bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–11–16
nineteen papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Gut bacteria help mice to stay lean.
  2. Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in citrin deficiency.
  3. Gut-primed neutrophils activate Kupffer cells to promote hepatic injury in mouse sepsis.
  4. Quiet custodians of CD8+ T cell fate.
  5. Aging and immunity.
  6. The missing piece: Solving the 50-year puzzle of BMP synthesis in neurodegeneration.
  7. Butyrate promotes T cell 'stemness' to support immunity to melanoma.
  8. Three rising stars in ageing research.
  9. Metabolite maps reveal spatial gradients in liver and intestinal tissue.
  10. FOXP3 expression depends on cell-type-specific cis-regulatory elements and transcription factor circuitry.
  11. Heat shock protein DNAJA2 controls insulin signaling and glucose homeostasis by preventing spontaneous insulin receptor endocytosis.
  12. An islet-resident macrophage antioxidant program preserves β cell physiology.
  13. Retroelements orchestrate gut tolerance.
  14. Dynamic dosage changes in X-linked transposable elements during mammalian dosage compensation.
  15. Termination of the integrated stress response.
  16. C-reactive protein is a broad-spectrum capsule-binding receptor for hepatic capture of blood-borne bacteria.
  17. Clonal Hematopoiesis-An Opportunity to Confront the Heart Failure Epidemic.
  18. Personalised prevention therapy in type 1 diabetes.
  19. Functional and Metabolic Heterogeneity of Dendritic Cells in Self-Tolerance and Autoimmunity.
  1. Nature. 2025 Nov 12.
    Gut bacteria help mice to stay lean.
      
    Keywords:  Metabolism
    DOI:  https://doi.org/10.1038/d41586-025-03661-w
  2. Nat Metab. 2025 Nov 14.
    Glycerol-3-phosphate activates ChREBP, FGF21 transcription and lipogenesis in citrin deficiency.
    Vinod Tiwari, Byungchang Jin, Olivia Sun, Edwin D J Lopez Gonzalez, Min-Hsuan Chen, Xiwei Wu, Hardik Shah, Andrew Zhang, Mark A Herman, Cassandra N Spracklen, Russell P Goodman, Charles Brenner.
      Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P-ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms part of a system that communicates metabolic states from the liver to the brain in a manner that alters food and alcohol choices. The data provide a framework for understanding FGF21 induction in varied conditions, suggest ways to develop FGF21-inducing drugs and suggest potential drug candidates for lean metabolic-dysfunction-associated steatotic liver disease and support of urea cycle function in CD.
    DOI:  https://doi.org/10.1038/s42255-025-01399-3
  3. Nat Commun. 2025 Nov 10. 16(1): 9657
    Gut-primed neutrophils activate Kupffer cells to promote hepatic injury in mouse sepsis.
    Atsushi Murao, Alok Jha, Takayuki Kato, Junji Shimizu, Yuichi Akama, Monowar Aziz, Ping Wang.
      Sepsis-induced liver injury is common, but the underlying mechanisms remain poorly understood. Given the critical role of gut-liver crosstalk in sepsis, we hypothesize that gut-trained neutrophils, migrating via the portal vein, release neutrophil extracellular traps (NETs) to activate Kupffer cells, thereby exacerbating hepatic injury during sepsis. Here we show that iNOS expression in Kupffer cells increases in septic wild type mice but decreases in PAD4-/- mice. In vitro, NETs stimulate Kupffer cell IL-6 and TNF release, while conditioned media from NET-treated Kupffer cells induces hepatocyte death. Inhibition of neutrophil elastase and protease-activated receptor-1 (PAR-1) mitigates IL-6 and TNF secretion by Kupffer cells. Ex vivo, portal vein neutrophils from septic mice produce more NETs and induce greater Kupffer cell activation than systemic neutrophils, with this effect attenuated in PAD4-/- neutrophils. Furthermore, gut intraepithelial lymphocytes (IELs) interact with neutrophils during sepsis and facilitate NETosis, and IEL-primed neutrophils also induce Kupffer cell activation in vitro and in vivo. Our data thus suggest that IEL-facilitated, gut-derived neutrophil NETs activate Kupffer cells to contribute to sepsis-induced liver injury.
    DOI:  https://doi.org/10.1038/s41467-025-65572-8
  4. Nat Immunol. 2025 Nov 14.
    Quiet custodians of CD8+ T cell fate.
    Charalampos Spilianakis.
      
    DOI:  https://doi.org/10.1038/s41590-025-02334-0
  5. Immunity. 2025 Nov 11. pii: S1074-7613(25)00473-X. [Epub ahead of print]58(11): 2609-2612
    Aging and immunity.
    Christoph A Thaiss, Ye Tian, Daniel A Winer, Michelle Linterman, Adrian Liston, Corina Amor, Scott W Lowe, Guang-Hui Liu.
      Time marches endlessly on … but what does that mean for the immune system? Here, investigators discuss how aging impacts the immune response and how immune cells can shape the aging process, with broader implications for modifying immunity to improve not only longevity but also health span.
    DOI:  https://doi.org/10.1016/j.immuni.2025.10.019
  6. Science. 2025 Nov 13. 390(6774): 685-686
    The missing piece: Solving the 50-year puzzle of BMP synthesis in neurodegeneration.
    Uche Medoh.
      Solving the 50-year puzzle of BMP synthesis in neurodegeneration.
    DOI:  https://doi.org/10.1126/science.aec9580
  7. Nat Rev Immunol. 2025 Nov 14.
    Butyrate promotes T cell 'stemness' to support immunity to melanoma.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-025-01245-3
  8. Nature. 2025 Nov;647(8089): S14-S15
    Three rising stars in ageing research.
    Sandy Ong, Felicity Nelson.
      
    Keywords:  Ageing; Alzheimer's disease; Cardiovascular biology; Obesity
    DOI:  https://doi.org/10.1038/d41586-025-03526-2
  9. Nature. 2025 Nov 12.
    Metabolite maps reveal spatial gradients in liver and intestinal tissue.
      
    Keywords:  Imaging; Metabolism; Physiology
    DOI:  https://doi.org/10.1038/d41586-025-03457-y
  10. Immunity. 2025 Nov 13. pii: S1074-7613(25)00474-1. [Epub ahead of print]
    FOXP3 expression depends on cell-type-specific cis-regulatory elements and transcription factor circuitry.
    Jennifer M Umhoefer, Maya M Arce, Sivakanthan Kasinathan, Sean Whalen, Rama Dajani, Sanjana Subramanya, Laine Goudy, Julia A Belk, Royce Zhou, Minh T N Pham, Wenxi Zhang, Rosmely Hernandez, Carinna Tran, Nikhita Kirthivasan, Jacob W Freimer, Cody T Mowery, Vinh Nguyen, Mineto Ota, Benjamin G Gowen, Dimitre R Simeonov, Gemma L Curie, Zhongmei Li, Andy Y Chen, Jacob E Corn, Howard Y Chang, Qizhi Tang, Luke A Gilbert, Ansuman T Satpathy, Katherine S Pollard, Alexander Marson.
      FOXP3 is a lineage-defining transcription factor (TF) for immune-suppressive regulatory T cells (Treg cells). Although mice exclusively express FOXP3 in Treg cells, stimulated conventional CD4+ T cells (Tconv cells) also transiently express FOXP3 in humans. Mechanisms governing these distinct expression patterns need elucidation. Here, we performed CRISPR screens tiling the FOXP3 locus and targeting TFs in human Treg and Tconv cells to identify cis-regulatory elements (CREs) and trans-regulators of FOXP3. Tconv cell FOXP3 expression depended on a subset of Treg cell CREs, as well as Tconv-cell-selective positive (NS+) and negative (NS-) CREs. Combinatorial silencing of Tconv cell CREs revealed their epistatic logic. These CREs are occupied and regulated by TFs that we identified as FOXP3 regulators. Finally, mutagenesis of murine NS- CRE revealed its essentiality for restricting FOXP3 expression to Treg cells. We map CRE and TF circuitry to reveal distinct cell- and species-specific regulation of FOXP3 expression.
    Keywords:  CRISPR; FOXP3; T cells; enhancers; epigenetics; gene regulation; regulatory T cells; transcription factors
    DOI:  https://doi.org/10.1016/j.immuni.2025.10.020
  11. Nat Commun. 2025 Nov 13. 16(1): 9973
    Heat shock protein DNAJA2 controls insulin signaling and glucose homeostasis by preventing spontaneous insulin receptor endocytosis.
    Yuanhua Qin, Wenjun Wu, Kequan Lin, Anthony J Davis, Yaping Huang.
      Dysregulation of heat shock protein DNAJA2 induces genomic instability and was consequently hypothesized to promote tumorigenesis. However, DNAJA2 knockout mice do not develop cancer but exhibit neonatal lethality and the underlying mechanism remains unknown. Here, we demonstrate that DNAJA2 maintains homeostatic glucose metabolism by regulating insulin signaling. Mechanistically, DNAJA2 binds to the insulin receptor (IR) and prevents adaptor protein 2 (AP2)-mediated spontaneous IR endocytosis by inhibiting the IR-AP2 interaction. Thus, DNAJA2 defects lead to reduced IR localization on the plasma membrane and suppression of the insulin-stimulated signaling cascade, thereby inhibiting glycogen synthesis and storage in the liver during embryogenesis, further resulting in neonatal lethality of DNAJA2-deficient mice. Analysis of public datasets reveals a strong association between DNAJA2 and metabolic phenotypes, including type 2 diabetes mellitus (T2DM) and obesity, in both humans and mice. In conclusion, our study elucidates the mechanism by which DNAJA2 regulates IR endocytosis, insulin signaling and glucose metabolism, shedding light on the pathogenesis of metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-025-64948-0
  12. Sci Immunol. 2025 Nov 14. 10(113): eadz5181
    An islet-resident macrophage antioxidant program preserves β cell physiology.
    Amélie Grosjean, Aude Jalon, Claire Leveau, Marc Diedisheim, David Alejandro Bejarano, Joyceline Cuenco, Kevin Mulder, Zhaoyuan Liu, Audrey Le Guernic, Marie-Laure Island, Jarne Walkiers, Gamze Ates, Clément Materne, Andreia Goncalves, Ivan Nemazanyy, Laura G Baudrin, Sylvain Baulande, Martine Ropert, Jean-François Gautier, Ahmed Hamaï, Andreas Schlitzer, Florent Ginhoux, Ann Massie, Nicolas Venteclef, Elise Dalmas.
      Pancreatic islet-resident macrophages (IRMs) display an activated phenotype and contribute to islet development and remodeling, yet their origin, heterogeneity, and functional roles remain poorly understood. Using complementary fate-mapping systems, we show that, in adult mice, around half of IRMs originate from circulating monocytes and undergo minimal turnover. Integrated multiple single-cell RNA sequencing analyses of mouse and human islets identified four major IRM cell states that collectively reveal their inflammatory and metabolic activation. Among these, a transcriptional program driven by the cystine-glutamate antiporter SLC7A11 and enriched in CD9high IRMs was associated with enhanced antioxidant defense, mitochondrial activity, and iron-lipid metabolic pathways. We found that Slc7a11-expressing IRMs preserve β cell redox homeostasis and insulin secretion, both at baseline and under stress. These findings position IRMs as specialized immune sentinels in the endocrine pancreas and identify SLC7A11 as a key macrophage-intrinsic safeguard against oxidative stress, with broad implications for islet resilience and metabolic health.
    DOI:  https://doi.org/10.1126/sciimmunol.adz5181
  13. Nat Rev Immunol. 2025 Nov 11.
    Retroelements orchestrate gut tolerance.
    Laura Rosenberg, Nicolas Vabret.
      
    DOI:  https://doi.org/10.1038/s41577-025-01243-5
  14. Nat Commun. 2025 Nov 11. 16(1): 9918
    Dynamic dosage changes in X-linked transposable elements during mammalian dosage compensation.
    Chunyao Wei, Barry Kesner, Uri Weissbein, Peera Wasserzug-Pash, Priyojit Das, Jeannie T Lee.
      In mammals, X-linked dosage compensation involves X-chromosome inactivation to balance X chromosome dosage between males and females, and hyperactivation of the remaining X-chromosome (Xa-hyperactivation) to achieve X-autosome balance in both sexes. Studies of both processes have largely focused on coding genes and have not accounted for transposable elements which comprise 50% of the X-chromosome with numerous epigenetic functions. Here we develop a new bioinformatic pipeline tailored to repetitive elements with capability for allelic discrimination. We then apply the pipeline to our recent So-Smart-Seq analysis of single embryos to comprehensively interrogate whether X-linked transposable elements are subject to either X-chromosome inactivation or Xa-hyperactivation. We observe significant differences in repeat silencing in parentally driven "imprinted" versus zygotically driven "random" X-chromosome inactivation. Chromosomal positioning, genetic background and evolutionary age impact their silencing. In contrast, transposable elements do not undergo Xa-hyperactivation. Evolutionary and functional implications are discussed.
    DOI:  https://doi.org/10.1038/s41467-025-64865-2
  15. Science. 2025 Nov 13. eadw5137
    Termination of the integrated stress response.
    Claudia De Miguel, Sigurdur R Thorkelsson, Agnieszka Fatalska, George Hodgson, Chao Wang, Anne Bertolotti.
      Stress responses enable cells to detect, adapt to, and survive challenges. The benefit of these signaling pathways depends on their reversibility. The integrated stress response (ISR) is elicited by phosphorylation of translation initiation factor eIF2, which traps and inhibits rate-limiting translation factor eIF2B thereby attenuating translation initiation. Termination of this pathway thus requires relieving eIF2B from P-eIF2 inhibition. Here, we found that eIF2 phosphatase subunits PPP1R15A and PPP1R15B (R15B) bound P-eIF2 in complex with eIF2B. Biochemical investigations guided by cryo-EM structures of native eIF2-eIF2B and P-eIF2-eIF2B complexes bound to R15B demonstrated that R15B enabled dephosphorylation of otherwise dephosphorylation-incompetent P-eIF2 on eIF2B. This sheds light on ISR termination, revealing that R15B rescues eIF2B from P-eIF2 inhibition, thereby safeguarding translation and cell fitness.
    DOI:  https://doi.org/10.1126/science.adw5137
  16. EMBO J. 2025 Nov 10.
    C-reactive protein is a broad-spectrum capsule-binding receptor for hepatic capture of blood-borne bacteria.
    Danyu Chen, Jiao Hu, Mengran Zhu, Yufeng Xie, Hantian Yao, Haoran An, Yumin Meng, Juanjuan Wang, Xueting Huang, Yanni Liu, Zhujun Shao, Ye Xiang, Jianxun Qi, George Fu Gao, Jing-Ren Zhang.
      Plasma C-reactive protein (CRP) is widely used as a biomarker for bacterial infections due to its massive induction during infections. However, the biological function of CRP remains largely undefined. Here we show that CRP enables liver resident macrophages (Kupffer cells) to capture and eliminate a wide range of invasive bacteria from the bloodstream of mice, and thereby provides rapid and sterilizing immunity. Mechanistically, CRP binds to at least 20 capsule types of Gram-positive and -negative pathogens, and shuffles the encapsulated bacteria to Kupffer cells embedded in the lining of the liver sinusoidal vasculatures by the complement-dependent and -independent pathways. The complement-dependent mode involves the activation of complement C3 at the bacterial surface, and the capture of the C3-opsonized bacteria by the CRIg and CR3 complement receptors on Kupffer cells. Cryo-electron microscopy analysis revealed a flexible structural framework for CRP's recognition of structurally diverse capsular polysaccharides. Because human CRP also possesses the broad capsule-binding activities, our findings provide a biological reason for the massive rise of plasma CRP during bacterial infections.
    Keywords:  C-reactive Protein; Capsule; Encapsulated Bacteria; Kupffer Cell and Complement System
    DOI:  https://doi.org/10.1038/s44318-025-00623-w
  17. JAMA Cardiol. 2025 Nov 09.
    Clonal Hematopoiesis-An Opportunity to Confront the Heart Failure Epidemic.
    Domingo A Pascual-Figal, José J Fuster.
      
    DOI:  https://doi.org/10.1001/jamacardio.2025.4672
  18. Lancet. 2025 Nov 11. pii: S0140-6736(25)02005-7. [Epub ahead of print]
    Personalised prevention therapy in type 1 diabetes.
    Bart O Roep.
      
    DOI:  https://doi.org/10.1016/S0140-6736(25)02005-7
  19. Immunol Rev. 2025 Nov;336(1): e70068
    Functional and Metabolic Heterogeneity of Dendritic Cells in Self-Tolerance and Autoimmunity.
    Jianru Chen, Juan Liu, Xuetao Cao.
      Dendritic cells (DCs) demonstrate remarkable functional and metabolic heterogeneity that governs the balance between immune tolerance and autoimmune pathogenesis. Under homeostatic conditions, tolerogenic DC subsets maintain immunological equilibrium through distinct metabolic programs and the production of immunoregulatory metabolites, promoting T cell anergy and regulatory T cell (Treg) differentiation. In contrast, autoimmune conditions trigger pathogenic metabolic rewiring, shifting DCs toward glycolysis and enhanced lipid synthesis, which drives DC hyperactivation and breakdown of self-tolerance. This metabolic reprogramming is coordinately regulated by external microenvironmental cues and internal signaling pathways, leading to heterogeneous DC responses in diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and psoriasis. Targeting metabolic regulators offers promising therapeutic strategies to restore immune tolerance and prevent harmful autoimmunity and inflammation. The review highlights the intricate interplay between DC metabolism and function, emphasizing how metabolic heterogeneity underpins their dual roles in immune regulation and autoimmunity. Future exploration of subset-specific metabolic preferences and spatiotemporal metabolic dynamics will facilitate the development of precision immunotherapies for autoimmune diseases.
    Keywords:  autoimmunity; dendritic cell; immune homeostasis; immunometabolism; self‐tolerance
    DOI:  https://doi.org/10.1111/imr.70068
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