bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–10–19
23 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. The probiotic home: where microbes are welcome guests.
  2. This gene causes obesity - and shields against heart disease.
  3. Alzheimer's alphabet soup: Find the letters "Z-DNA-ZBP1-RIPK1".
  4. The co-inhibitory receptor TIGIT promotes tissue-protective functions in T cells.
  5. Resident memory T cells call the shots in tissue immunity.
  6. Economics Nobel prize won by researchers who showed how science boosts growth.
  7. αTIGIT-IL2 achieves tumor regression by promoting tumor-infiltrating regulatory T cell fragility in mouse models.
  8. Global health is in crisis - who will step in to fix it?
  9. A brief digital cognitive test improves Alzheimer's disease detection.
  10. Reprogramming mitochondrial metabolism and epigenetics of macrophages via miR-10a liposomes for atherosclerosis therapy.
  11. Towards a reference cell atlas of liver diversity over the human lifespan.
  12. Men's brains shrink faster than women's: what that means for Alzheimer's.
  13. Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel.
  14. Fibroblasts take center stage in brain repair.
  15. A single blood test could reveal the biological stage of Alzheimer's disease.
  16. Faulty mitochondria cause deadly diseases: fixing them is about to get a lot easier.
  17. Microglia-specific regulation of lipid metabolism in Alzheimer's disease revealed by microglial depletion in 5xFAD Mice.
  18. Molecular mechanisms in innate immunity.
  19. Antigen-presenting cells as arbiters of mucosal tolerance and immunity.
  20. Japan declares a flu epidemic - what this means for other nations.
  21. Nutrient allocation fuels T cell-mediated immunity.
  22. Deep mutational scanning of the human insulin receptor ectodomain to inform precision therapy for insulin resistance.
  23. Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides and cardiovascular disease risk.
  1. Nature. 2025 Oct 14.
    The probiotic home: where microbes are welcome guests.
    Katherine Bourzac.
      
    Keywords:  Architecture; Microbiome; Public health
    DOI:  https://doi.org/10.1038/d41586-025-03291-2
  2. Nature. 2025 Oct 16.
    This gene causes obesity - and shields against heart disease.
    Heidi Ledford.
      
    Keywords:  Brain; Cardiovascular biology; Metabolism; Obesity
    DOI:  https://doi.org/10.1038/d41586-025-03387-9
  3. Immunity. 2025 Oct 14. pii: S1074-7613(25)00421-2. [Epub ahead of print]58(10): 2367-2369
    Alzheimer's alphabet soup: Find the letters "Z-DNA-ZBP1-RIPK1".
    Jake A Gertie, Hachung Chung.
      Neuroinflammation contributes to Alzheimer's disease (AD), but the molecules and pathways that initiate inflammation are unclear. In this issue of Immunity, Song et al. demonstrate that ZBP1-RIPK1 signaling in microglia can drive AD, wherein ZBP1 is activated by left-handed Z-DNA leaking from mitochondria, presenting new molecular targets for AD therapeutics.
    DOI:  https://doi.org/10.1016/j.immuni.2025.09.010
  4. Nat Immunol. 2025 Oct 15.
    The co-inhibitory receptor TIGIT promotes tissue-protective functions in T cells.
    Camilla Panetti, Rahel Daetwyler, Anja Moncsek, Nikolaos Patikas, Andreas Agrafiotis, Adelynn Tang, Francesco Andreata, Valeria Fumagalli, Jean De Lima, Lifen Wen, Carolyn G King, Ajithkumar Vasanthakumar, Matteo Iannacone, Axel Kallies, Alexander Yermanos, Martin Hemberg, Nicole Joller.
      The co-inhibitory receptor TIGIT suppresses excessive immune responses in autoimmune conditions while also restraining antitumor immunity. In viral infections, TIGIT alone does not affect viral control but has been shown to limit tissue pathology. However, the underlying mechanisms are incompletely understood. Here we found TIGIT+ T cells to express not only an immunoregulatory gene signature but also a tissue repair gene signature. Specifically, after viral infection, TIGIT directly drives expression of the tissue growth factor amphiregulin (Areg), which is strongly reduced in the absence of TIGIT. We identified regulatory T (Treg) cells, but not CD8+ T cells, as the critical T cell subset mediating these tissue-protective effects. In Treg cells, TIGIT engagement after T cell antigen receptor stimulation induces the transcription factor Blimp-1, which then promotes Areg production and tissue repair. Thus, we uncovered a nonclassical function of the co-inhibitory receptor TIGIT, wherein it not only limits immune pathology by suppressing the immune response but also actively fosters tissue regeneration by inducing the tissue growth factor Areg in T cells.
    DOI:  https://doi.org/10.1038/s41590-025-02300-w
  5. Immunity. 2025 Oct 14. pii: S1074-7613(25)00428-5. [Epub ahead of print]58(10): 2364-2366
    Resident memory T cells call the shots in tissue immunity.
    Sigrun Stulz, Georg Gasteiger.
      Vaccines that induce immunity in tissues are urgently needed. In this issue of Immunity, Joag et al. demonstrate that systemic vaccination of primates induces tissue-resident CD8+ T cells in numerous organs that can activate antiviral responses by stromal, parenchymal, and immune cells.
    DOI:  https://doi.org/10.1016/j.immuni.2025.09.017
  6. Nature. 2025 Oct 13.
    Economics Nobel prize won by researchers who showed how science boosts growth.
    Philip Ball.
      
    DOI:  https://doi.org/10.1038/d41586-025-03364-2
  7. Nat Commun. 2025 Oct 17. 16(1): 9223
    αTIGIT-IL2 achieves tumor regression by promoting tumor-infiltrating regulatory T cell fragility in mouse models.
    Tianci Wang, Yupu Xu, Zhengfeng Zhang, Yaqi Wu, Long Chen, Xiaodong Zheng, Hui Peng, Qiang Zou, Rui Sun, Hongdi Ma, Haoyu Sun, Zhigang Tian, Xiaohu Zheng.
      Administration of IL-2 may promote the suppressive function and proliferation of Treg cells that cause immune tolerance in patients with cancer, which causes low-dose IL-2 to fail in achieving an optimal anti-tumor effect. Here, we designed an immunocytokine by fusing IL-2 and an anti-TIGIT monoclonal antibody, named αTIGIT-IL2, that targets Treg cells and promotes their fragility in the tumor milieu. These fragile-like Treg cells show impaired suppressive function and high IFN-γ production, triggering an immune-reactive tumor microenvironment. Such inflammation leads to the recruitment and functional reprogramming of intratumoral neutrophils, improving cross-talk between neutrophils and CD8+ T cells and enhancing the antitumor ability of CD8+ T cells. Combination therapy with αTIGIT-IL2 and PD-1 blocker could eliminate triple-negative breast cancer (TNBC) tumors resistant to immune checkpoint blockade (ICB) therapy. These findings provide the basis for developing a new generation of immunocytokines that target Treg cells and promote their fragility in the tumor milieu, resulting in robust antitumor immunity.
    DOI:  https://doi.org/10.1038/s41467-025-64296-z
  8. Nature. 2025 Oct 16.
    Global health is in crisis - who will step in to fix it?
    Fred Schwaller.
      
    DOI:  https://doi.org/10.1038/d41586-025-03384-y
  9. Nat Med. 2025 Oct 16.
    A brief digital cognitive test improves Alzheimer's disease detection.
      
    DOI:  https://doi.org/10.1038/s41591-025-04024-8
  10. Nat Commun. 2025 Oct 14. 16(1): 9117
    Reprogramming mitochondrial metabolism and epigenetics of macrophages via miR-10a liposomes for atherosclerosis therapy.
    Fei Fang, Erxiang Wang, Hanqiao Yang, Ting Zhao, Qiwei Wang, Zhen Zhang, Yang Song, Xiaoheng Liu.
      Disruption in the dynamic stability of macrophage pro/anti-inflammatory phenotypes within plaques significantly impacts chronic vascular inflammation and exacerbates atherosclerosis. Reprogramming macrophages from pro-inflammatory to anti-inflammatory phenotype mitigates atherosclerosis progression. However, chronic inflammatory stimulation induces a closed chromatin state in atherosclerotic macrophages, inhibiting their phenotype reprogramming. This study demonstrates that restoring mitochondrial respiration increases histone acetylation (AcH3) and enhances chromatin accessibility in atherosclerotic macrophages, restarting macrophage phenotype reprogramming. Additionally, we identified that miR-10a can facilitate mitochondrial respiration and reorganize macrophage reprogramming. To optimize delivery, prolong circulation time, and target pro-inflammatory macrophages, we developed red blood cell membrane-modified liposome nanoparticles (miR-10a@H-MNP) to deliver miR-10a. Hyaluronic acid was conjugated to the liposomes to specifically target pro-inflammatory macrophages in plaque. Intravenous administration of miR-10a@H-MNP significantly alleviated atherosclerosis progression in male mice. Thus, the epigenomic priming approach developed here effectively triggers macrophage reprogramming in atherosclerosis, presenting a promising metabolically based epigenetic modulation method for plaque clearance.
    DOI:  https://doi.org/10.1038/s41467-025-64201-8
  11. Nat Rev Gastroenterol Hepatol. 2025 Oct 13.
    Towards a reference cell atlas of liver diversity over the human lifespan.
    Sarah A Taylor, Gary D Bader, Sonya MacParland, Alan C Mullen, Tallulah Andrews, Alex G Cuenca, Ramanuj DasGupta, Adam J Gehring, Dominic Grün, Martin Guilliams, Aliya Gulamhusein, Neil C Henderson, Gideon Hirschfield, Stacey S Huppert, Shalev Itzkovitz, Z Gordon Jiang, Georg M Lauer, Ian McGilvray, Krupa R Mysore, Carlos J Pirola, Gerald Quon, Mohammad Rahbari, Aviv Regev, Amanda Ricciuto, Charlotte L Scott, Ankur Sharma, Silvia Sookoian, Michelle M Tana, Sarah A Teichmann, Ludovic Vallier, Ioannis S Vlachos, Bruce Wang, Mei Zhen.
      The goal of the Human Liver Cell Atlas (HLiCA) is to create a comprehensive map that defines the normal functions of diverse liver cell types and their spatial relationships over the human lifespan. This project fits within the goals of the Human Cell Atlas to create comprehensive reference maps of all human cells as a basis for both understanding human health and diagnosing, monitoring and treating disease. Through collection of samples from diverse individuals, data integration across technologies and overcoming liver-specific challenges for experimental methods, the HLiCA will map as many cell types and states as possible in healthy human livers from individuals across all ages and many ancestries. Establishing this HLiCA of healthy livers is a critical step to begin to understand perturbations in disease. The HLiCA will be available on an open-access platform to facilitate data sharing and dissemination. We expect that creation of the HLiCA will help to lay the foundation for new research initiatives to advance our understanding of liver disease, improve methods of tissue engineering, and identify novel prognostic biomarkers and therapies to improve patient outcomes. We describe key experimental and computational challenges to overcome in building the atlas and the potential impact of the atlas on disease research.
    DOI:  https://doi.org/10.1038/s41575-025-01114-3
  12. Nature. 2025 Oct 13.
    Men's brains shrink faster than women's: what that means for Alzheimer's.
    Rachel Fieldhouse.
      
    Keywords:  Ageing; Brain; Neurodegeneration
    DOI:  https://doi.org/10.1038/d41586-025-03353-5
  13. Nat Metab. 2025 Oct 16.
    Interaction of sortilin with apolipoprotein E3 enables neurons to use long-chain fatty acids as alternative metabolic fuel.
    Anna K Greda, Jemila P Gomes, Vanessa Schmidt-Krueger, Ewa Zurawska-Plaksej, Raphaela Fritsche-Guenther, Ina-Maria Rudolph, Narasimha S Telugu, Cagla Cömert, Jennifer Kirwan, Séverine Kunz, Michael Rothe, Mogens Johannsen, Sebastian Diecke, Peter Bross, Thomas E Willnow.
      Sortilin (SORT1) is a lipoprotein receptor that shows genome-wide association with hypercholesterolaemia, explained by its ability to control hepatic output of lipoproteins. Although SORT1 also shows genome-wide association with Alzheimer disease and frontotemporal lobe dementia, the most prevalent forms of age-related dementias, sortilin's contribution to human brain lipid metabolism and health remains unclear. Here we show that sortilin mediates neuronal uptake of polyunsaturated fatty acids carried by apolipoprotein E (apoE). Using humanized mouse strains and induced pluripotent stem cell-based cell models of brain lipid homeostasis, we demonstrate that internalized lipids are converted into ligands for peroxisome proliferator-activated receptor alpha inducing transcription profiles that enable neurons to use long-chain fatty acids as metabolic fuel when glucose is limited. This pathway works with apoE3 but cannot operate with the Alzheimer disease risk factor apoE4, which disrupts sortilin's endocytic activity. Our data indicate a role for the lipoprotein receptor sortilin in metabolic fuel choice in neurons, which may be crucial when glucose supply is limited, such as in the ageing brain.
    DOI:  https://doi.org/10.1038/s42255-025-01389-5
  14. Nat Immunol. 2025 Oct 15.
    Fibroblasts take center stage in brain repair.
    Lidia Garcia-Bonilla, Josef Anrather, Costantino Iadecola.
      
    DOI:  https://doi.org/10.1038/s41590-025-02310-8
  15. Nat Aging. 2025 Oct 16.
    A single blood test could reveal the biological stage of Alzheimer's disease.
      
    DOI:  https://doi.org/10.1038/s43587-025-01008-8
  16. Nature. 2025 Oct;646(8085): 530-532
    Faulty mitochondria cause deadly diseases: fixing them is about to get a lot easier.
    Gemma Conroy.
      
    Keywords:  Biotechnology; CRISPR-Cas9 genome editing; Diseases; Gene therapy; Genomics
    DOI:  https://doi.org/10.1038/d41586-025-03307-x
  17. Nat Commun. 2025 Oct 15. 16(1): 9156
    Microglia-specific regulation of lipid metabolism in Alzheimer's disease revealed by microglial depletion in 5xFAD Mice.
    Ziying Xu, Sepideh Kiani Shabestari, Savannah Barannikov, Kevin F Bieniek, Mathew Blurton-Jones, Juan Pablo Palavicini, Xianlin Han.
      Abnormal lipid metabolism is observed in Alzheimer's disease (AD), but its contribution to disease progression remains unclear. Genetic studies indicate that microglia, the brain's resident immune cells, influence lipid processing during AD. Here, we show that microglia-the brain's resident immune cells-selectively regulate lipid accumulation that associated with disease pathology in both AD mouse models and human postmortem brains. Using lipidomics and histological analysis, we identify a striking buildup of arachidonic acid-containing bis(monoacylglycero)phosphate in response to amyloid plaques, which depends on microglial activity and the AD risk gene GRN. In contrast, lysophosphatidylcholine and lysophosphatidylethanolamine accumulate independently of microglia, correlating instead with astrocyte activation and oxidative stress. These results connect dysregulated lipid metabolism in AD to distinct brain cell types and molecular pathways. Our findings highlight microglial lipid homeostasis as a potential therapeutic target for modifying disease progression in AD.
    DOI:  https://doi.org/10.1038/s41467-025-64161-z
  18. Mol Cell. 2025 Oct 16. pii: S1097-2765(25)00786-5. [Epub ahead of print]85(20): 3729
    Molecular mechanisms in innate immunity.
    Heather Bisbee.
      
    DOI:  https://doi.org/10.1016/j.molcel.2025.09.026
  19. Nat Immunol. 2025 Oct 17.
    Antigen-presenting cells as arbiters of mucosal tolerance and immunity.
    Tilman L B Hoelting, Tyler Park, Chrysothemis C Brown.
      Within the intestine, the immune system encounters a vast array of microbial antigens, as well as dietary components. Antigen-presenting cells (APCs) play a critical role in tailoring an appropriate immune response, ensuring both tolerance to innocuous antigens and protection from pathogens. An explosion of single-cell transcriptomic studies has revealed new subsets of APCs within mucosal tissues and lymph nodes, most notably within the gut. Harnessing their full potential to elicit protective immunity during oral vaccination or restoration of tolerance in inflammatory or allergic diseases requires an in-depth understanding of their unique functional roles and differentiation programs. Here we review the growing understanding of APC heterogeneity and discuss how balance and cooperation between distinct subsets shape mucosal immunity, inflammation and tolerance.
    DOI:  https://doi.org/10.1038/s41590-025-02320-6
  20. Nature. 2025 Oct 14.
    Japan declares a flu epidemic - what this means for other nations.
    Rachel Fieldhouse.
      
    Keywords:  Epidemiology; Infection; Public health
    DOI:  https://doi.org/10.1038/d41586-025-03367-z
  21. Cell Metab. 2025 Oct 15. pii: S1550-4131(25)00393-6. [Epub ahead of print]
    Nutrient allocation fuels T cell-mediated immunity.
    Joseph Longo, McLane J Watson, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.
      T cell activation and function are intricately linked to metabolic reprogramming. The classic view of T cell metabolic reprogramming centers on glucose as the dominant bioenergetic fuel, where T cell receptor (TCR) stimulation promotes a metabolic switch from relying primarily on oxidative phosphorylation (OXPHOS) for energy production to aerobic glycolysis (i.e., the Warburg effect). More recently, studies have revealed this classic model to be overly simplistic. Activated T cells run both glycolysis and OXPHOS programs concurrently, allocating diverse nutrient sources toward distinct biosynthetic and bioenergetic fates. Moreover, studies of T cell metabolism in vivo and ex vivo highlight that physiologic nutrient availability influences how glucose is allocated by T cells to fuel both optimal proliferation and effector function. Here, we summarize recent advancements that support a revised model of effector T cell metabolism, where strategic nutrient allocation fuels optimal T cell-mediated immunity.
    Keywords:  T cells; adaptive immunity; effector function; glucose; immunometabolism; nutrient allocation
    DOI:  https://doi.org/10.1016/j.cmet.2025.09.008
  22. Nat Commun. 2025 Oct 15. 16(1): 9143
    Deep mutational scanning of the human insulin receptor ectodomain to inform precision therapy for insulin resistance.
    Vahid Aslanzadeh, Gemma V Brierley, Rupa Kumar, Hasan Çubuk, Corinne Vigouroux, Kenneth A Matreyek, Grzegorz Kudla, Robert K Semple.
      The insulin receptor entrains tissue growth and metabolism to nutritional conditions. Complete loss of function in humans leads to extreme insulin resistance and infantile mortality, while loss of 80-90% function permits longevity of decades. Even low-level activation of severely compromised receptors, for example by anti-receptor monoclonal antibodies, thus offers the potential for decisive clinical benefit. A barrier to genetic diagnosis and translational research is the increasing identification of variants of uncertain significance in the INSR gene, encoding the insulin receptor. By coupling saturation mutagenesis to flow-based assays, we stratified approximately 14,000 INSR extracellular missense variants by cell surface expression, insulin binding, and insulin- or monoclonal antibody-stimulated signalling. Resulting function scores correlate strongly with clinical syndromes, offer insights into dynamics of insulin binding, and reveal novel potential gain-of-function variants. This INSR sequence-function map has biochemical, diagnostic and translational utility, aiding rapid identification of variants amenable to activation by non-canonical INSR agonists.
    DOI:  https://doi.org/10.1038/s41467-025-64178-4
  23. Nat Med. 2025 Oct 16.
    Obesity due to MC4R deficiency is associated with reduced cholesterol, triglycerides and cardiovascular disease risk.
    Stefanie Zorn, Rebecca Bounds, Alice Williamson, Katherine Lawler, Ruth Hanssen, Julia Keogh, Elana Henning, Miriam Smith, Barbara A Fielding, A Margot Umpleby, Summaira Yasmeen, Maria Marti-Solano, Claudia Langenberg, Martin Wabitsch, Tinh-Hai Collet, I Sadaf Farooqi.
      Obesity causes dyslipidemia and is a major risk factor for cardiovascular disease. However, the mechanisms coupling weight gain and lipid metabolism are poorly understood. Brain melanocortin 4 receptors (MC4Rs) regulate body weight and lipid metabolism in mice, but the relevance of these findings to humans is unclear. Here we investigated lipid levels in men and women with obesity due to MC4R deficiency. Among 7,719 people from the Genetics of Obesity Study cohort, we identified 316 probands and 144 adult family members with loss-of-function (LoF) MC4R mutations. Adults with MC4R deficiency had lower levels of total and low-density lipoprotein (LDL)-cholesterol and triglycerides than 336,728 controls from the UK Biobank, after adjusting for adiposity. Carriers of LoF MC4R variants within the UK Biobank had lower lipid levels and a lower risk of cardiovascular disease, after accounting for body weight, compared to noncarriers. After a high-fat meal, the postprandial rise in triglyceride-rich lipoproteins and metabolomic markers of fatty acid oxidation were reduced in people with MC4R deficiency compared to controls, changes that favor triglyceride storage in adipose tissue. We concluded that central MC4Rs regulate lipid metabolism and cardiovascular disease risk in humans, highlighting potential therapeutic approaches for cardiovascular risk reduction.
    DOI:  https://doi.org/10.1038/s41591-025-03976-1
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