bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–06–28
25 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Mitochondrial stress response drives microglial senescence.
  2. Cell atlas of brain aneurysms reveals fibroblast-macrophage crosstalk.
  3. Are GLP-1 receptor agonists gerotherapeutics or just treatments for obesity?
  4. How long-term dietary cholesterol can slow down its own clearance by liver cells.
  5. Circulating metabolites at the crossroads of lifestyle and brain health.
  6. An integrated cell atlas of 2.4 million cardiac cells across 209 individuals in health and disease.
  7. Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover.
  8. A hidden predictor of sudden cardiac death uncovered by deep learning.
  9. Meta-analysis of DNA methylation aging signatures in 17 human tissues.
  10. Fattening mother's milk with oxytocin.
  11. The metabolic basis of regulated cell death.
  12. FDA Approves First Over-the-Counter Continuous Glucose Monitor for Children.
  13. Cluster replicability in single-cell and single-nucleus atlases of the mouse brain.
  14. Exercise and glucagon-like peptide 1 receptor agonists in cardiovascular disease beyond weight loss.
  15. Recognising and mitigating LLM Pollution in online behavioural research.
  16. Therapeutic targeting of AREL1 in hepatic stellate cells attenuates MASH-related liver fibrosis.
  17. Diet and Dementia Risk in Individuals With Prevalent Neuropathology.
  18. Threat assessment shapes neutrophil cell fate upon inflammasome activation.
  19. cDC1s license CD8+ T cell-mediated neurodegeneration.
  20. HeartMap charts new territory in cardiac disease biology.
  21. Collagen-producing eye cell atlas reveals distinct fibroblast fates in early injury vs. fibrotic subretinal disease.
  22. Mitochondria-endoplasmic reticulum contact sites as hubs where mitochondria acquire iron.
  23. An important new data source for obesity trends in England.
  24. Host metabolism can produce many indoles and phenols independently of the microbiome.
  25. Quantitative cytokine profiling of primary human macrophages reveals distinct single-cell modes of trained immunity.
  1. Nat Neurosci. 2026 Jun 26.
    Mitochondrial stress response drives microglial senescence.
    Luca Peruzzotti-Jametti, Stefano Pluchino.
      
    DOI:  https://doi.org/10.1038/s41593-026-02264-6
  2. Nat Neurosci. 2026 Jun 24.
    Cell atlas of brain aneurysms reveals fibroblast-macrophage crosstalk.
      
    DOI:  https://doi.org/10.1038/s41593-026-02368-z
  3. Nat Aging. 2026 Jun 22.
    Are GLP-1 receptor agonists gerotherapeutics or just treatments for obesity?
    James G Peyer.
      
    DOI:  https://doi.org/10.1038/s43587-026-01165-4
  4. Nature. 2026 Jun 25.
    How long-term dietary cholesterol can slow down its own clearance by liver cells.
      
    Keywords:  Cell biology; Metabolism; Physiology
    DOI:  https://doi.org/10.1038/d41586-026-01899-6
  5. Nat Aging. 2026 Jun 24.
    Circulating metabolites at the crossroads of lifestyle and brain health.
    Marta Guasch-Ferré.
      
    DOI:  https://doi.org/10.1038/s43587-026-01119-w
  6. Nat Cardiovasc Res. 2026 Jun 26.
    An integrated cell atlas of 2.4 million cardiac cells across 209 individuals in health and disease.
    Yesh Datar, Mark Chaffin, Bridget Simonson, Alex Mandia, Patrick T Ellinor.
      Cardiovascular disease remains the leading cause of global mortality. Understanding its complexity requires dissecting the heart's cellular landscape. Here we present HeartMap, a comprehensive single-nucleus RNA sequencing atlas of the adult human heart. This resource integrates data from nine studies, encompassing over 2.4 million nuclei, 209 individuals, eight anatomical regions and seven disease and healthy states. After rigorous data harmonization and method comparison of batch correction methods, we characterized transcriptional diversity across 14 cell types. To demonstrate the utility of HeartMap, we identified robust disease-associated gene signatures in dilated cardiomyopathy by comparing multiple studies. Notably, we identified distinct activated fibroblast populations, enriched for COL22A1 or TNC, that display variable prevalence across cardiomyopathies. HeartMap provides a valuable tool for exploring cardiac disease at the single-cell level, facilitating both fundamental research and potential therapeutic development.
    DOI:  https://doi.org/10.1038/s44161-026-00831-5
  7. Nature. 2026 Jun 24.
    Dietary cholesterol activates a Ral-dependent pathway driving LDLR turnover.
    Xue Feng, Shuo Zhang, Yuqi Wang, Twisha Kurlagunda, Allyssa Sit, Priyadarshini Jaishankar, Pusu Yang, Sadatsugu Sakane, Se Yong Park, Churaibhon Wisessaowapak, Kaylee Nguyen, Jamie Yan, Himani Pothulu, Catherine Dinh, Felicia Chu, Yuyao Ren, Bichen Zhang, Patrick Secrest, Linmeng Han, Chao-Wei Hung, Preethi Veeragandham, Yuliya Skorobogatko, Tatiana Kisseleva, Philip L S M Gordts, Adam R Renslo, Peng Zhao, Amit R Majithia, Alan R Saltiel.
      Metabolism of the hepatic low-density lipoprotein receptor (LDLR) is a key determinant of cholesterol homeostasis1,2. The molecular switches that coordinate LDLR trafficking and turnover in response to nutritional cues, including high dietary cholesterol, remain poorly defined3-6. Here we identify a new pathway regulated by Ral GTPases that links extracellular cholesterol signals to the intracellular trafficking machinery controlling LDLR turnover. Chronic dietary cholesterol activates the Ral proteins by increasing RAS activity, routing LDLR to lysosomes for degradation and inhibiting its recycling independently of transcriptional regulation or PCSK9. Constitutive activation of Ral via RalGAPB deletion or overexpression of constitutively active Ral mutants in hepatocytes reduces LDLR levels and impairs cholesterol clearance. Ral engages the endocytic RalBP1-REPS1 complex to promote LDLR internalization and lysosomal routing, where LDLR is degraded by the lysosomal protease cathepsin A (CTSA). Ral activation directs CTSA towards lysosomes for maturation while limiting its secretion, further promoting LDLR degradation in lysosomes. Genetic variants in this pathway significantly associate with altered cholesterol in humans. Pharmacological inhibition of CTSA activity increases hepatic LDLR function and improves cholesterol clearance, offering a potential new therapeutic strategy for hypercholesterolaemia and cardiovascular disease.
    DOI:  https://doi.org/10.1038/s41586-026-10697-z
  8. Nature. 2026 Jul;655(8121): 43-45
    A hidden predictor of sudden cardiac death uncovered by deep learning.
    Changxin Lai.
      
    Keywords:  Cardiovascular biology; Health care; Machine learning; Medical research
    DOI:  https://doi.org/10.1038/d41586-026-01806-z
  9. Nat Aging. 2026 Jun 26.
    Meta-analysis of DNA methylation aging signatures in 17 human tissues.
    Macsue Jacques, Kirsten Seale, Sarah Voisin, Anna Lysenko, Robin Grolaux, Bernadette Jones-Freeman, Severine Lamon, Mandhri Abeysooriya, Itamar Levinger, Carlie Bauer, Adam P Sharples, Aino Heikkinen, Elina Sillanpaa, Miina Ollikainen, Cassandra Smith, James R Broatch, Navabeh Zarekookandeh, Linn Gillberg, Ida Blom, Jesse R Poganik, Mahdi Moqri, Vadim N Gladyshev, Matthew Taper, Cassandra Malecki, Sean Lal, Nathalie Saurat, Steve Horvath, Andrew Teschendorff, Nir Eynon.
      Epigenetic changes, in particular DNA methylation, accumulate with age across different tissues, but whether these changes follow consistent patterns across different organs remains poorly understood. Here we show, through a meta-analysis of more than 15,000 human methylation profiles spanning 17 tissues, that aging produces both conserved and tissue-specific epigenetic signatures. We identify systemic shifts in methylation levels, increases in methylation variability, and growing molecular disorder across tissues. Network analysis revealed tightly connected gene clusters that are not modified by beneficial interventions, alongside a more modifiable cluster linked to NAD+ metabolism, supporting NAD+ as a potential therapeutic target in aging. A gene encoding a cell-adhesion protein, PCDHGA1, emerged as a conserved hub across tissues, implicating cell-to-cell communication pathways in aging across multiple organs. Our methylation atlas therefore provides a resource for dissecting the molecular basis of human aging and for identifying potential biomarkers and translational therapies.
    DOI:  https://doi.org/10.1038/s43587-026-01164-5
  10. Sci Signal. 2026 Jun 23. 19(943): eaej7898
    Fattening mother's milk with oxytocin.
    Wei Wong.
      Oxytocin-induced lipolysis in adipocytes in the lactating mammary gland ensures a high lipid content in milk.
    DOI:  https://doi.org/10.1126/scisignal.aej7898
  11. Cell Metab. 2026 Jun 25. pii: S1550-4131(26)00227-5. [Epub ahead of print]
    The metabolic basis of regulated cell death.
    Jiao Liu, Jiayi Wang, Rui Kang, Guido Kroemer, Daolin Tang.
      Regulated cell death (RCD) has long been conceptualized as a genetically encoded signaling process, yet its outcome is ultimately dictated by cellular metabolism. Here, we propose that cellular metabolism functions as a gatekeeper of RCD, establishing permissive or restrictive states that determine cell fate. Bioenergetic capacity, redox balance, lipid composition, and metal availability impose metabolic constraints that bias cells toward survival or distinct death modalities. At the systems level, organelle-resolved metabolism and inter-organelle communication coordinate the spatial control of death processes. We further position RCD pathways along a metabolic continuum, ranging from energy-dependent apoptosis to chemistry-driven ferroptosis. This framework explains the plasticity of death responses and suggests that metabolic reprogramming can redirect cell fate. Targeting metabolic dependencies thus offers a strategy to control cell death in disease.
    DOI:  https://doi.org/10.1016/j.cmet.2026.06.001
  12. JAMA. 2026 Jun 26.
    FDA Approves First Over-the-Counter Continuous Glucose Monitor for Children.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2026.8314
  13. Nat Commun. 2026 Jun 23.
    Cluster replicability in single-cell and single-nucleus atlases of the mouse brain.
    Leon French, Hamsini Suresh, Jesse Gillis.
      Single-cell RNA sequencing has advanced our understanding of cellular heterogeneity. Ensuring the replicability of identified cell clusters across studies is essential for determining their biological robustness. We assess the replicability of cell clusters identified in two large mouse brain atlases, one generated using single-cell RNA sequencing and the other with single nuclei. Both profile over 4 million cells and group them into over 5,000 clusters. Using transcriptome-wide neighbor voting, we identify 2,009 reciprocally matched cluster pairs with consistent spatial localization and coordinated gene expression, which were also observed in datasets from multiple species. Reciprocal clusters are enriched in the cerebellum, where lower diversity aids replicability, while the hypothalamus's heterogeneity limits agreement. Distinguishing close clusters is much more challenging than differentiating a cluster from most others, especially when using marker genes. By incorporating replicability data, we provide a stronger foundation for investigating the atlas-defined clusters and their biological meaning.
    DOI:  https://doi.org/10.1038/s41467-026-74171-0
  14. Nat Metab. 2026 Jun 24.
    Exercise and glucagon-like peptide 1 receptor agonists in cardiovascular disease beyond weight loss.
    Alex J Jordan, Michael McDermott.
      
    DOI:  https://doi.org/10.1038/s42255-026-01560-6
  15. Nat Commun. 2026 Jun 25. pii: 5578. [Epub ahead of print]17(1):
    Recognising and mitigating LLM Pollution in online behavioural research.
    Raluca Rilla, Tobias Werner, Hiromu Yakura, Iyad Rahwan, Anne-Marie Nussberger.
      
    DOI:  https://doi.org/10.1038/s41467-026-74621-9
  16. Nat Commun. 2026 Jun 21.
    Therapeutic targeting of AREL1 in hepatic stellate cells attenuates MASH-related liver fibrosis.
    Yang-Wen-Qing Zhang, Xiaoyu Pan, Minghe Zhang, Junyu Zhang, Hui Ren, Xinyu Zong, Xiaomian Li, Kequan Xu, Peng Xia, Tiangen Wu, Weijie Ma, Xi Chen, Chengming Qu, Wenzhi He, Yufeng Yuan.
      Fibrosis resulting from metabolic-associated steatohepatitis (MASH) is increasingly recognized as the predominant form of liver fibrosis. Although the activation of hepatic stellate cells (HSCs) is essential for liver fibrosis, the mechanisms underlying HSC activation in MASH remain inadequately understood. Integrated analysis of large-scale single-cell and single-nucleus RNA sequencing data from human healthy and fibrosis samples reveals a distinct subpopulation of HSCs in MASH. AREL1 is a characteristic gene of this subpopulation and is uniquely upregulated in MASH-related fibrosis. HSC-specific knockout of Arel1 markedly attenuates liver fibrosis in MASH model male mice. Mechanistically, AREL1 is regulated by cholesterol and facilitates HSC activation through the AREL1-ILK axis, subsequently activating the PI3K-AKT signaling pathway. Moreover, therapeutic knockdown of Arel1 using vitamin A-modified lipid nanoparticles markedly ameliorates MASH-related liver fibrosis. Here, we show a unique mechanism underlying HSC activation in MASH-driven fibrosis and present the targeted knockdown of AREL1 in HSCs as a therapeutic avenue.
    DOI:  https://doi.org/10.1038/s41467-026-74481-3
  17. JAMA Netw Open. 2026 Jun 01. 9(6): e2620261
    Diet and Dementia Risk in Individuals With Prevalent Neuropathology.
    Sokratis Charisis, Nikolaos Scarmeas.
      
    DOI:  https://doi.org/10.1001/jamanetworkopen.2026.20261
  18. Sci Adv. 2026 Jun 26. 12(26): eaeb4830
    Threat assessment shapes neutrophil cell fate upon inflammasome activation.
    See Jie Yow, Bing-Chen Wu, Hai Shin Pung, Safwah Nasuha Rosli, Hui Wen Yeap, Ghin Ray Goh, Kay En Low, Isabelle Bonne, Jizhong Shi, Shuizhou Yu, Motomi Osato, Davey Kneafsey, Gabrielle Chappell, Ye Chean Teh, Shu Zhen Chong, Melissa S F Ng, Immanuel Kwok, Jelena S Bezbradica, Dave Boucher, Kaiwen W Chen.
      Inflammasomes are cytosolic multiprotein complexes that activate caspase-1, which promotes inflammation and host defense by driving cytokine maturation and pyroptosis. Several studies reported that caspase-1 selectively drives cytokine maturation without concomitant pyroptosis in neutrophils, yet the molecular mechanisms by which neutrophils resist caspase-1-dependent pyroptosis remain unclear. Here, we report that granulocyte-macrophage colony-stimulating factor (GM-CSF) licenses neutrophil pyroptosis upon NLRP3 and Pyrin activation by amplifying TLR4-driven inflammasome priming. Single priming with the TLR1/2 agonist, Pam3CSK4, was also sufficient to license neutrophils to pyroptosis upon NLRP3 and Pyrin activation, as Pam3CSK4 triggered superior inflammasome priming compared to LPS, the prototypic inflammasome priming agent. We further demonstrate that neutrophil pyroptosis requires autocrine TNFR1 signaling and provides genetic evidence that Ninj1K45Q/K45Q mutation disrupts plasma membrane rupture in pyroptotic neutrophils. In contrast, NLRC4 expression was not further induced by GM-CSF and therefore does not enhance susceptibility to NLRC4-dependent pyroptosis. Collectively, our data demonstrate that the inflammatory environment dictates neutrophil cell fate upon inflammasome activation.
    DOI:  https://doi.org/10.1126/sciadv.aeb4830
  19. Nat Rev Immunol. 2026 Jun 22.
    cDC1s license CD8+ T cell-mediated neurodegeneration.
    Jonathan K Monteiro, Véronique E Miron.
      
    DOI:  https://doi.org/10.1038/s41577-026-01329-8
  20. Nat Cardiovasc Res. 2026 Jun 26.
    HeartMap charts new territory in cardiac disease biology.
    David W Staudt, Mark Mercola.
      
    DOI:  https://doi.org/10.1038/s44161-026-00835-1
  21. Proc Natl Acad Sci U S A. 2026 Jun 30. 123(26): e2519056123
    Collagen-producing eye cell atlas reveals distinct fibroblast fates in early injury vs. fibrotic subretinal disease.
    Ema Ozaki, Said Aktas, Kelly Mulfaul, Kiva Brennan, Christophe Roubeix, Sarah Palko, Katie Robb, Tai-Hsien Ou Yang, Marie-Claire Schanne-Klein, Anna Toidze, Avril Watson, Mark Cahill, Peter D Westenskow, Derrick Feenstra, Sarah L Doyle.
      Fibrosis is the end-stage of a maladaptive process that occurs when the body's normal wound-healing strategy becomes dysregulated. Subretinal fibrosis is the end stage of neovascular age-related macular degeneration (nAMD), the most common cause of central vision loss in people over the age of 50. The cellular sources of excess extracellular matrix (ECM) contributing to subretinal fibrosis are unknown, as is the heterogeneity of cells involved in the fibrotic process. Here we identify cells contributing to subretinal fibrosis by using Col1a1-YFP reporter mice to noninvasively image collagen production in real-time in vivo in two disease models, 1) a resolving retinal injury model and 2) a fibrotic model of subretinal disease. We create a collagen-producing eye cell atlas for subretinal injury and demonstrate subretinal fibroblast heterogeneity in healthy, resolving, and fibrotic tissue. We identify distinct molecular characteristics of general repair/resolving fibroblast populations versus pathogenic pro-fibrotic collagen-producing fibroblasts. Integration of this collagen-producing eye cell atlas with a published collagen-producing lung cell atlas shows conserved pro-fibrotic fibroblasts in both organs, yet also uncovers tissue-specific fibroblast populations unique to subretinal fibrosis. A Fap+Fgl2+ fibroblast population significantly expands in subretinal fibrosis that expresses the highest levels of collagens and distinctively expresses ECM components Periostin, Col15a1 and Col6a5. Immunolabeling of mouse and human-donor eye tissue support the fibroblastic expression and perivascular location of periostin as clearly distinguishing between bona fide fibrosis and early disease in nAMD. Our collagen-producing eye cell atlas is a valuable resource for studying distinct fibroblast subsets in homeostasis, early injury, and fibrosis.
    Keywords:  collagen-atlas; fibroblast; neovascular age-related macular degeneration; scRNA-sequencing; subretinal fibrosis
    DOI:  https://doi.org/10.1073/pnas.2519056123
  22. Nat Cell Biol. 2026 Jun 26.
    Mitochondria-endoplasmic reticulum contact sites as hubs where mitochondria acquire iron.
      
    DOI:  https://doi.org/10.1038/s41556-026-02008-5
  23. Lancet Diabetes Endocrinol. 2026 Jun 24. pii: S2213-8587(26)00130-0. [Epub ahead of print]
    An important new data source for obesity trends in England.
    Martin Gulliford.
      
    DOI:  https://doi.org/10.1016/S2213-8587(26)00130-0
  24. Nat Metab. 2026 Jun 23.
    Host metabolism can produce many indoles and phenols independently of the microbiome.
    Jenna E AbuSalim, Kellen Olszewski, Salma Youssef, Sarah J Mitchell, Craig J Hunter, Jessica Little, Ashley Sidebottom, Jacob A Boyer, Steve D Knutson, Laith Z Samarah, Michael R MacArthur, Alessa L Henneberg, Rolf-Peter Ryseck, Christiane A Opitz, David W C MacMillan, Mohamed S Donia, Eric G Pamer, Sabrina Imam, Christopher J Lehmann, Olatoyosi Odenike, Joshua D Rabinowitz.
      Indole and phenol metabolites are typically thought to be products of bacterial digestion of tryptophan (indoles) and phenylalanine or tyrosine (phenols). Interest in controlling gut microbial production of these metabolites has continually grown because they have important physiological impacts, with indoles agonizing aryl hydrocarbon receptor signalling and phenols being associated with healthy body weight. Although there is a growing body of research on which bacteria produce these metabolites, the host contribution to their circulating pools has not been characterized. Here, through stable isotope tracing in cell culture, mice and rats, we show that mammalian cells can make aryl-pyruvates, aryl-lactates, aryl-acetates and aryl-carboxylic acids independently of the microbiome. We demonstrate that circulating levels of these metabolites in mice and human patients are robust to perturbations of the microbiome. By contrast, bacterial metabolism is required to synthesize aryl-propionates and free indole, phenol and p-cresol. Overall, these results suggest that host metabolism is a major contributor to circulating indole and phenol metabolite pools.
    DOI:  https://doi.org/10.1038/s42255-026-01550-8
  25. Cell Syst. 2026 Jun 23. pii: S2405-4712(26)00130-4. [Epub ahead of print] 101648
    Quantitative cytokine profiling of primary human macrophages reveals distinct single-cell modes of trained immunity.
    Aoife O'Farrell, Zijian Niu, Arjun Raj.
      Macrophages can remember prior activation and subsequently augment their response to restimulation through trained immunity. However, it remains uncertain how trained immunity phenotypes manifest in individual cells. Here, we leverage highly quantitative single-molecule RNA imaging across 90,857 individual macrophages from 26 human donors to reveal inflammatory response dynamics in trained vs. untrained populations at single-cell resolution. Different inflammatory response genes showed distinct single-cell behavior in trained populations upon restimulation. Although training increased transcription of these response genes early after restimulation, untrained populations eventually "caught up" to the transcriptional output of trained populations, highlighting the importance of sampling timescale when interpreting transcriptional assays of training. Training did not significantly alter the relationship between the transcriptional activation of different genes within the same single cell, and any single cell appeared to be capable of training. Overall, these results revealed gene-specific single-cell transcriptional changes that generate population-wide training phenotypes in macrophages.
    Keywords:  RNA FISH; inflammatory response; innate immune memory; macrophages; single cell; trained immunity
    DOI:  https://doi.org/10.1016/j.cels.2026.101648
This page is being maintained by Thomas Krichel. It was last updated on 2026‒06‒28 at 14:14.