bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–05–03
twenty-two papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Mapping specific lipid-protein interactions in living cells.
  2. Sex differences in Alzheimer's.
  3. Whole mouse profiling.
  4. SLC33A1-mediated glutathione transport regulates ER redox balance and function.
  5. Foxp3: The epigenetic engineer of regulatory T cell identity.
  6. US faculty members report high levels of anxiety.
  7. Nuclear genetic modulation of tissue-specific mitochondrial RNA processing contributes to common disease risk.
  8. THEMIS attenuates MASH by suppressing disease-associated hepatocyte induction and hepatocyte senescence in mice.
  9. Genetic association and machine learning improve the prediction of type 1 diabetes risk.
  10. The mechanics of LPS recognition.
  11. GLP-1R-GIPR-PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice.
  12. ATM lifts the cGAS handbrake on DNA replication.
  13. Antibody-siRNA conjugates enable macrophage-specific osteopontin inhibition to suppress atrial fibrillation.
  14. Impaired glucose tolerance and mild diabetes induce β-cell dysfunction in mice.
  15. Mitochondria can spawn new 'organelles' - hinting at how modern cells evolved.
  16. Tracking the turning point in Alzheimer's disease.
  17. Coupled cross-sectional and longitudinal non-negative matrix factorization reveals dominant brain aging trajectories in 48,949 individuals.
  18. IFNγ blockade in Mycobacterium tuberculosis infected macaques alters the granuloma environment but not bacterial control.
  19. Submicrometre sampling of living cells by macrophages.
  20. Why you should 'feed a cold': eating primes immune cells for action.
  21. Higher racial diversity in US business and law schools is linked to higher graduate salaries.
  22. Ten lessons from a decade of scientific translation at the Crick.
  1. Nat Cell Biol. 2026 May 01.
    Mapping specific lipid-protein interactions in living cells.
      
    DOI:  https://doi.org/10.1038/s41556-026-01952-6
  2. Nat Immunol. 2026 May;27(5): 885
    Sex differences in Alzheimer's.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-026-02519-1
  3. Nat Immunol. 2026 May;27(5): 885
    Whole mouse profiling.
    Nicholas J Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-026-02518-2
  4. Nat Cell Biol. 2026 May 01.
    SLC33A1-mediated glutathione transport regulates ER redox balance and function.
      
    DOI:  https://doi.org/10.1038/s41556-026-01929-5
  5. Sci Immunol. 2026 May;11(119): eaeg4759
    Foxp3: The epigenetic engineer of regulatory T cell identity.
    Mieke Metzemaekers, Ralph Stadhouders.
      Foxp3 exerts context-dependent chromatin-remodeling activity to establish key epigenetic programs that define the functional identity of regulatory T cells (see related Research Article by Wei et al.).
    DOI:  https://doi.org/10.1126/sciimmunol.aeg4759
  6. Nature. 2026 May 01.
    US faculty members report high levels of anxiety.
    Amanda Heidt.
      
    Keywords:  Careers; Institutions; Lab life
    DOI:  https://doi.org/10.1038/d41586-026-01252-x
  7. Nat Commun. 2026 Apr 30.
    Nuclear genetic modulation of tissue-specific mitochondrial RNA processing contributes to common disease risk.
    Eleonora Centanini, Oliver Pain, Patrick F Chinnery, Alan Hodgkinson.
      Mitochondrial dysfunction is widely implicated in human disease, yet whether it plays a causal role and why effects are tissue-specific remain unclear. Here, we analyse over 15,000 RNA-sequencing datasets from 49 tissue types integrated with germline genetic data to investigate the impact of mitochondrial DNA (mtDNA) transcription on disease risk. We identify 25 nuclear genetic variants associated with mtDNA transcript abundance, revealing gene- and tissue-specific regulatory architectures. We then develop tissue-specific genetic scores to predict mtDNA transcript levels and validate them in independent datasets. Applying these scores to 377,439 UK Biobank participants reveals significant associations between predicted mtDNA transcript abundance and multiple common diseases and quantitative traits, many showing marked tissue specificity, including associations with hypertension and Parkinson's disease in biologically relevant tissues. These findings provide genetic evidence that variation in mtDNA transcriptional processes contributes to complex disease biology and highlight mitochondrial RNA processing as a compelling therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-026-72649-5
  8. J Clin Invest. 2026 May 01. pii: e199303. [Epub ahead of print]136(9):
    THEMIS attenuates MASH by suppressing disease-associated hepatocyte induction and hepatocyte senescence in mice.
    Xiaoxue Qiu, You Lu, Yuwei Tang, Linkang Zhou, Yu-Tung Lee, Ziyi Meng, Zhimin Chen, Fnu Pradeepa, Lanuza Ap Faccioli, Zhiping Hu, Alejandro Soto-Gutierrez, Siming Li, Jiandie D Lin.
      Hepatocyte senescence is increasingly recognized as a pathogenic driver of metabolic dysfunction-associated steatohepatitis (MASH). Through single-nucleus transcriptomic profiling, we identified a discrete population of disease-associated hepatocytes (daHep) exhibiting enrichment for senescence markers in MASH livers. The emergence of senescent hepatocytes was associated with a marked induction of hepatic thymocyte selection associated (THEMIS) expression in both murine and human MASH. Genetic ablation of Themis, either globally or specifically in hepatocytes, resulted in significant expansion of daHep and senescent hepatocyte populations and exacerbated MASH pathology in mice. Single-nucleus transcriptomic analysis revealed a central role for THEMIS in shaping the cellular landscape of both parenchymal and nonparenchymal compartments within the MASH liver microenvironment. Conversely, adeno-associated virus-mediated overexpression of THEMIS suppressed hepatocyte senescence and attenuated diet-induced MASH. Mechanistic studies revealed that THEMIS deficiency promoted aberrant ERK phosphorylation and hepatocyte senescence. These findings establish THEMIS as a critical hepatoprotective factor that restrains hepatocyte senescence and mitigates metabolic liver disease progression.
    Keywords:  Cellular senescence; Hepatology; Metabolism
    DOI:  https://doi.org/10.1172/JCI199303
  9. Nat Genet. 2026 Apr 30.
    Genetic association and machine learning improve the prediction of type 1 diabetes risk.
    Carolyn McGrail, Timothy J Sears, Emily N Griffin, Alexandra L Ghaben, Patrick Smadbeck, Jason Flannick, Parul Kudtarkar, Hannah Carter, Kyle Gaulton.
      Type 1 diabetes (T1D) has a large genetic component, and expanded genetic studies of T1D can enhance biological and therapeutic discovery and improve risk prediction. Here we performed genome-wide genetic association and fine-mapping analyses in 20,355 T1D and 797,363 nondiabetic individuals of European ancestry and in 10,107 T1D and 19,639 nondiabetic individuals at the MHC locus, which identified 160 risk signals. We trained a machine learning model, T1GRS, to predict T1D using genetic risk, which improved classification in Europeans and performed similarly in African Americans, compared to previous scores. T1GRS particularly improved prediction in T1D, with fewer high-risk HLA haplotypes and more complex risk profiles, and revealed 154 nonlinear interactions between MHC and non-MHC loci. Finally, we identified four genetic subclusters based on T1GRS features with significant differences in age of onset and diabetic complications. Overall, improved genetic discovery and prediction will have wide clinical, therapeutic and research applications for T1D.
    DOI:  https://doi.org/10.1038/s41588-026-02578-y
  10. Nat Immunol. 2026 May;27(5): 885
    The mechanics of LPS recognition.
    Ioana Staicu.
      
    DOI:  https://doi.org/10.1038/s41590-026-02521-7
  11. Nature. 2026 Apr 29.
    GLP-1R-GIPR-PPARα/γ/δ quintuple agonism corrects obesity and diabetes in mice.
    Daniela Liskiewicz, Aaron Novikoff, Ahmed Khalil, Seun Akindehin, Jonathan E Campbell, Pietra Candela, Russell L Castelino, Callum Coupland, Maxime Culot, W Scott Dodson, Jonathan D Douros, Hannes Embring, Annette Feuchtinger, Brian Finan, Cristina Garcia-Caceres, Xiao-Bing Gao, Fabien Gosselet, Gerald Grandl, Robert M Gutgesell, Daniel T Haas, Martin Jastroch, Ezgi Karaoglu, Pamela Kakimoto, Anna Cristina Kaltenbach, Michaela Keuper, Christine M Kusminski, Danielle C Leander, Arkadiusz Liskiewicz, Xue Liu, Gandhari Maity-Kumar, Sara Martinez Martinez, Stephanie A Mowery, Ruben Nogueiras, Marshall Paisley, Diego Perez-Tilve, Patricia S S Petersen, Paul T Pfluger, Sneha Prakash, Sabine Steffens, Alberto Cebrian-Serrano, Monica Tost, Jordan Wean, Christian Weber, Junichi Yoshida, Zachary Gerhart-Hines, Tamas L Horvath, Philipp E Scherer, Randy J Seeley, Richard D DiMarchi, Matthias H Tschöp, Natalie Krahmer, Patrick J Knerr, Timo D Müller.
      There are increasing numbers of effective drugs to improve obesity-linked metabolic dysfunction; GLP-1R-GIPR co-agonism is effective in the management of obesity and type 2 diabetes1,2, and lanifibranor-a nuclear-acting small-molecule triple agonist of PPARα, PPARγ and PPARδ-is in clinical phase 3 trials for the treatment of metabolic dysfunction-associated steatohepatitis3. Here, seeking to further improve the metabolic efficacy of GLP-1R-GIPR co-agonism, we report the development of a unimolecular quintuple agonist that combines the body weight-reducing and blood glucose-lowering effects of GLP-1R-GIPR co-agonism with the insulin-sensitizing and anti-inflammatory effects of lanifibranor via its targeted delivery into GLP-1R- and GIPR-expressing cells. In vitro, GLP-1-GIP-lanifibranor is indistinguishable from GLP-1-GIP in relation to incretin receptor signalling and shows equal stimulation of insulin secretion in isolated mouse islets. In vivo, however, GLP-1-GIP-lanifibranor outperforms GLP-1R-GIPR co-agonism and semaglutide, further decreasing body weight, food intake and hyperglycaemia in obese and insulin-resistant mice through synergistic incretin and PPAR action. The metabolic action of GLP-1-GIP-lanifibranor is blunted in mice with genetic or pharmacological inhibition of GLP-1R, GIPR or PPARδ and is absent in DIO double incretin receptor-knockout mice, collectively suggesting that GLP-1-GIP-lanifibranor has substantial therapeutic value in the treatment of obesity and diabetes.
    DOI:  https://doi.org/10.1038/s41586-026-10427-5
  12. Nat Cell Biol. 2026 Apr 29.
    ATM lifts the cGAS handbrake on DNA replication.
    Yea-Lih Lin, Philippe Pasero.
      
    DOI:  https://doi.org/10.1038/s41556-026-01944-6
  13. Nat Cardiovasc Res. 2026 Apr 29.
    Antibody-siRNA conjugates enable macrophage-specific osteopontin inhibition to suppress atrial fibrillation.
    Na Li.
      
    DOI:  https://doi.org/10.1038/s44161-026-00808-4
  14. Nat Commun. 2026 Apr 30.
    Impaired glucose tolerance and mild diabetes induce β-cell dysfunction in mice.
    Elizabeth Haythorne, Matthew Lloyd, Chris A Smith, Martijn van de Bunt, Maria Rohm, Alice Elphick, Malgorzata Cyranka, Fiona M Gribble, Frank Reimann, Frances M Ashcroft.
      Severe chronic hyperglycaemia ( > 15 mM) causes impaired glycolytic and mitochondrial metabolism in pancreatic β-cells, leading to dramatically reduced insulin secretion and content. However, patients with type 2 diabetes often experience many years of reduced β-cell function and impaired glucose tolerance preceding diabetes diagnosis. It is postulated that β-cell function may be compromised by relatively small changes in glycaemia, initiating a gradual decline that underlies diabetes progression. We therefore investigated the extent to which impaired glucose tolerance and chronic mild hyperglycaemia are detrimental to β-cells. We show that chronic elevation of blood glucose of just 2-3 mM is sufficient to impair β-cell function, causing marked changes in metabolic gene expression and reducing insulin content, metabolic enzyme activity, mitochondrial oxidative phosphorylation and insulin secretion. Smaller but significant changes are produced by impaired glucose tolerance. These findings demonstrate that altered β-cell metabolism is an early event in type 2 diabetes development and highlight a need for therapeutic intervention during prediabetes.
    DOI:  https://doi.org/10.1038/s41467-026-71528-3
  15. Nature. 2026 Apr 27.
    Mitochondria can spawn new 'organelles' - hinting at how modern cells evolved.
    Viviane Callier.
      
    Keywords:  Cell biology; Evolution; Immunology
    DOI:  https://doi.org/10.1038/d41586-026-01295-0
  16. Science. 2026 Apr 30. 392(6797): 468-469
    Tracking the turning point in Alzheimer's disease.
    Bart De Strooper, Henrik Zetterberg.
      A blood biomarker reveals the mechanistic shift from amyloid to tau pathology.
    DOI:  https://doi.org/10.1126/science.aeb6987
  17. Nat Commun. 2026 Apr 25.
    Coupled cross-sectional and longitudinal non-negative matrix factorization reveals dominant brain aging trajectories in 48,949 individuals.
    Ioanna Skampardoni, Guray Erus, Ilya M Nasrallah, Zhijian Yang, Michael R Duggan, Keenan A Walker, Alexander Getka, Kyunglok Baik, Randa Melhem, Sindhuja T Govindarajan, Susan M Resnick, Haochang Shou, Konstantina Nikita, Christos Davatzikos.
      Machine learning can unravel heterogeneous patterns of brain aging and neurodegeneration, but existing methods offer limited insights into disease progression due to reliance on cross-sectional data. We introduce Coupled Cross-sectional and Longitudinal Non-negative Matrix Factorization (CCL-NMF) to capture dominant brain aging patterns by simultaneously leveraging cross-sectional and longitudinal neuroimaging data. CCL-NMF allows individuals to co-express multiple patterns, capturing mixed neuropathologic processes. Applied to neuroimaging data from 48,949 individuals from the harmonized iSTAGING study, CCL-NMF identifies seven distinct, reproducible, and biologically relevant neuroanatomical patterns. Subject-specific loading coefficients quantifying the individual expression of these patterns show distinct associations with cognition, genetic, and lifestyle factors. To support broader application, a regression-based tool was developed to estimate loadings in external cohorts without rerunning the full framework. By enabling individualized estimation of distinct brain aging patterns, these findings may improve risk assessment and therapeutic evaluation in neurodegenerative diseases. Although demonstrated using structural MRI, this framework is generalizable to other imaging modalities and biomarker types.
    DOI:  https://doi.org/10.1038/s41467-026-72091-7
  18. Nat Commun. 2026 Apr 25.
    IFNγ blockade in Mycobacterium tuberculosis infected macaques alters the granuloma environment but not bacterial control.
    Shunsuke Sakai, Sivaranjani Namasivayam, Keith D Kauffman, Eduardo Fukutani, Artur T L Queiroz, Christine E Nelson, Erin F McCaffrey, Ploenchan Chetchotisakd, Jay Buchanan, Alan Sher, Carl G Feng, Joel D Ernst, Steven M Holland, Katrin D Mayer-Barber, Bruno B Andrade, Christa S Zerbe, Laura E Via, Daniel L Barber.
      IFNγ is considered the primary mediator of adaptive immunity to Mycobacterium tuberculosis (Mtb) infection. In mice, control of Mtb requires IFNγ. In humans, IFNγ is critical for resistance to infection with non-tuberculous mycobacteria (NTM), but its relative requirement for control of pulmonary tuberculosis (TB) is less clear. Here we block IFNγR1 signaling in macaques at different times following Mtb infection. IFNγ blockade from day 45 to 49 post-infection rapidly reduced 18FDG-PET/CT scores and broadly enhanced anti-viral-like inflammatory responses. Strikingly, IFNγR1 blockade for the first three months of infection had no impact on bacterial loads despite suppression of bioactive IFNγ in granulomas and changes to host immune responses and granuloma structure. We find individuals from Mtb endemic regions with anti-IFNγ neutralizing autoantibodies who develop NTM disease and not TB despite evidence of previous exposure to Mtb. Lastly, we show that mice over-estimate the importance IFNγ in host resistance to TB due to a species-specific induction of iNOS by IFNγ. Thus, while IFNγ has immunoregulatory effects in granulomas, normal resistance to TB in macaques and humans likely requires little IFNγR1 signaling during infection, indicating that the major mechanisms of adaptive immunity to Mtb infection remain unknown.
    DOI:  https://doi.org/10.1038/s41467-026-72421-9
  19. Nature. 2026 Apr 29.
    Submicrometre sampling of living cells by macrophages.
    Amy C Fan, Rukman R Thota, Nina Serwas, Vivasvan S Vykunta, Kyle Marchuk, Megan K Ruhland, Lauren Liu, Grace Johnson, Austin Edwards, Matthew F Krummel.
      An effective immune system must sample and develop healthy self-identity to prevent autoimmunity and to discern pathogenic insults1-3. Self-proteins are presented to T cells in the thymus during immune cell development2,3 and must be presented throughout the body to maintain regulatory T cell populations4-6 and to provide tonic signals to sustain conventional T cells over time7-9. Observations of continuous apoptosis in some organs together with the ingestion of that material by myeloid populations has led to a conventional understanding of ongoing cell death as a major source of self-antigens10. Here we used a series of companion imaging and vesicular labelling technologies to reveal an alternative process undertaken by macrophages that results in non-destructive, direct sampling of living cells. This process requires cell-cell contact, does not require caspase activation and occurs via trogocytosis-like stretching of the target cell into the macrophage, which leads to the generation of submicrometre-sized vesicles that contain cytoplasm. Using a high-dimensional flow-based method for labelling vesicles, we demonstrate that live-sampled material is distinctly processed and is poorly subjected to fusion with lysosomes. The material also produces differential effects on the presentation of antigen to CD4 T cells compared with CD8 T cells. Disruption of this trafficking by redirecting antigen to the lysosome significantly reduced the associated macrophage-mediated priming of CD8 T cells. These results demonstrate an important and substantial sampling of living cells by the immune system, with clear consequences for maintaining the border of immunity.
    DOI:  https://doi.org/10.1038/s41586-026-10435-5
  20. Nature. 2026 Apr 29.
    Why you should 'feed a cold': eating primes immune cells for action.
    Nick Petrić Howe.
      
    Keywords:  Immunology; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-026-01362-6
  21. Nature. 2026 Apr 29.
    Higher racial diversity in US business and law schools is linked to higher graduate salaries.
    Debanjan Mitra, Peter N Golder, Mariya Topchy.
      
    Keywords:  Economics; Education; Policy; Sociology
    DOI:  https://doi.org/10.1038/d41586-026-01273-6
  22. Nat Med. 2026 Apr 27.
    Ten lessons from a decade of scientific translation at the Crick.
    Stephen Mayhew, Dave Allen, David Roblin.
      
    DOI:  https://doi.org/10.1038/s41591-026-04355-0
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