bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–12–22
thirty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. A bile acid could explain how calorie restriction slows ageing.
  2. Transposon-derived decoy fine-tunes IFN responses.
  3. Muscle spindle macrophages regulate motor coordination.
  4. Identification of antigen-presenting cell-T cell interactions driving immune responses to food.
  5. Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids.
  6. How to find your place in science through an industry postdoc.
  7. The Nature Podcast festive spectacular 2024.
  8. Histone methyltransferase SETDB1 safeguards mouse fetal hematopoiesis by suppressing activation of cryptic enhancers.
  9. Daily briefing: How synthetic 'mirror life' bacteria could infect the world.
  10. Brain change trajectories in healthy adults correlate with Alzheimer's related genetic variation and memory decline across life.
  11. The small-drone revolution is coming - scientists need to ensure it will be safe.
  12. Spatial transcriptomic clocks reveal cell proximity effects in brain ageing.
  13. Should offensive species names be changed? The organisms that honour dictators, racists and criminals.
  14. Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice.
  15. Regulation of lipid storage and inflammation in the liver by CEACAM1.
  16. Heart failure phenotypes in people with type 1 diabetes.
  17. Unveiling adipose populations linked to metabolic health in obesity.
  18. HIF-2α drives TH2 cells.
  19. Autocrine TGF-β1 drives tissue-specific differentiation and function of resident NK cells.
  20. The danger of flipping an outside lipid to the inside.
  21. Efficacy of CTLA-4 checkpoint therapy is dependent on IL-21 signaling to mediate cytotoxic reprogramming of PD-1+CD8+ T cells.
  22. Metformin targets mitochondrial complex I to lower blood glucose levels.
  23. Design tips for reproducible studies linking the brain to behaviour.
  24. Guardians of the cell: mitochondria as a rheostat for cellular NAD+ levels.
  25. Carbohydrates-Last Food Order Improves Time in Range and Reduces Glycemic Variability.
  26. Endothelial BMAL1 decline during aging leads to bone loss by destabilizing extracellular fibrillin-1.
  27. Dysregulation of PI4P in the trans Golgi regions activates the mammalian Golgi stress response.
  28. Corticosteroids reduce pathological angiogenesis yet compromise reparative vascular remodeling in a model of retinopathy.
  29. Long COVID is associated with lower percentages of mature, cytotoxic NK cell phenotypes.
  30. Impaired Awareness and Symptomatology of Hypoglycemia in Adults with Type 1 Diabetes using Continuous Glucose Monitoring.
  1. Nature. 2024 Dec 18.
    A bile acid could explain how calorie restriction slows ageing.
    David A Sinclair.
      
    Keywords:  Ageing; Metabolism; Microbiome; Nutrition
    DOI:  https://doi.org/10.1038/d41586-024-04062-1
  2. Nat Rev Immunol. 2024 Dec 19.
    Transposon-derived decoy fine-tunes IFN responses.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-024-01126-1
  3. Nat Rev Immunol. 2024 Dec 16.
    Muscle spindle macrophages regulate motor coordination.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-024-01125-2
  4. Science. 2024 Dec 19. eado5088
    Identification of antigen-presenting cell-T cell interactions driving immune responses to food.
    Maria C C Canesso, Tiago B R Castro, Sandra Nakandakari-Higa, Ainsley Lockhart, Julia Luehr, Juliana Bortolatto, Roham Parsa, Daria Esterházy, Mengze Lyu, Tian-Tian Liu, Kenneth M Murphy, Gregory F Sonnenberg, Bernardo S Reis, Gabriel D Victora, Daniel Mucida.
      The intestinal immune system must concomitantly tolerate food and commensals and protect against pathogens. Antigen-presenting cells (APCs) orchestrate these immune responses by presenting luminal antigens to CD4+ T cells and inducing their differentiation into regulatory (pTreg) or inflammatory (Th) subsets. We used a proximity labeling method (LIPSTIC) to identify APCs that presented dietary antigens under tolerizing and inflammatory conditions and understand cellular mechanisms by which tolerance to food is induced and can be disrupted by infection. Helminth infections disrupted tolerance induction proportionally to the reduction in the ratio between tolerogenic APCs, including migratory dendritic cells (cDC1s) and Rorγt+ APCs, and inflammatory APCs, that were primarily cDC2s. These inflammatory cDC2s expanded by helminth infection did not present dietary antigens, thus avoiding diet-specific Th2 responses.
    DOI:  https://doi.org/10.1126/science.ado5088
  5. J Lipid Res. 2024 Dec 13. pii: S0022-2275(24)00235-9. [Epub ahead of print] 100730
    Type I IFN induces long-chain acyl-CoA synthetase 1 to generate a phosphatidic acid reservoir for lipotoxic saturated fatty acids.
    Shelley Barnhart, Masami Shimizu-Albergine, Eyal Kedar, Vishal Kothari, Baohai Shao, Melissa Krueger, Cheng-Chieh Hsu, Jingjing Tang, Jenny E Kanter, Farah Kramer, Danijel Djukovic, Vadim Pascua, Yueh-Ming Loo, Lucrezia Colonna, Sadie J Van den Bogaerde, Jie An, Michael Gale, Karen Reue, Edward A Fisher, Sina A Gharib, Keith B Elkon, Karin E Bornfeldt.
      Long-chain acyl-CoA synthetase 1 (ACSL1) catalyzes the conversion of long-chain fatty acids to acyl-CoAs. ACSL1 is required for β-oxidation in tissues that rely on fatty acids as fuel, but no consensus exists on why ACSL1 is induced by inflammatory mediators in immune cells. We used a comprehensive and unbiased approach to investigate the role of ACSL1 induction by interferon type I (IFN-I) in myeloid cells in vitro and in a mouse model of IFN-I overproduction. Our results show that IFN-I induces ACSL1 in macrophages via its interferon-α/β receptor, and consequently that expression of ACSL1 is increased in myeloid cells from individuals with systemic lupus erythematosus (SLE), an autoimmune condition characterized by increased IFN production. Taking advantage of a myeloid cell-targeted ACSL1-deficient mouse model and a series of lipidomics, proteomics, metabolomics and functional analyses, we show that IFN-I leverages induction of ACSL1 to increase accumulation of fully saturated phosphatidic acid species in macrophages. Conversely, ACSL1 induction is not needed for IFN-I's ability to induce the prototypical IFN-stimulated protein signature or to suppress proliferation or macrophage metabolism. Loss of ACSL1 in IFN-I stimulated myeloid cells enhances apoptosis and secondary necrosis in vitro, especially in the presence of increased saturated fatty acid load, and in a mouse model of atherosclerosis associated with IFN overproduction, resulting in larger lesion necrotic cores. We propose that ACSL1 induction is a mechanism used by IFN-I to increase phosphatidic acid saturation while protecting the cells from saturated fatty acid-induced cell death.
    Keywords:  Bis[monoacylglycerol]phosphates; Enzymology/Enzyme mechanisms; Glycerophospholipids; Inflammation; Lipotoxicity; Macrophage; Phospholipids/Phosphatidic acid
    DOI:  https://doi.org/10.1016/j.jlr.2024.100730
  6. Nature. 2025 Jan;637(8044): 241-242
    How to find your place in science through an industry postdoc.
    Chris Woolston.
      
    Keywords:  Careers; Health care; Industry; Lab life
    DOI:  https://doi.org/10.1038/d41586-024-04169-5
  7. Nature. 2024 Dec 18.
    The Nature Podcast festive spectacular 2024.
    Nick Petrić Howe, Benjamin Thompson.
      
    Keywords:  Cancer; Diabetes; Diseases; Obesity
    DOI:  https://doi.org/10.1038/d41586-024-04225-0
  8. Proc Natl Acad Sci U S A. 2024 Dec 24. 121(52): e2409656121
    Histone methyltransferase SETDB1 safeguards mouse fetal hematopoiesis by suppressing activation of cryptic enhancers.
    Maryam Kazerani, Filippo Cernilogar, Alessandra Pasquarella, Maria Hinterberger, Alexander Nuber, Ludger Klein, Gunnar Schotta.
      The H3K9me3-specific histone methyltransferase SETDB1 is critical for proper regulation of developmental processes, but the underlying mechanisms are only partially understood. Here, we show that deletion of Setdb1 in mouse fetal liver hematopoietic stem and progenitor cells (HSPCs) results in compromised stem cell function, enhanced myeloerythroid differentiation, and impaired lymphoid development. Notably, Setdb1-deficient HSPCs exhibit reduced quiescence and increased proliferation, accompanied by the acquisition of a lineage-biased transcriptional program. In Setdb1-deficient HSPCs, we identify genomic regions that are characterized by loss of H3K9me3 and increased chromatin accessibility, suggesting enhanced transcription factor (TF) activity. Interestingly, hematopoietic TFs like PU.1 bind these cryptic enhancers in wild-type HSPCs, despite the H3K9me3 status. Thus, our data indicate that SETDB1 restricts activation of nonphysiological TF binding sites which helps to ensure proper maintenance and differentiation of fetal liver HSPCs.
    Keywords:  ERV; H3K9me3; epigenetics; hematopoietic stem cells; heterochromatin
    DOI:  https://doi.org/10.1073/pnas.2409656121
  9. Nature. 2024 Dec 17.
    Daily briefing: How synthetic 'mirror life' bacteria could infect the world.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-04223-2
  10. Nat Commun. 2024 Dec 17. 15(1): 10651
    Brain change trajectories in healthy adults correlate with Alzheimer's related genetic variation and memory decline across life.
    Alzheimer’s Disease Neuroimaging Initiative
      Throughout adulthood and ageing our brains undergo structural loss in an average pattern resembling faster atrophy in Alzheimer's disease (AD). Using a longitudinal adult lifespan sample (aged 30-89; 2-7 timepoints) and four polygenic scores for AD, we show that change in AD-sensitive brain features correlates with genetic AD-risk and memory decline in healthy adults. We first show genetic risk links with more brain loss than expected for age in early Braak regions, and find this extends beyond APOE genotype. Next, we run machine learning on AD-control data from the Alzheimer's Disease Neuroimaging Initiative using brain change trajectories conditioned on age, to identify AD-sensitive features and model their change in healthy adults. Genetic AD-risk linked with multivariate change across many AD-sensitive features, and we show most individuals over age ~50 are on an accelerated trajectory of brain loss in AD-sensitive regions. Finally, high genetic risk adults with elevated brain change showed more memory decline through adulthood, compared to high genetic risk adults with less brain change. Our findings suggest quantitative AD risk factors are detectable in healthy individuals, via a shared pattern of ageing- and AD-related neurodegeneration that occurs along a continuum and tracks memory decline through adulthood.
    DOI:  https://doi.org/10.1038/s41467-024-53548-z
  11. Nature. 2025 Jan;637(8044): 29-30
    The small-drone revolution is coming - scientists need to ensure it will be safe.
    Xun Huang.
      
    Keywords:  Engineering; Policy; Technology
    DOI:  https://doi.org/10.1038/d41586-024-04167-7
  12. Nature. 2024 Dec 18.
    Spatial transcriptomic clocks reveal cell proximity effects in brain ageing.
    Eric D Sun, Olivia Y Zhou, Max Hauptschein, Nimrod Rappoport, Lucy Xu, Paloma Navarro Negredo, Ling Liu, Thomas A Rando, James Zou, Anne Brunet.
      Old age is associated with a decline in cognitive function and an increase in neurodegenerative disease risk1. Brain ageing is complex and is accompanied by many cellular changes2. Furthermore, the influence that aged cells have on neighbouring cells and how this contributes to tissue decline is unknown. More generally, the tools to systematically address this question in ageing tissues have not yet been developed. Here we generate a spatially resolved single-cell transcriptomics brain atlas of 4.2 million cells from 20 distinct ages across the adult lifespan and across two rejuvenating interventions-exercise and partial reprogramming. We build spatial ageing clocks, machine learning models trained on this spatial transcriptomics atlas, to identify spatial and cell-type-specific transcriptomic fingerprints of ageing, rejuvenation and disease, including for rare cell types. Using spatial ageing clocks and deep learning, we find that T cells, which increasingly infiltrate the brain with age, have a marked pro-ageing proximity effect on neighbouring cells. Surprisingly, neural stem cells have a strong pro-rejuvenating proximity effect on neighbouring cells. We also identify potential mediators of the pro-ageing effect of T cells and the pro-rejuvenating effect of neural stem cells on their neighbours. These results suggest that rare cell types can have a potent influence on their neighbours and could be targeted to counter tissue ageing. Spatial ageing clocks represent a useful tool for studying cell-cell interactions in spatial contexts and should allow scalable assessment of the efficacy of interventions for ageing and disease.
    DOI:  https://doi.org/10.1038/s41586-024-08334-8
  13. Nature. 2024 Dec 16.
    Should offensive species names be changed? The organisms that honour dictators, racists and criminals.
    Benjamin Thompson.
      
    Keywords:  Communication; Ethics; Publishing; Society
    DOI:  https://doi.org/10.1038/d41586-024-04200-9
  14. Science. 2024 Dec 20. 386(6728): eadp6547
    Boosting neuronal activity-driven mitochondrial DNA transcription improves cognition in aged mice.
    Wenwen Li, Jiarui Li, Jing Li, Chen Wei, Tal Laviv, Meiyi Dong, Jingran Lin, Mariah Calubag, Lesley A Colgan, Kai Jin, Bing Zhou, Ying Shen, Haohong Li, Yihui Cui, Zhihua Gao, Tao Li, Hailan Hu, Ryohei Yasuda, Huan Ma.
      Deciphering the complex interplay between neuronal activity and mitochondrial function is pivotal in understanding brain aging, a multifaceted process marked by declines in synaptic function and mitochondrial performance. Here, we identified an age-dependent coupling between neuronal and synaptic excitation and mitochondrial DNA transcription (E-TCmito), which operates differently compared to classic excitation-transcription coupling in the nucleus (E-TCnuc). We demonstrated that E-TCmito repurposes molecules traditionally associated with E-TCnuc to regulate mitochondrial DNA expression in areas closely linked to synaptic activation. The effectiveness of E-TCmito weakens with age, contributing to age-related neurological deficits in mice. Boosting brain E-TCmito in aged animals ameliorated these impairments, offering a potential target to counteract age-related cognitive decline.
    DOI:  https://doi.org/10.1126/science.adp6547
  15. Eur J Clin Invest. 2024 Dec;54 Suppl 2 e14338
    Regulation of lipid storage and inflammation in the liver by CEACAM1.
    Sonia M Najjar, John E Shively.
      This review focuses on a special aspect of hepatic lipid storage and inflammation that occurs during nutritional excess in obesity. Mounting evidence supports that prolonged excess fatty acid (FA) uptake in the liver is strongly associated with hepatic lipid storage and inflammation and that the two processes are closely linked by a homeostatic mechanism. There is also strong evidence that bacterial lipids may enter the gut by a common mechanism with lipid absorption and that there is a set point to determine when their uptake triggers an inflammatory response in the liver. In fact, the progression from high uptake of FAs in the liver resulting in Metabolic dysfunction-associated steatotic liver disease (MASLD) to the development of the more serious Metabolic dysfunction-associated steatohepatitis (MASH) depends on the degree of inflammation and its progression from an acute to a chronic state. Thus, MASLD/MASH implicates both excess fatty acids and progressive inflammation in the aetiology of liver disease. We start the discussion by introduction of CD36, a major player in FA and lipopolysaccharide (LPS) uptake in the duodenum, liver and adipose tissue. We will then introduce CEACAM1, a major player in the regulation of hepatic de novo lipogenesis and the inflammatory response in the liver, and its dual association with CD36 in enterocytes and hepatocytes. We conclude that CEACAM1 and CD36 together regulate lipid droplet formation and inflammation in the liver.
    Keywords:  CD36; CEACAM1; LPS; fatty liver disease; inflammation
    DOI:  https://doi.org/10.1111/eci.14338
  16. Diabetes Obes Metab. 2024 Dec 17.
    Heart failure phenotypes in people with type 1 diabetes.
    Abigail P Erwin, James T Patrie, William B Horton.
      
    Keywords:  heart failure; type 1 diabetes mellitus
    DOI:  https://doi.org/10.1111/dom.16133
  17. Cell Metab. 2024 Dec 11. pii: S1550-4131(24)00452-2. [Epub ahead of print]
    Unveiling adipose populations linked to metabolic health in obesity.
    Isabel Reinisch, Adhideb Ghosh, Falko Noé, Wenfei Sun, Hua Dong, Peter Leary, Arne Dietrich, Anne Hoffmann, Matthias Blüher, Christian Wolfrum.
      Precision medicine is still not considered as a standard of care in obesity treatment, despite a large heterogeneity in the metabolic phenotype of individuals with obesity. One of the strongest factors influencing the variability in metabolic disease risk is adipose tissue (AT) dysfunction; however, there is little understanding of the link between distinct cell populations, cell-type-specific transcriptional programs, and disease severity. Here, we generated a comprehensive cellular map of subcutaneous and visceral AT of individuals with metabolically healthy and unhealthy obesity. By combining single-nucleus RNA-sequencing data with bulk transcriptomics and clinical parameters, we identified that mesothelial cells, adipocytes, and adipocyte-progenitor cells exhibit the strongest correlation with metabolic disease. Furthermore, we uncovered cell-specific transcriptional programs, such as the transitioning of mesothelial cells to a mesenchymal phenotype, that are involved in uncoupling obesity from metabolic disease. Together, these findings provide valuable insights by revealing biological drivers of clinical endpoints.
    Keywords:  adipocytes; adipose tissue; insulin resistance; insulin sensitivity; mesothelial cells; metabolically healthy obesity; obesity; precision medicine; snRNA-seq; visceral adipose tissue
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.006
  18. Sci Signal. 2024 Dec 17. 17(867): eadv2653
    HIF-2α drives TH2 cells.
    John F Foley.
      Inhibiting HIF-2α impairs the development and function of asthma-promoting helper T cells in mice.
    DOI:  https://doi.org/10.1126/scisignal.adv2653
  19. J Exp Med. 2025 Mar 03. pii: e20240930. [Epub ahead of print]222(3):
    Autocrine TGF-β1 drives tissue-specific differentiation and function of resident NK cells.
    Colin Sparano, Darío Solís-Sayago, Nathan Sébastien Zangger, Lukas Rindlisbacher, Hannah Van Hove, Marijne Vermeer, Frederike Westermann, Caroline Mussak, Elisa Rallo, Stanislav Dergun, Gioana Litscher, Yishu Xu, Mitchell Bijnen, Christin Friedrich, Melanie Greter, Vanda Juranić Lisnić, Burkhard Becher, Georg Gasteiger, Annette Oxenius, Sonia Tugues.
      Group 1 innate lymphoid cells (ILCs) encompass NK cells and ILC1s, which have non-redundant roles in host protection against pathogens and cancer. Despite their circulating nature, NK cells can establish residency in selected tissues during ontogeny, forming a distinct functional subset. The mechanisms that initiate, maintain, and regulate the conversion of NK cells into tissue-resident NK (trNK) cells are currently not well understood. Here, we identify autocrine transforming growth factor-β (TGF-β) as a cell-autonomous driver for NK cell tissue residency across multiple glandular tissues during development. Cell-intrinsic production of TGF-β was continuously required for the maintenance of trNK cells and synergized with Hobit to enhance cytotoxic function. Whereas autocrine TGF-β was redundant in tumors, our study revealed that NK cell-derived TGF-β allowed the expansion of cytotoxic trNK cells during local infection with murine cytomegalovirus (MCMV) and contributed to viral control in the salivary gland. Collectively, our findings reveal tissue-specific regulation of trNK cell differentiation and function by autocrine TGF-β1, which is relevant for antiviral immunity.
    DOI:  https://doi.org/10.1084/jem.20240930
  20. Proc Natl Acad Sci U S A. 2024 Dec 24. 121(52): e2421371121
    The danger of flipping an outside lipid to the inside.
    Todd R Graham.
      
    DOI:  https://doi.org/10.1073/pnas.2421371121
  21. Nat Immunol. 2024 Dec 19.
    Efficacy of CTLA-4 checkpoint therapy is dependent on IL-21 signaling to mediate cytotoxic reprogramming of PD-1+CD8+ T cells.
    Zhen Zhang, Marlene Langenbach, Sagar Sagar, Viktor Fetsch, Jonas Stritzker, Elizabeth Severa, Ke Meng, Frances Winkler, Nisha Rana, Katharina Zoldan, Ira Godbole, Sabrina Solis, Jeffrey S Weber, David Rafei-Shamsabadi, Saskia Lehr, Rebecca Diehl, Ana Cecilia Venhoff, Reinhard E Voll, Nico Buettner, Christoph Neumann-Haefelin, Tobias Boettler, Maike Hofmann, Melanie Boerries, Frank Meiss, Robert Zeiser, Robert Thimme, Ramin S Herati, Bertram Bengsch.
      The mechanisms underlying the efficacy of anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) therapy are incompletely understood. Here, by immune profiling responding PD-1+CD8+ T (TResp) cell populations from patients with advanced melanoma, we identified differential programming of TResp cells in response to combination therapy, from an exhausted toward a more cytotoxic effector program. This effect does not occur with anti-PD-1 monotherapy. Single-cell transcriptome and T cell receptor repertoire analysis was used to identify altered effector programming of expanding PD-1+CD8+ T cell clones with distinct regulon usage, STAT1 and STAT3 utilization and antitumor specificity connected to interleukin (IL)-21 signaling in combination and anti-CTLA-4 monotherapy. Therapeutic efficacy of CTLA-4 blockade was lost in B16F10 melanoma models with either Il21r- deficiency or anti-IL-21 receptor blockade. Together, these results show how IL-21 signaling to TResp is critical for anti-CTLA-4-based checkpoint therapies and highlight major signaling differences to anti-PD-1 monotherapy.
    DOI:  https://doi.org/10.1038/s41590-024-02027-0
  22. Sci Adv. 2024 Dec 20. 10(51): eads5466
    Metformin targets mitochondrial complex I to lower blood glucose levels.
    Colleen R Reczek, Ram P Chakrabarty, Karis B D'Alessandro, Zachary L Sebo, Rogan A Grant, Peng Gao, G R Budinger, Navdeep S Chandel.
      Metformin is among the most prescribed antidiabetic drugs, but the primary molecular mechanism by which metformin lowers blood glucose levels is unknown. Previous studies have proposed numerous mechanisms by which acute metformin lowers blood glucose, including the inhibition of mitochondrial complex I of the electron transport chain (ETC). Here, we used transgenic mice that globally express the Saccharomyces cerevisiae internal alternative NADH dehydrogenase (NDI1) protein to determine whether the glucose-lowering effect of acute oral administration of metformin requires inhibition of mitochondrial complex I of the ETC in vivo. NDI1 is a yeast NADH dehydrogenase enzyme that complements the loss of mammalian mitochondrial complex I electron transport function and is insensitive to pharmacologic mitochondrial complex I inhibitors including metformin. We demonstrate that NDI1 expression attenuates metformin's ability to lower blood glucose levels under standard chow and high-fat diet conditions. Our results indicate that acute oral administration of metformin targets mitochondrial complex I to lower blood glucose.
    DOI:  https://doi.org/10.1126/sciadv.ads5466
  23. Nature. 2024 Dec;636(8043): 581-583
    Design tips for reproducible studies linking the brain to behaviour.
    Roselyne J Chauvin, Nico U F Dosenbach.
      
    Keywords:  Brain; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-03650-5
  24. Nat Metab. 2024 Dec;6(12): 2215-2217
    Guardians of the cell: mitochondria as a rheostat for cellular NAD+ levels.
    Fiona M Fitzpatrick, Nora Kory.
      
    DOI:  https://doi.org/10.1038/s42255-024-01160-2
  25. Diabetes Care. 2024 Dec 17. pii: dc241956. [Epub ahead of print]
    Carbohydrates-Last Food Order Improves Time in Range and Reduces Glycemic Variability.
    Samir Touhamy, Kathyayini Palepu, Ampadi Karan, Katie C Hootman, Jessica Riad, Sriharsha Sripadrao, Alice S Zhao, Ashley Giannita, Debra D'Angelo, Laura C Alonso, Louis J Aronne, Alpana P Shukla.
      
    DOI:  https://doi.org/10.2337/dc24-1956
  26. J Clin Invest. 2024 Dec 16. pii: e176660. [Epub ahead of print]134(24):
    Endothelial BMAL1 decline during aging leads to bone loss by destabilizing extracellular fibrillin-1.
    Ying Yin, Qingming Tang, Jingxi Yang, Shiqi Gui, Yifan Zhang, Yufeng Shen, Xin Zhou, Shaoling Yu, Guangjin Chen, Jiwei Sun, Zhenshuo Han, Luoying Zhang, Lili Chen.
      The occurrence of aging is intricately associated with alterations in circadian rhythms that coincide with stem cell exhaustion. Nonetheless, the extent to which the circadian system governs skeletal aging remains inadequately understood. Here, we noticed that skeletal aging in male mice was accompanied by a decline in a core circadian protein, BMAL1, especially in bone marrow endothelial cells (ECs). Using male mice with endothelial KO of aryl hydrocarbon receptor nuclear translocator-like protein 1 (Bmal1), we ascertained that endothelial BMAL1 in bone played a crucial role in ensuring the stability of an extracellular structural component, fibrillin-1 (FBN1), through regulation of the equilibrium between the extracellular matrix (ECM) proteases thrombospondin type 1 domain-containing protein 4 (THSD4) and metalloproteinase with thrombospondin motifs 4 (ADAMTS4), which promote FBN1 assembly and breakdown, respectively. The decline of endothelial BMAL1 during aging prompted excessive breakdown of FBN1, leading to persistent activation of TGF-β/SMAD3 signaling and exhaustion of bone marrow mesenchymal stem cells. Meanwhile, the free TGF-β could promote osteoclast formation. Further analysis revealed that activation of ADAMTS4 in ECs lacking BMAL1 was stimulated by TGF-β/SMAD3 signaling through an ECM-positive feedback mechanism, whereas THSD4 was under direct transcriptional control by endothelial BMAL1. Our investigation has elucidated the etiology of bone aging in male mice by defining the role of ECs in upholding the equilibrium within the ECM, consequently coordinating osteogenic and osteoclastic activities and retarding skeletal aging.
    Keywords:  Aging; Bone biology; Bone disease; Cellular senescence; Extracellular matrix
    DOI:  https://doi.org/10.1172/JCI176660
  27. J Biol Chem. 2024 Dec 13. pii: S0021-9258(24)02577-8. [Epub ahead of print] 108075
    Dysregulation of PI4P in the trans Golgi regions activates the mammalian Golgi stress response.
    Kanae Sasaki, Marika Toide, Takuya Adachi, Fumi Morishita, Yuto Watanabe, Hajime Tajima Sakurai, Sadao Wakabayashi, Satoshi Kusumi, Toshiyuki Yamaji, Kaori Sakurai, Daisuke Koga, Kentaro Hanada, Masafumi Yohda, Hiderou Yoshida.
      The Golgi stress response is an important cytoprotective system that enhances Golgi function in response to cellular demand, while cells damaged by prolonged Golgi stress undergo cell death. OSW-1, a natural compound with anticancer activity, potently inhibits OSBP that transports cholesterol and phosphatidylinositol-4-phosphate (PI4P) at contact sites between the endoplasmic reticulum and the Golgi apparatus. Previously, we reported that OSW-1 induces the Golgi stress response, resulting in Golgi stress-induced transcription and cell death. However, the underlying molecular mechanism has been unknown. To reveal the mechanism of a novel pathway of the Golgi stress response regulating transcriptional induction and cell death (the PI4P pathway), we performed a genome-wide knockout screen and found that transcriptional induction as well as cell death induced by OSW-1 was repressed by the loss of regulators of PI4P synthesis, such as PITPNB and PI4KB. Our data indicate that OSW-1 induces Golgi stress-dependent transcriptional induction and cell death through dysregulation of the PI4P metabolism in the Golgi.
    Keywords:  Golgi stress response; OSW-1; cancer; phosphatidylinositol-4-phosphate; the Genome-wide CRISPR-Cas9 knockout screening
    DOI:  https://doi.org/10.1016/j.jbc.2024.108075
  28. Proc Natl Acad Sci U S A. 2024 Dec 24. 121(52): e2411640121
    Corticosteroids reduce pathological angiogenesis yet compromise reparative vascular remodeling in a model of retinopathy.
    Masayuki Hata, Maki Hata, Agnieszka Dejda, Frédérique Pilon, Roberto Diaz-Marin, Frédérik Fournier, Jean-Sebastien Joyal, Gael Cagnone, Yotaro Ochi, Sergio Crespo-Garcia, Ariel M Wilson, Przemyslaw Sapieha.
      Tissue inflammation is often broadly associated with cellular damage, yet sterile inflammation also plays critical roles in beneficial tissue remodeling. In the central nervous system, this is observed through a predominantly innate immune response in retinal vascular diseases such as age-related macular degeneration, diabetic retinopathy, and retinopathy of prematurity. Here, we set out to elucidate the dynamics of the immune response during progression and regression of pathological neovascularization in retinopathy. In a mouse model of oxygen-induced retinopathy, we report that dexamethasone, a broad-spectrum corticosteroid, suppresses initial formation of pathological preretinal neovascularization in early stages of disease, yet blunts reparative inflammation by impairing distinct myeloid cell populations, and hence reduces beneficial vascular remodeling in later stages of disease. Using genetic depletion of distinct components of the innate immune response, we demonstrate that CX3C chemokine receptor 1-expressing microglia contribute to angiogenesis. Conversely, myeloid cells expressing lysozyme 2 are recruited to sites of damaged blood vessels and pathological neovascularization where they partake in a reparative process that ultimately restores circulatory homeostasis to the retina. Hence, the Janus-faced properties of anti-inflammatory drugs should be considered, particularly in stages associated with persistent neovascularization.
    Keywords:  angiogenesis; dexamethasone; inflammation; retina; retinopathy
    DOI:  https://doi.org/10.1073/pnas.2411640121
  29. J Clin Invest. 2024 Dec 17. pii: e188182. [Epub ahead of print]
    Long COVID is associated with lower percentages of mature, cytotoxic NK cell phenotypes.
    Tasha Tsao, Amanda M Buck, Lilian Grimbert, Brian H LaFranchi, Belen Altamirano Poblano, Emily A Fehrman, Thomas Dalhuisen, Priscilla Y Hsue, J Daniel Kelly, Jeffrey N Martin, Steven G Deeks, Peter W Hunt, Michael J Peluso, Oscar A Aguilar, Timothy J Henrich.
      
    Keywords:  Immunology; Infectious disease; Innate immunity; NK cells
    DOI:  https://doi.org/10.1172/JCI188182
  30. J Clin Endocrinol Metab. 2024 Dec 05. pii: dgae846. [Epub ahead of print]
    Impaired Awareness and Symptomatology of Hypoglycemia in Adults with Type 1 Diabetes using Continuous Glucose Monitoring.
    Yu Kuei Lin, Wen Ye, Emily Hepworth, Michael R Rickels, Stephanie A Amiel, Jane Speight, James A M Shaw.
       CONTEXT & OBJECTIVE: Sparse large-scale studies have characterized hypoglycemia symptomatology in adults with type 1 diabetes (T1D) who use continuous glucose monitoring (CGM). This research aimed to evaluate the relationship of impaired awareness of hypoglycemia (IAH) with hypoglycemia symptomatology and frequency in this population.
    DESIGN: A cross-sectional survey was conducted in 2023. HypoA-Q was used to evaluate hypoglycemia frequency, symptomatology, and awareness.
    SETTING & PARTICIPANTS: Registrants who used CGM in the T1D Exchange, a U.S. national T1D registry.
    RESULTS: Surveys were completed by 1,480 adults with T1D who used CGM (53% female; mean diabetes duration 26 years). Compared to those with intact hypoglycemia awareness, IAH was associated with less frequent hypoglycemia symptom presentation across various glucose levels and lower glucose concentrations for first presenting hypoglycemia symptoms when awake (P<0.05 for all). More than 70% of individuals with IAH did not regularly experience symptoms during episodes with glucose <54 mg/dL. When asleep, those with IAH were less frequently awoken by symptoms, more frequently awoken by others who recognized their hypoglycemia, and more frequently acknowledged hypoglycemia after an episode (P<0.05 for all) despite using CGM. With reduced symptoms, both when awake and asleep, those with IAH experienced more hypoglycemic episodes that they were unable to self-treat than those with intact awareness (P<0.05).
    CONCLUSION: IAH continues to be associated with a significant reduction in detection of hypoglycemia symptoms, both when awake and asleep, in adults using CGM. Current diabetes technologies do not fully protect adults with type 1 diabetes from hypoglycemia.
    Keywords:  continuous glucose monitors; hypoglycemia; hypoglycemia symptomatology; impaired awareness of hypoglycemia; type 1 diabetes
    DOI:  https://doi.org/10.1210/clinem/dgae846
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