CoA to the acetylation of the nuclear factor-kappaB subunit p65. Deletion of lysine acetyltransferase 2a or carnitine palmitoyltransferase 1a reduces metastasis formation in lean and high-fat diet mice, and lung and liver metastases from patients with breast cancer show coexpression of both proteins. In conclusion, palmitate-rich environments foster metastases growth by increasing p65 acetylation, resulting in a pro-metastatic nuclear factor-kappaB signaling.
    DOI:  https://doi.org/10.1038/s43018-023-00513-2
  47. Immunity. 2023 Jan 26. pii: S1074-7613(23)00011-0. [Epub ahead of print]
    Spermine enhances antiviral and anticancer responses by stabilizing DNA binding with the DNA sensor cGAS.
    Lina Wang, Siru Li, Kai Wang, Na Wang, Qiaoling Liu, Zhen Sun, Li Wang, Lulu Wang, Quentin Liu, Chengli Song, Qingkai Yang.
      Self-nonself discrimination is vital for the immune system to mount responses against pathogens while maintaining tolerance toward the host and innocuous commensals during homeostasis. Here, we investigated how indiscriminate DNA sensors, such as cyclic GMP-AMP synthase (cGAS), make this self-nonself distinction. Screening of a small-molecule library revealed that spermine, a well-known DNA condenser associated with viral DNA, markedly elevates cGAS activation. Mechanistically, spermine condenses DNA to enhance and stabilize cGAS-DNA binding, optimizing cGAS and downstream antiviral signaling. Spermine promotes condensation of viral, but not host nucleosome, DNA. Deletion of viral DNA-associated spermine, by propagating virus in spermine-deficient cells, reduced cGAS activation. Spermine depletion subsequently attenuated cGAS-mediated antiviral and anticancer immunity. Collectively, our results reveal a pathogenic DNA-associated molecular pattern that facilitates nonself recognition, linking metabolism and pathogen recognition.
    Keywords:  DNA condensation; DNA sensing; cGAS; phase separation
    DOI:  https://doi.org/10.1016/j.immuni.2023.01.001
  48. Mol Biol Cell. 2023 Feb 03. mbcE22090432
    CCPG1 recognizes ER luminal proteins for selective ER-phagy.
    Shunsuke Ishii, Haruka Chino, Koji L Ode, Yoshitaka Kurikawa, Hiroki R Ueda, Akira Matsuura, Noboru Mizushima, Eisuke Itakura.
      The endoplasmic reticulum (ER) is a major cell compartment where protein synthesis, folding and post-translational modifications occur with assistance from a wide variety of chaperones and enzymes. Quality control systems selectively eliminate abnormal proteins that accumulate inside the ER due to cellular stresses. ER-phagy, i.e., selective autophagy of the ER, is a mechanism that maintains or re-establishes cellular and ER-specific homeostasis through removal of abnormal proteins. However, how ER luminal proteins are recognized by the ER-phagy machinery remains unclear. Here, we applied the aggregation-prone protein, six-repeated islet amyloid polypeptide (6xIAPP), as a model ER-phagy substrate, and found that cell cycle progression 1 (CCPG1), which is an ER-phagy receptor, efficiently mediates its degradation via ER-phagy. We also identified prolyl 3-hydroxylase family member 4 (P3H4) as an endogenous cargo of CCPG1-dependent ER-phagy. The ER luminal region of CCPG1 contains several highly conserved regions that we refer to as cargo interaction regions (CIRs); these directly interact with specific luminal cargos for ER-phagy. Notably, 6xIAPP and P3H4 directly interact with different CIRs. These findings indicate that CCPG1 is a bispecific ER-phagy receptor for ER luminal proteins and the autophagosomal membrane that contributes to the efficient removal of aberrant ER-resident proteins through ER-phagy.
    DOI:  https://doi.org/10.1091/mbc.E22-09-0432
  49. Nat Rev Genet. 2023 Feb 03.
    Human-specific genetics: new tools to explore the molecular and cellular basis of human evolution.
    Alex A Pollen, Umut Kilik, Craig B Lowe, J Gray Camp.
      Our ancestors acquired morphological, cognitive and metabolic modifications that enabled humans to colonize diverse habitats, develop extraordinary technologies and reshape the biosphere. Understanding the genetic, developmental and molecular bases for these changes will provide insights into how we became human. Connecting human-specific genetic changes to species differences has been challenging owing to an abundance of low-effect size genetic changes, limited descriptions of phenotypic differences across development at the level of cell types and lack of experimental models. Emerging approaches for single-cell sequencing, genetic manipulation and stem cell culture now support descriptive and functional studies in defined cell types with a human or ape genetic background. In this Review, we describe how the sequencing of genomes from modern and archaic hominins, great apes and other primates is revealing human-specific genetic changes and how new molecular and cellular approaches - including cell atlases and organoids - are enabling exploration of the candidate causal factors that underlie human-specific traits.
    DOI:  https://doi.org/10.1038/s41576-022-00568-4
  50. Nat Commun. 2023 Feb 03. 14(1): 604
    Atlas of plasma NMR biomarkers for health and disease in 118,461 individuals from the UK Biobank.
    Heli Julkunen, Anna Cichońska, Mika Tiainen, Harri Koskela, Kristian Nybo, Valtteri Mäkelä, Jussi Nokso-Koivisto, Kati Kristiansson, Markus Perola, Veikko Salomaa, Pekka Jousilahti, Annamari Lundqvist, Antti J Kangas, Pasi Soininen, Jeffrey C Barrett, Peter Würtz.
      Blood lipids and metabolites are markers of current health and future disease risk. Here, we describe plasma nuclear magnetic resonance (NMR) biomarker data for 118,461 participants in the UK Biobank. The biomarkers cover 249 measures of lipoprotein lipids, fatty acids, and small molecules such as amino acids, ketones, and glycolysis metabolites. We provide an atlas of associations of these biomarkers to prevalence, incidence, and mortality of over 700 common diseases ( nightingalehealth.com/atlas ). The results reveal a plethora of biomarker associations, including susceptibility to infectious diseases and risk of various cancers, joint disorders, and mental health outcomes, indicating that abundant circulating lipids and metabolites are risk markers beyond cardiometabolic diseases. Clustering analyses indicate similar biomarker association patterns across different disease types, suggesting latent systemic connectivity in the susceptibility to a diverse set of diseases. This work highlights the value of NMR based metabolic biomarker profiling in large biobanks for public health research and translation.
    DOI:  https://doi.org/10.1038/s41467-023-36231-7
  51. J Clin Invest. 2023 Feb 01. pii: e166283. [Epub ahead of print]133(3):
    Unlocking life-threatening COVID-19 through two types of inborn errors of type I IFNs.
    Jean-Laurent Casanova, Mark S Anderson.
      Since 2003, rare inborn errors of human type I IFN immunity have been discovered, each underlying a few severe viral illnesses. Autoantibodies neutralizing type I IFNs due to rare inborn errors of autoimmune regulator (AIRE)-driven T cell tolerance were discovered in 2006, but not initially linked to any viral disease. These two lines of clinical investigation converged in 2020, with the discovery that inherited and/or autoimmune deficiencies of type I IFN immunity accounted for approximately 15%-20% of cases of critical COVID-19 pneumonia in unvaccinated individuals. Thus, insufficient type I IFN immunity at the onset of SARS-CoV-2 infection may be a general determinant of life-threatening COVID-19. These findings illustrate the unpredictable, but considerable, contribution of the study of rare human genetic diseases to basic biology and public health.
    DOI:  https://doi.org/10.1172/JCI166283
  52. Nat Commun. 2023 Jan 30. 14(1): 476
    Influence of circadian clocks on adaptive immunity and vaccination responses.
    Louise Madeleine Ince, Coline Barnoud, Lydia Kay Lutes, Robert Pick, Chen Wang, Flore Sinturel, Chien-Sin Chen, Alba de Juan, Jasmin Weber, Stephan J Holtkamp, Sophia Martina Hergenhan, Jennifer Geddes-McAlister, Stefan Ebner, Paola Fontannaz, Benjamin Meyer, Maria Vono, Stéphane Jemelin, Charna Dibner, Claire-Anne Siegrist, Felix Meissner, Frederik Graw, Christoph Scheiermann.
      The adaptive immune response is under circadian control, yet, why adaptive immune reactions continue to exhibit circadian changes over long periods of time is unknown. Using a combination of experimental and mathematical modeling approaches, we show here that dendritic cells migrate from the skin to the draining lymph node in a time-of-day-dependent manner, which provides an enhanced likelihood for functional interactions with T cells. Rhythmic expression of TNF in the draining lymph node enhances BMAL1-controlled ICAM-1 expression in high endothelial venules, resulting in lymphocyte infiltration and lymph node expansion. Lymph node cellularity continues to be different for weeks after the initial time-of-day-dependent challenge, which governs the immune response to vaccinations directed against Hepatitis A virus as well as SARS-CoV-2. In this work, we present a mechanistic understanding of the time-of-day dependent development and maintenance of an adaptive immune response, providing a strategy for using time-of-day to optimize vaccination regimes.
    DOI:  https://doi.org/10.1038/s41467-023-35979-2
  53. Nat Commun. 2023 Jan 28. 14(1): 463
    The function and evolution of a genetic switch controlling sexually dimorphic eye differentiation in honeybees.
    Oksana Netschitailo, Yidong Wang, Anna Wagner, Vivien Sommer, Eveline C Verhulst, Martin Beye.
      Animals develop sex-specific morphological structures that are diverse between organisms. However, understanding the developmental and evolutionary mechanisms governing these traits is still limited and largely restricted to DM domain genes, which are conserved, sex-specific developmental regulators identified in genetic models. Here, we report a sex-specific developmental regulator gene, glubschauge (glu) that selectively regulates sexually dimorphic eye differentiation in honeybees. We found that the sex determination gene feminizer (fem) controls sex-specific splicing of glu transcripts, establishing a genetic switch in which Glu proteins with a zinc finger (ZnF) domain are only expressed in females. We showed that female coding sequence was essential and sufficient for partial feminization. Comparative sequence and functional studies revealed that the evolutionary origination of the genetic switch was followed by the mutational origin of the essential ZnF domain. Our results demonstrate that glu is a newly evolved sex-specific genetic switch for region-specific regulation of a dimorphic character.
    DOI:  https://doi.org/10.1038/s41467-023-36153-4
  54. Nat Commun. 2023 Feb 02. 14(1): 563
    G9a/GLP inhibition during ex vivo lymphocyte expansion increases in vivo cytotoxicity of engineered T cells against hepatocellular carcinoma.
    Maxine S Y Lam, Jose Antonio Reales-Calderon, Jin Rong Ow, Joey J Y Aw, Damien Tan, Ragavi Vijayakumar, Erica Ceccarello, Tommaso Tabaglio, Yan Ting Lim, Wang Loo Chien, Fritz Lai, Anthony Tan Tanoto, Qingfeng Chen, Radoslaw M Sobota, Giulia Adriani, Antonio Bertoletti, Ernesto Guccione, Andrea Pavesi.
      Engineered T cells transiently expressing tumor-targeting receptors are an attractive form of engineered T cell therapy as they carry no risk of insertional mutagenesis or long-term adverse side-effects. However, multiple rounds of treatment are often required, increasing patient discomfort and cost. To mitigate this, we sought to improve the antitumor activity of transient engineered T cells by screening a panel of small molecules targeting epigenetic regulators for their effect on T cell cytotoxicity. Using a model for engineered T cells targetting hepatocellular carcinoma, we find that short-term inhibition of G9a/GLP increases T cell antitumor activity in in vitro models and an orthotopic mouse model. G9a/GLP inhibition increases granzyme expression without terminal T cell differentiation or exhaustion and results in specific changes in expression of genes and proteins involved in pro-inflammatory pathways, T cell activation and cytotoxicity.
    DOI:  https://doi.org/10.1038/s41467-023-36160-5
  55. Nat Immunol. 2023 Feb;24(2): 207-208
    Immunologic prediction of long COVID.
    Randy Q Cron.
      
    DOI:  https://doi.org/10.1038/s41590-022-01396-8
  56. Sci Adv. 2023 Feb 03. 9(5): eadd9789
    Chaperoning of specific tau structure by immunophilin FKBP12 regulates the neuronal resilience to extracellular stress.
    Lulu Jiang, Pijush Chakraborty, Lushuang Zhang, Melissa Wong, Shannon E Hill, Chelsea Joy Webber, Jenna Libera, Laura J Blair, Benjamin Wolozin, Markus Zweckstetter.
      Alzheimer's disease and related tauopathies are characterized by the pathogenic misfolding and aggregation of the microtubule-associated protein tau. Understanding how endogenous chaperones modulate tau misfolding could guide future therapies. Here, we show that the immunophilin FKBP12, the 12-kDa FK506-binding protein (also known as FKBP prolyl isomerase 1A), regulates the neuronal resilience by chaperoning a specific structure in monomeric tau. Using a combination of mouse and cell experiments, in vitro aggregation experiments, nuclear magnetic resonance-based structural analysis of monomeric tau, site-specific phosphorylation and mutation, as well as structure-based analysis using the neural network-based structure prediction program AlphaFold, we define the molecular factors that govern the binding of FKBP12 to tau and its influence on tau-induced neurotoxicity. We further demonstrate that tyrosine phosphorylation of tau blocks the binding of FKBP12 to two highly specific structural motifs in tau. Our data together with previous results demonstrating FKBP12/tau colocalization in neurons and neurofibrillary tangles support a critical role of FKBP12 in regulating tau pathology.
    DOI:  https://doi.org/10.1126/sciadv.add9789
  57. Sci Adv. 2023 Feb 03. 9(5): eadd6165
    RNA binding protein DDX5 restricts RORγt+ Treg suppressor function to promote intestine inflammation.
    Shengyun Ma, Qiyuan Yang, Nicholas Chen, Anna Zheng, Nazia Abbasi, Gaowei Wang, Parth R Patel, Benjamin S Cho, Brian A Yee, Lunfeng Zhang, Hiutung Chu, Sylvia M Evans, Gene W Yeo, Ye Zheng, Wendy Jia Men Huang.
      Retinoid-related orphan receptor (RAR) gamma (RORγt)-expressing regulatory T cells (RORγt+ Tregs) play pivotal roles in preventing T cell hyperactivation and maintaining tissue homeostasis, in part by secreting the anti-inflammation cytokine interleukin-10 (IL-10). Here, we report that hypoxia-induced factor 1α (HIF1α) is the master transcription factor for Il10 in RORγt+ Tregs. This critical anti-inflammatory pathway is negatively regulated by an RNA binding protein DEAD box helicase 5 (DDX5). As a transcriptional corepressor, DDX5 restricts the expression of HIF1α and its downstream target gene Il10 in RORγt+ Tregs. T cell-specific Ddx5 knockout (DDX5ΔT) mice have augmented RORγt+ Treg suppressor activities and are better protected from intestinal inflammation. Genetic ablation or pharmacologic inhibition of HIF1α restores enteropathy susceptibility in DDX5ΔT mice. The DDX5-HIF1α-IL-10 pathway is conserved in mice and humans. These findings reveal potential therapeutic targets for intestinal inflammatory diseases.
    DOI:  https://doi.org/10.1126/sciadv.add6165
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