bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–04–27
28 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. A protein tunnel that shuttles lipids around the cell.
  2. Interferon-β treatment restores myeloid function and reverses immunosuppression in sepsis.
  3. DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis.
  4. A host-pathogen metabolic synchrony that facilitates disease tolerance.
  5. Blood cancer driven by 'one hit' mutation event undergoes rapid growth.
  6. The mammalian longevity associated acetylome.
  7. IKAROS levels are associated with antigen escape in CD19- and CD22-targeted therapies for B-cell malignancies.
  8. Healthy diets for healthy aging.
  9. A guide to the Nature Index.
  10. Microglia drive amyloid-β clearance in immunized patients with Alzheimer's disease.
  11. Mitochondrial DNA signals driving immune responses: Why, How, Where?
  12. Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice.
  13. A plant dual-kinase protein traps a pathogen effector to trigger immunity.
  14. Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice.
  15. Endothelium calls macrophages for destruction.
  16. Parkinson's gut-microbiota links raise treatment possibilities.
  17. Targeting CD38 immunometabolic checkpoint improves metabolic fitness and cognition in a mouse model of Alzheimer's disease.
  18. Aberrant phase separation drives membranous organelle remodeling and tumorigenesis.
  19. Psychedelic control of neuroimmune interactions governing fear.
  20. Hypothalamic PNOC/NPY neurons constitute mediators of leptin-controlled energy homeostasis.
  21. Border-zone cardiomyocytes and macrophages regulate extracellular matrix remodeling to promote cardiomyocyte protrusion during cardiac regeneration.
  22. Defective autophagy in CD4 T cells drives liver fibrosis via type 3 inflammation.
  23. Clinical trials by the numbers.
  24. Microglia and CD8+ T cell activation precede neuronal loss in a murine model of spastic paraplegia 15.
  25. Structural basis of lipid transfer by a bridge-like lipid-transfer protein.
  26. The balance between conventional and unconventional T follicular helper cells influences autoreactive B cell responses.
  27. Efficient in vivo labeling of endogenous proteins with SMART delineates retina cellular and synaptic organization.
  28. IL-10 targets IRF transcription factors to suppress IFN and inflammatory response genes by epigenetic mechanisms.
  1. Nature. 2025 Apr 23.
    A protein tunnel that shuttles lipids around the cell.
      
    Keywords:  Cell biology; Structural biology
    DOI:  https://doi.org/10.1038/d41586-025-01167-z
  2. Nat Immunol. 2025 Apr 23.
    Interferon-β treatment restores myeloid function and reverses immunosuppression in sepsis.
      
    DOI:  https://doi.org/10.1038/s41590-025-02143-5
  3. Nat Commun. 2025 Apr 24. 16(1): 3867
    DHODH modulates immune evasion of cancer cells via CDP-Choline dependent regulation of phospholipid metabolism and ferroptosis.
    Da Teng, Kenneth D Swanson, Ruiheng Wang, Aojia Zhuang, Haofeng Wu, Zhixin Niu, Li Cai, Faith R Avritt, Lei Gu, John M Asara, Yaqing Zhang, Bin Zheng.
      The ability of cancer cells to evade immune destruction is governed by various intrinsic factors including their metabolic state. Here we demonstrate that inactivation of dihydroorotate dehydrogenase (DHODH), a pyrimidine synthesis enzyme, increases cancer cell sensitivity to T cell cytotoxicity through induction of ferroptosis. Lipidomic and metabolomic analyses reveal that DHODH inhibition reduces CDP-choline level and attenuates the synthesis of phosphatidylcholine (PC) via the CDP-choline-dependent Kennedy pathway. To compensate this loss, there is increased synthesis from phosphatidylethanolamine via the phospholipid methylation pathway resulting in increased generation of very long chain polyunsaturated fatty acid-containing PCs. Importantly, inactivation of Dhodh in cancer cells promotes the infiltration of interferon γ-secreting CD8+ T cells and enhances the anti-tumor activity of PD-1 blockade in female mouse models. Our findings reveal the importance of DHODH in regulating immune evasion through a CDP-choline dependent mechanism and implicate DHODH as a promising target to improve the efficacy of cancer immunotherapies.
    DOI:  https://doi.org/10.1038/s41467-025-59307-y
  4. Nat Commun. 2025 Apr 19. 16(1): 3729
    A host-pathogen metabolic synchrony that facilitates disease tolerance.
    Ying-Tsun Chen, Gaurav Kumar Lohia, Samantha Chen, Zihua Liu, Tania Wong Fok Lung, Chu Wang, Sebastián A Riquelme.
      Disease tolerance mitigates organ damage from non-resolving inflammation during persistent infections, yet its underlying mechanisms remain unclear. Here we show, in a Pseudomonas aeruginosa pneumonia mouse model, that disease tolerance depends on the mitochondrial metabolite itaconate, which mediates cooperative host-pathogen interactions. In P. aeruginosa, itaconate modifies key cysteine residues in TCA cycle enzymes critical for succinate metabolism, inducing bioenergetic stress and promoting the formation biofilms that are less immunostimulatory and allow the bacteria to integrate into the local microbiome. Itaconate incorporates into the central metabolism of the biofilm, driving exopolysaccharide production-particularly alginate-which amplifies airway itaconate signaling. This itaconate-alginate interplay limits host immunopathology by enabling pulmonary glutamine assimilation, activating glutaminolysis, and thereby restrain detrimental inflammation caused by the inflammasome. Clinical sample analysis reveals that P. aeruginosa adapts to this metabolic environment through compensatory mutations in the anti-sigma-factor mucA, which restore the succinate-driven bioenergetics and disrupt the metabolic synchrony essential for sustaining disease tolerance.
    DOI:  https://doi.org/10.1038/s41467-025-59134-1
  5. Nature. 2025 Apr 23.
    Blood cancer driven by 'one hit' mutation event undergoes rapid growth.
      
    Keywords:  Cancer; Genetics
    DOI:  https://doi.org/10.1038/d41586-025-01170-4
  6. Nat Commun. 2025 Apr 22. 16(1): 3749
    The mammalian longevity associated acetylome.
    S Feldman-Trabelsi, N Touitou, R Nagar, Z Schwartz, A Michelson, S Shaki, M Y Avivi, B Lerrer, S Snir, H Y Cohen.
      Despite extensive studies at the genomic, transcriptomic and metabolomic levels, the underlying mechanisms regulating longevity are incompletely understood. Post-translational protein acetylation is suggested to regulate aspects of longevity. To further explore the role of acetylation, we develop the PHARAOH computational tool based on the 100-fold differences in longevity within the mammalian class. Analyzing acetylome and proteome data across 107 mammalian species identifies 482 and 695 significant longevity-associated acetylated lysine residues in mice and humans, respectively. These sites include acetylated lysines in short-lived mammals that are replaced by permanent acetylation or deacetylation mimickers, glutamine or arginine, respectively, in long-lived mammals. Conversely, glutamine or arginine residues in short-lived mammals are replaced by reversibly acetylated lysine in long-lived mammals. Pathway analyses highlight the involvement of mitochondrial translation, cell cycle, fatty acid oxidation, transsulfuration, DNA repair and others in longevity. A validation assay shows that substituting lysine 386 with arginine in mouse cystathionine beta synthase, to attain the human sequence, increases the pro-longevity activity of this enzyme. Likewise, replacing the human ubiquitin-specific peptidase 10 acetylated lysine 714 with arginine as in short-lived mammals, reduces its anti-neoplastic function. Overall, in this work we propose a link between the conservation of protein acetylation and mammalian longevity.
    DOI:  https://doi.org/10.1038/s41467-025-58762-x
  7. Nat Commun. 2025 Apr 23. 16(1): 3800
    IKAROS levels are associated with antigen escape in CD19- and CD22-targeted therapies for B-cell malignancies.
    Pablo Domizi, Jolanda Sarno, Astraea Jager, Milton Merchant, Kaithlen Zen B Pacheco, Sean A Yamada-Hunter, Maria Caterina Rotiroti, Yuxuan Liu, Reema Baskar, Warren D Reynolds, Brian J Sworder, Bita Sahaf, Sean C Bendall, Charles G Mullighan, Ash A Alizadeh, Allison B Leahy, Regina M Myers, Bonnie Yates, Hao-Wei Wang, Nirali N Shah, Robbie G Majzner, Crystal L Mackall, Stephan A Grupp, David M Barrett, Elena Sotillo, Kara L Davis.
      Antigen escape relapse is a major challenge in targeted immunotherapies, including CD19- and CD22-directed chimeric antigen receptor (CAR) T-cell for B-cell acute lymphoblastic leukemia (B-ALL). To identify tumor-intrinsic factors driving antigen loss, we perform single-cell analyses on 61 B-ALL patient samples treated with CAR T cells. Here we show that low levels of IKAROS in pro-B-like B-ALL cells before CAR T treatment correlate with antigen escape. IKAROSlow B-ALL cells undergo epigenetic and transcriptional changes that diminish B-cell identity, making them resemble progenitor cells. This shift leads to reduced CD19 and CD22 surface expression. We demonstrate that CD19 and CD22 expression is IKAROS dose-dependent and reversible. Furthermore, IKAROSlow cells exhibit higher resistance to CD19- and CD22-targeted therapies. These findings establish a role for IKAROS as a regulator of antigens targeted by widely used immunotherapies and in the risk of antigen escape relapse, identifying it as a potential prognostic target.
    DOI:  https://doi.org/10.1038/s41467-025-58868-2
  8. Nat Aging. 2025 Apr 24.
    Healthy diets for healthy aging.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-025-00871-9
  9. Nature. 2025 Apr 23.
    A guide to the Nature Index.
      
    Keywords:  Cancer; Databases
    DOI:  https://doi.org/10.1038/d41586-025-01156-2
  10. Nat Med. 2025 Apr 22.
    Microglia drive amyloid-β clearance in immunized patients with Alzheimer's disease.
      
    DOI:  https://doi.org/10.1038/s41591-025-03677-9
  11. Cell Commun Signal. 2025 Apr 22. 23(1): 192
    Mitochondrial DNA signals driving immune responses: Why, How, Where?
    Luca Giordano, Sarah A Ware, Claudia J Lagranha, Brett A Kaufman.
      There has been a recent expansion in our understanding of DNA-sensing mechanisms. Mitochondrial dysfunction, oxidative and proteostatic stresses, instability and impaired disposal of nucleoids cause the release of mitochondrial DNA (mtDNA) from the mitochondria in several human diseases, as well as in cell culture and animal models. Mitochondrial DNA mislocalized to the cytosol and/or the extracellular compartments can trigger innate immune and inflammation responses by binding DNA-sensing receptors (DSRs). Here, we define the features that make mtDNA highly immunogenic and the mechanisms of its release from the mitochondria into the cytosol and the extracellular compartments. We describe the major DSRs that bind mtDNA such as cyclic guanosine-monophosphate-adenosine-monophosphate synthase (cGAS), Z-DNA-binding protein 1 (ZBP1), NOD-, LRR-, and PYD- domain-containing protein 3 receptor (NLRP3), absent in melanoma 2 (AIM2) and toll-like receptor 9 (TLR9), and their downstream signaling cascades. We summarize the key findings, novelties, and gaps of mislocalized mtDNA as a driving signal of immune responses in vascular, metabolic, kidney, lung, and neurodegenerative diseases, as well as viral and bacterial infections. Finally, we define common strategies to induce or inhibit mtDNA release and propose challenges to advance the field.
    Keywords:  Circulating cell-free DNA; DNA-sensing receptors; Inflammation; Innate immunity; Mitochondria; Mitochondrial DNA
    DOI:  https://doi.org/10.1186/s12964-025-02042-0
  12. Nat Metab. 2025 Apr;7(4): 823-841
    Hepatic gluconeogenesis and PDK3 upregulation drive cancer cachexia in flies and mice.
    Ying Liu, Ezequiel Dantas, Miriam Ferrer, Ting Miao, Mujeeb Qadiri, Yifang Liu, Aram Comjean, Emma E Davidson, Tiffany Perrier, Tanvir Ahmed, Yanhui Hu, Marcus D Goncalves, Tobias Janowitz, Norbert Perrimon.
      Cachexia, a severe wasting syndrome characterized by tumour-induced metabolic dysregulation, is a leading cause of death in people with cancer, yet its underlying mechanisms remain poorly understood. Here we show that a longitudinal full-body single-nuclei-resolution transcriptome analysis in a Drosophila model of cancer cachexia captures interorgan dysregulations. Our study reveals that the tumour-secreted interleukin-like cytokine Upd3 induces fat-body expression of Pepck1 and Pdk, key regulators of gluconeogenesis, disrupting glucose metabolism and contributing to cachexia. Similarly, in mouse cancer cachexia models, we observe IL-6-JAK-STAT-signalling-mediated induction of Pck1 and Pdk3 expression in the liver. Increased expression of these genes in fly, mouse, and human correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a previously unknown mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumour-induced metabolic disruptions and identifies potential therapeutic targets to mitigate cachexia in people with cancer.
    DOI:  https://doi.org/10.1038/s42255-025-01265-2
  13. Nat Genet. 2025 Apr 23.
    A plant dual-kinase protein traps a pathogen effector to trigger immunity.
      
    DOI:  https://doi.org/10.1038/s41588-025-02176-4
  14. Cell Rep. 2025 Apr 24. pii: S2211-1247(25)00380-8. [Epub ahead of print]44(5): 115609
    Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice.
    Netherlands Brain Bank
      Microglia are parenchymal brain macrophages that are established during embryogenesis and form a self-containing cellular compartment that resists seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMΦs) accumulate in the brain of aging mice with distinct topologies, including the nigrostriatum and medulla but not the frontal cortex. Parenchymal MoMΦs adopt bona fide microglia morphology and expression profiles. Due to their hematopoietic stem cell (HSC) derivation, monocyte-derived microglia (MoMg) are unlike yolk-sac-derived cells, targets of clonal hematopoiesis (CH). Indeed, using a chimeric transfer model, we show that the hematopoietic expression of DNMT3AR882H, a prominent human CH variant, renders MoMg pathogenic and promotes motor deficits resembling atypical Parkinsonian disorders. Collectively, we establish that MoMg progressively seed the brain of healthy aging mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can cause brain pathology.
    Keywords:  ARCH; CH; CHIP; CP: Immunology; CP: Neuroscience; DNMT3A R882H; HSC; brain macrophages; clonal hematopoiesis; microglia; monocytes
    DOI:  https://doi.org/10.1016/j.celrep.2025.115609
  15. Nat Immunol. 2025 Apr 22.
    Endothelium calls macrophages for destruction.
    Emmanuel L Gautier.
      
    DOI:  https://doi.org/10.1038/s41590-025-02123-9
  16. Nature. 2025 Apr 24.
    Parkinson's gut-microbiota links raise treatment possibilities.
    Sarah DeWeerdt.
      
    Keywords:  Microbiome; Neurodegeneration; Parkinson's disease
    DOI:  https://doi.org/10.1038/d41586-025-01253-2
  17. Nat Commun. 2025 Apr 20. 16(1): 3736
    Targeting CD38 immunometabolic checkpoint improves metabolic fitness and cognition in a mouse model of Alzheimer's disease.
    Javier María Peralta Ramos, Giulia Castellani, Denise Kviatcovsky, Tommaso Croese, Afroditi Tsitsou-Kampeli, Chiara Burgaletto, Miguel Angel Abellanas, Liora Cahalon, Sarah Phoebeluc Colaiuta, Tomer-Meir Salame, Yael Kuperman, Alon Savidor, Maxim Itkin, Sergey Malitsky, Sharon Ovadia, Shir Ferrera, Limor Kalfon, Shiran Kadmani, Nadra Samra, Rotem Paz, Lior Rokach, Roberto Furlan, Judith Aharon-Peretz, Tzipora C Falik-Zaccai, Michal Schwartz.
      Protective immunity, essential for brain maintenance and repair, may be compromised in Alzheimer's disease (AD). Here, using high-dimensional single-cell mass cytometry, we find a unique immunometabolic signature in circulating CD4+ T cells preceding symptom onset in individuals with familial AD, featured by the elevation of CD38 expression. Using female 5xFAD mice, a mouse model of AD, we show that treatment with an antibody directed to CD38 leads to restored metabolic fitness, improved cognitive performance, and attenuated local neuroinflammation. Comprehensive profiling across distinct immunological niches in 5xFAD mice, reveals a high level of disease-associated CD4+ T cells that produce IL-17A in the dural meninges, previously linked to cognitive decline. Targeting CD38 leads to abrogation of meningeal TH17 immunity and cortical IL-1β, breaking the negative feedback loop between these two compartments. Taken together, the present findings suggest CD38 as an immunometabolic checkpoint that could be adopted as a pre-symptomatic biomarker for early diagnosis of AD, and might also be therapeutically targeted alone or in combination with other immunotherapies for disease modification.
    DOI:  https://doi.org/10.1038/s41467-025-58494-y
  18. Mol Cell. 2025 Apr 18. pii: S1097-2765(25)00304-1. [Epub ahead of print]
    Aberrant phase separation drives membranous organelle remodeling and tumorigenesis.
    Xinyu Wang, Amin Jiang, Quan Meng, Tao Jiang, Huaide Lu, Xiaohan Geng, Zikuo Song, Xinyao Hu, Zhu Yu, Wencong Xu, Chao Ning, Yajing Lin, Dong Li.
      Membrane remodeling is essential for numerous cellular functions. Although liquid-liquid phase separation (LLPS) of intrinsically disordered region (IDR)-rich proteins could drive dramatic membrane remodeling of artificial giant unilamellar vesicles, it remains elusive whether LLPS-mediated membrane-remodeling functions in live cells and what role it plays in specific bioprocesses. Here, we show that three IDR-rich integral transmembrane fusion proteins (MFPs), generated by chromosomal translocations, can lead to de novo remodeling of their located membranous organelles. Taking FUS-CREB3L2, prevalent in low-grade fibromyxoid sarcoma (LGFMS), as a proof of concept, we recorded super-resolution long-time imaging of endoplasmic reticulum (ER) remodeling dynamics as accumulating FUS-CREB3L2, meanwhile causing spontaneous ER stress to hijack the X-box-binding protein 1 (XBP1) pathway. We further reveal the underlying mechanisms of how FUS-CREB3L2 transduces its tumorigenic signals and aberrant LLPS effects from the ER membrane into the nucleus autonomously, which activates hundreds of LGFMS-specific genes de novo compared with CREB3L2, thus sufficiently reprogramming the cells into an LGFMS-like status.
    Keywords:  ER stress; FUS-CREB3L2; fusion proteins; membrane remodeling; phase separation; spontaneous regulated intramembrane proteolysis
    DOI:  https://doi.org/10.1016/j.molcel.2025.04.001
  19. Nature. 2025 Apr 23.
    Psychedelic control of neuroimmune interactions governing fear.
    Elizabeth N Chung, Jinsu Lee, Carolina M Polonio, Joshua Choi, Camilo Faust Akl, Michael Kilian, Wiebke M Weiß, Georgia Gunner, Mingyu Ye, Tae Hyun Heo, Sienna S Drake, Liu Yang, Catarina R G L d'Eca, Joon-Hyuk Lee, Liwen Deng, Daniel Farrenkopf, Anton M Schüle, Hong-Gyun Lee, Oreoluwa Afolabi, Sharmin Ghaznavi, Stelios M Smirnakis, Isaac M Chiu, Vijay K Kuchroo, Francisco J Quintana, Michael A Wheeler.
      Neuroimmune interactions-signals transmitted between immune and brain cells-regulate many aspects of tissue physiology1, including responses to psychological stress2-5, which can predispose individuals to develop neuropsychiatric diseases6-9. Still, the interactions between haematopoietic and brain-resident cells that influence complex behaviours are poorly understood. Here, we use a combination of genomic and behavioural screens to show that astrocytes in the amygdala limit stress-induced fear behaviour through epidermal growth factor receptor (EGFR). Mechanistically, EGFR expression in amygdala astrocytes inhibits a stress-induced, pro-inflammatory signal-transduction cascade that facilitates neuron-glial crosstalk and stress-induced fear behaviour through the orphan nuclear receptor NR2F2 in amygdala neurons. In turn, decreased EGFR signalling and fear behaviour are associated with the recruitment of meningeal monocytes during chronic stress. This set of neuroimmune interactions is therapeutically targetable through the administration of psychedelic compounds, which reversed the accumulation of monocytes in the brain meninges along with fear behaviour. Together with validation in clinical samples, these data suggest that psychedelics can be used to target neuroimmune interactions relevant to neuropsychiatric disorders and potentially other inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41586-025-08880-9
  20. Cell. 2025 Apr 21. pii: S0092-8674(25)00403-9. [Epub ahead of print]
    Hypothalamic PNOC/NPY neurons constitute mediators of leptin-controlled energy homeostasis.
    Marie H Solheim, Sima Stroganov, Weiyi Chen, P Sicilia Subagia, Corinna A Bauder, Daria Wnuk-Lipinski, Almudena Del Río-Martín, Tamara Sotelo-Hitschfeld, Cait A Beddows, Paul Klemm, Garron T Dodd, Sofia Lundh, Anna Secher, F Thomas Wunderlich, Lukas Steuernagel, Jens C Brüning.
      Leptin acts in the brain to suppress appetite, yet the responsible neurocircuitries underlying leptin's anorectic effect are incompletely defined. Prepronociceptin (PNOC)-expressing neurons mediate diet-induced hyperphagia and weight gain in mice. Here, we show that leptin regulates appetite and body weight via PNOC neurons, and that loss of leptin receptor (Lepr) expression in PNOC-expressing neurons in the arcuate nucleus of the hypothalamus (ARC) causes hyperphagia and obesity. Restoring Lepr expression in PNOC neurons on a Lepr-null obese background substantially reduces body weight. Lepr inactivation in PNOC neurons increases neuropeptide Y (Npy) expression in a subset of hypothalamic PNOC neurons that do not express agouti-related peptide (Agrp). Selective chemogenetic activation of PNOC/NPY neurons promotes feeding to the same extent as activating all PNOCARC neurons, and overexpression of Npy in PNOCARC neurons promotes hyperphagia and obesity. Thus, we introduce PNOC/NPYARC neurons as an additional critical mediator of leptin action and as a promising target for obesity therapeutics.
    Keywords:  AgRP; NPY; PNOC; POMC; energy homeostasis; food intake; hypothalamus; leptin; neurocircuits; nociceptin; obesity
    DOI:  https://doi.org/10.1016/j.cell.2025.04.001
  21. Nat Commun. 2025 Apr 23. 16(1): 3823
    Border-zone cardiomyocytes and macrophages regulate extracellular matrix remodeling to promote cardiomyocyte protrusion during cardiac regeneration.
    Florian Constanty, Bailin Wu, Ke-Hsuan Wei, I-Ting Lin, Julia Dallmann, Stefan Guenther, Till Lautenschlaeger, Rashmi Priya, Shih-Lei Lai, Didier Y R Stainier, Arica Beisaw.
      Despite numerous advances in our understanding of zebrafish cardiac regeneration, an aspect that remains less studied is how regenerating cardiomyocytes invade and replace the collagen-containing injured tissue. Here, we provide an in-depth analysis of the process of cardiomyocyte invasion. We observe close interactions between protruding border-zone cardiomyocytes and macrophages, and show that macrophages are essential for extracellular matrix remodeling at the wound border zone and cardiomyocyte protrusion into the injured area. Single-cell RNA-sequencing reveals the expression of mmp14b, encoding a membrane-anchored matrix metalloproteinase, in several cell types at the border zone. Genetic mmp14b mutation leads to decreased macrophage recruitment, collagen degradation, and subsequent cardiomyocyte protrusion into injured tissue. Furthermore, cardiomyocyte-specific overexpression of mmp14b is sufficient to enhance cardiomyocyte invasion into the injured tissue and along the apical surface of the wound. Altogether, our data provide important insights into the mechanisms underlying cardiomyocyte invasion of the collagen-containing injured tissue during cardiac regeneration.
    DOI:  https://doi.org/10.1038/s41467-025-59169-4
  22. Nat Commun. 2025 Apr 24. 16(1): 3860
    Defective autophagy in CD4 T cells drives liver fibrosis via type 3 inflammation.
    Rola Al Sayegh, Jinghong Wan, Charles Caër, Margot Azoulai, Maxime Gasperment, Sukriti Baweja, Marc-Anthony Chouillard, Janany Kandiah, Mathilde Cadoux, Morgane Mabire, Camille Pignolet, Tristan Thibault-Sogorb, Adel Hammoutene, Valérie Paradis, Loredana Saveanu, Rémy Nicolle, Hélène Gilgenkrantz, Emmanuel Weiss, Sophie Lotersztajn.
      Conventional CD4 T cells represent a major source of inflammatory mediators that drive progression of chronic liver disease to fibrosis and to end-stage cirrhosis. Identification of T cell pathways that limits the inflammatory response could thus have therapeutic relevance. Here we show, using both human samples and mouse models, that autophagy is deficient in CD4 T cells from patients with advanced fibrosis, and that loss of autophagy following genomic deletion of ATG5 in T cells is associated with the emergence of pathogenic IL-17A + IFN-γ + Th17 T cells that drive liver fibrosis in mice. Mechanistically, liver CD4 T cells lacking autophagy display a Th17 glycolytic phenotype associated with enhanced type 3 cytokine (i.e., IL-17A and GM-CSF) release, shifting hepatic myofibroblasts, hepatocytes and macrophages toward a proinflammatory phenotype. We also show that autophagy can be rescued in CD4 T cells from patients with extensive liver fibrosis, leading to decreased frequency of pathogenic Th17 cells and reduced GM-CSF levels; in addition, limited fibrosis is observed in mice in which Rubicon, a negative regulator of autophagy, is deleted specifically in their T cells. Our findings thus implicate autophagy in CD4 T cells as a key therapeutic target to control inflammation-driven fibrosis during chronic liver injury.
    DOI:  https://doi.org/10.1038/s41467-025-59218-y
  23. Nature. 2025 Apr;640(8060): S58-S59
    Clinical trials by the numbers.
    Benjamin Plackett.
      
    Keywords:  Cancer; Economics; Health care; Medical research; Public health
    DOI:  https://doi.org/10.1038/d41586-025-01152-6
  24. J Exp Med. 2025 Jul 07. pii: e20232357. [Epub ahead of print]222(7):
    Microglia and CD8+ T cell activation precede neuronal loss in a murine model of spastic paraplegia 15.
    Aleksej Frolov, Hao Huang, Dagmar Schütz, Maren Köhne, Nelli Blank-Stein, Collins Osei-Sarpong, Maren Büttner, Tarek Elmzzahi, Mukhran Khundadze, Marina Zahid, Michael Reuter, Matthias Becker, Elena De Domenico, Lorenzo Bonaguro, Axel Kallies, Helen Morrison, Christian A Hübner, Kristian Händler, Ralf Stumm, Elvira Mass, Marc D Beyer.
      In central nervous system (CNS) diseases characterized by late-onset neurodegeneration, the interplay between innate and adaptive immune responses remains poorly understood. This knowledge gap is exacerbated by the prolonged protracted disease course as it complicates the delineation of brain-resident and infiltrating cells. Here, we conducted comprehensive profiling of innate and adaptive immune cells in a murine model of spastic paraplegia 15 (SPG15), a complicated form of hereditary spastic paraplegia. Using fate-mapping of bone marrow-derived cells, we identified microgliosis accompanied by infiltration and local expansion of T cells in the CNS of Spg15-/- mice. Single-cell analysis revealed an expansion of disease-associated microglia (DAM) and effector CD8+ T cells prior to neuronal loss. Analysis of potential cell-cell communication pathways suggested bidirectional interactions between DAM and effector CD8+ T cells, potentially contributing to disease progression in Spg15-/- mice. In summary, we identified a shift in microglial phenotypes associated with the recruitment and expansion of T cells as a new characteristic of Spg15-driven neuropathology.
    DOI:  https://doi.org/10.1084/jem.20232357
  25. Nature. 2025 Apr 23.
    Structural basis of lipid transfer by a bridge-like lipid-transfer protein.
    Yunsik Kang, Katherine S Lehmann, Hannah Long, Amanda Jefferson, Maria Purice, Marc Freeman, Sarah Clark.
      Bridge-like lipid-transport proteins (BLTPs) are an evolutionarily conserved family of proteins that localize to membrane-contact sites and are thought to mediate the bulk transfer of lipids from a donor membrane, typically the endoplasmic reticulum, to an acceptor membrane, such as that of the cell or an organelle1. Although BLTPs are fundamentally important for a wide array of cellular functions, their architecture, composition and lipid-transfer mechanisms remain poorly characterized. Here we present the subunit composition and the cryogenic electron microscopy structure of the native LPD-3 BLTP complex isolated from transgenic Caenorhabditis elegans. LPD-3 folds into an elongated, rod-shaped tunnel of which the interior is filled with ordered lipid molecules that are coordinated by a track of ionizable residues that line one side of the tunnel. LPD-3 forms a complex with two previously uncharacterized proteins, one of which we have named Spigot and the other of which remains unnamed. Spigot interacts with the N-terminal end of LPD-3 where lipids are expected to enter the tunnel, and experiments in multiple model systems indicate that Spigot has a conserved role in BLTP function. Our LPD-3 complex structural data reveal protein-lipid interactions that suggest a model for how the native LPD-3 complex mediates bulk lipid transport and provides a foundation for mechanistic studies of BLTPs.
    DOI:  https://doi.org/10.1038/s41586-025-08918-y
  26. Cell Rep. 2025 Apr 18. pii: S2211-1247(25)00373-0. [Epub ahead of print]44(5): 115602
    The balance between conventional and unconventional T follicular helper cells influences autoreactive B cell responses.
    Chenfei He, Shan Wang, Marion Moreews, Shengduo Pei, Guangchun Chen, Quan-Zhen Li, Alberto Del Monte Monge, Almudena R Ramiro, Curtis Cai, Mauro Gaya, Patricia Barral, Marcus Buggert, Facundo D Batista, Mikael C I Karlsson.
      Invariant natural killer T (iNKT) cells are activated by glycolipids presented on CD1d. When iNKT cells interact with and activate B cells, they can differentiate into iNKT follicular helper (iNKTfh) cells, and here, we investigate how this, in turn, regulates conventional T follicular helper (Tfh) cells. This is done in an autoimmune model where antibodies are produced against self-antigens relevant to the autoimmune disease systemic lupus erythematosus (SLE). We find a balance between iNKTfh and Tfh cells that directs the B cell response and influences Tfh cell generation. This altered balance also affects the specificities and increases the autoantibody response. We also show that CD1d expression by B cells is essential for iNKTfh cell generation. In conclusion, our data shed light on how T cell help for B cells is divided between conventional and unconventional helper cell populations and how this has an impact on autoreactive B cell responses.
    Keywords:  CD1d; CP: Immunology; T follicular helper cells; apoptotic cells; autoimmune disease; germinal center
    DOI:  https://doi.org/10.1016/j.celrep.2025.115602
  27. Nat Commun. 2025 Apr 22. 16(1): 3768
    Efficient in vivo labeling of endogenous proteins with SMART delineates retina cellular and synaptic organization.
    Chuanping Zhao, Yan Cao, Noor Ibrahim, Yuchen Wang, Kirill A Martemyanov.
      A key application of CRISPR/Cas9-based genomic editing is modification of genes to introduce engineered sequences. However, the editing flexibility is severely constrained by the requirement for targeting sites in proximity to the desired modification site, which makes many modifications intractable. Here, we develop a strategy that overcomes this key limitation to allow CRISPR-based editing at any position with high efficiency. It relies on reconstructing the targeted gene using Silently Mutate And Repair Template (SMART) where we mutate the gap sequence in the repair template to prevent its base pairing with the target DNA while maintaining the same amino acid coding. Using vertebrate retina as a neuronal model system we document the application of SMART editing for labeling endogenous proteins in vivo with high efficiency. We show that SMART editing allows us to access numerous cell types in the retina and address fundamental cell biological questions pertaining to its organization. We propose that this approach will facilitate functional genomic studies in a wide range of systems and increase the precision of corrective gene therapies.
    DOI:  https://doi.org/10.1038/s41467-025-58945-6
  28. Nat Immunol. 2025 Apr 22.
    IL-10 targets IRF transcription factors to suppress IFN and inflammatory response genes by epigenetic mechanisms.
    Bikash Mishra, Mahesh Bachu, Ruoxi Yuan, Claire Wingert, Vidyanath Chaudhary, Caroline Brauner, Richard Bell, Lionel B Ivashkiv.
      Interleukin-10 (IL-10) is pivotal in suppressing innate immune activation, in large part by suppressing induction of inflammatory genes. Despite decades of research, the molecular mechanisms underlying this inhibition have not been resolved. Here we utilized an integrated epigenomic analysis to investigate IL-10-mediated suppression of LPS and TNF responses in primary human monocytes. Instead of inhibiting core TLR4-activated pathways such as NF-κB, MAPK-AP-1 and TBK1-IRF3 signaling, IL-10 targeted IRF transcription factor activity and DNA binding, particularly IRF5 and an IRF1-mediated amplification loop. This resulted in suppression of inflammatory NF-κB target genes and near-complete suppression of interferon-stimulated genes. Mechanisms of gene inhibition included downregulation of chromatin accessibility, de novo enhancer formation and IRF1-associated H3K27ac activating histone marks. These results provide a mechanism by which IL-10 suppresses inflammatory NF-κB target genes, highlight the role of IRF1 in inflammatory gene expression and describe the suppression of IFN responses by epigenetic mechanisms.
    DOI:  https://doi.org/10.1038/s41590-025-02137-3
This page is being maintained by Thomas Krichel. It was last updated on 2025‒04‒27 at 5:48.