bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–09–14
24 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Divergent cytokine and transcriptional signatures control functional T follicular helper cell heterogeneity.
  2. Mending a mother's mitochondrial DNA.
  3. Building immune tolerance in the thymus.
  4. Predicting obesity from childhood.
  5. Bacterial toxins rewire the trans-Golgi network to activate the inflammatory response.
  6. Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling.
  7. A brain center that controls consummatory responses.
  8. RNA-binding proteins pull in chromatin loops.
  9. Dysregulated RNA splicing impairs regeneration in alcohol-associated liver disease.
  10. ABCA7 variants impact phosphatidylcholine and mitochondria in neurons.
  11. Integrated single-cell atlas of human atherosclerotic plaques.
  12. Towards a personalized approach in senolytic trials.
  13. Daily briefing: How bad are ultra-processed foods, really?
  14. Autoimmune disease risk gene ANKRD55 promotes TH17 effector function through metabolic modulation.
  15. Structure and mechanism of the mitochondrial calcium transporter NCLX.
  16. Microglia-to-neuron signaling links APOE4 and inflammation to enhanced neuronal lipid metabolism and network activity.
  17. How did the oldest star clusters form?
  18. Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction-associated steatohepatitis.
  19. Immunometabolic defects of CD8+ T cells disrupt gut barrier integrity in people with HIV.
  20. A bivalent chromatin state regulates the function of composite transposons.
  21. Metabolic control of innate-like T cells.
  22. Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumours.
  23. Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan.
  24. SIRT2 and NAD+ Boosting Broadly Suppress Aging-Associated Inflammation.
  1. Nat Immunol. 2025 Sep 09.
    Divergent cytokine and transcriptional signatures control functional T follicular helper cell heterogeneity.
    Lennard Dalit, Chin Wee Tan, Amania A Sheikh, Ryan Munnings, Lauren J Howson, Carolina Alvarado, Tabinda Hussain, Aidil Zaini, Lucy Cooper, Alana Kirn, Lauren Hailes, Angela Nguyen, Bailey E Williams, Ming Z M Zheng, Carolien E van de Sandt, Laura K Mackay, Katie L Flanagan, Katherine Kedzierska, Nicola Harris, Jennifer A Juno, Colby Zaph, Nicole L La Gruta, Melissa J Davis, Stephen L Nutt, Kim L Good-Jacobson, Vanessa L Bryant, Joanna R Groom.
      CD4+ T follicular helper (TFH) cells support tailored B cell responses against multiple classes of pathogens. To reveal how diverse TFH phenotypes are established, we profiled mouse TFH cells in response to viral, helminth and bacterial infection. We identified a core TFH signature that is distinct from CD4+ T follicular regulatory and effector cells and identified pathogen-specific transcriptional modules that shape TFH function. Cytokine-transcriptional TFH programming demonstrated that type I interferon and TGFβ signaling direct individual TFH phenotypes to instruct B cell output. Cytokine-directed TFH transcriptional phenotypes are shared within human germinal centers, but distinct TFH phenotypes dominate between donors and following immune challenge or in antibody-mediated disease. Finally, we identified new cell surface markers that align with distinct TFH phenotypes. Thus, we provide a comprehensive resource of TFH diversity in humans and mice to enable immune monitoring during infection and disease and to inform the development of context-specific vaccines.
    DOI:  https://doi.org/10.1038/s41590-025-02258-9
  2. Nat Med. 2025 Sep 12.
    Mending a mother's mitochondrial DNA.
    Mike May.
      
    DOI:  https://doi.org/10.1038/d41591-025-00056-2
  3. Nat Genet. 2025 Sep;57(9): 2083
    Building immune tolerance in the thymus.
    Safia Danovi.
      
    DOI:  https://doi.org/10.1038/s41588-025-02339-3
  4. Nat Genet. 2025 Sep;57(9): 2083
    Predicting obesity from childhood.
    Margot Brandt.
      
    DOI:  https://doi.org/10.1038/s41588-025-02338-4
  5. Nat Immunol. 2025 Sep 09.
    Bacterial toxins rewire the trans-Golgi network to activate the inflammatory response.
      
    DOI:  https://doi.org/10.1038/s41590-025-02278-5
  6. Cell. 2025 Sep 10. pii: S0092-8674(25)00978-X. [Epub ahead of print]
    Microglia-astrocyte crosstalk regulates synapse remodeling via Wnt signaling.
    Travis E Faust, Yi-Han Lee, Ciara D O'Connor, Margaret A Boyle, Georgia Gunner, Violeta Durán-Laforet, Loris L Ferrari, Robert E Murphy, Ana Badimon, Kristina Sakers, Cagla Eroglu, Pinar Ayata, Anne Schaefer, Dorothy P Schafer.
      Astrocytes and microglia are emerging key regulators of activity-dependent synapse remodeling that engulf and remove synapses in response to changes in neural activity. Yet, the degree to which these cells communicate to coordinate this process remains an open question. Here, we use whisker removal in postnatal mice to induce activity-dependent synapse removal in the barrel cortex. We show that astrocytes do not engulf synapses in this paradigm. Instead, astrocytes reduce contact with synapses prior to microglia-mediated synapse engulfment. We further show that the reduced astrocyte-synapse contact is dependent on the release of Wnts from microglia downstream of neuron-to-microglia fractalkine ligand-receptor (CX3CL1-CX3CR1) signaling. These results demonstrate an activity-dependent mechanism by which microglia instruct astrocyte-synapse interactions, providing a permissive environment for microglia to remove synapses. We further show that this mechanism is critical to remodel synapses in a changing sensory environment and that this signaling is upregulated in several disease contexts.
    Keywords:  Wnt; astrocyte; microglia; synapse remodeling
    DOI:  https://doi.org/10.1016/j.cell.2025.08.023
  7. Cell. 2025 Sep 04. pii: S0092-8674(25)00976-6. [Epub ahead of print]
    A brain center that controls consummatory responses.
    Jose A Canovas, Li Wang, Ahmed A M Mohamed, Larry F Abbott, Charles S Zuker.
      The innate attraction to sweet mediates appetitive and consummatory responses. Here, we dissected the circuit driving responses to sweet and showed that amygdala neurons tuned to sweet connect to the bed nucleus of the stria-terminalis (BNST) to promote sweet-evoked consumption. Next, we demonstrate that the BNST functions as a central hub, transforming appetitive signals into consumption and linking sensory inputs to the internal state, not only for sweet but also for other stimuli such as salt or food, to flexibly regulate consummatory behaviors. Using single-cell functional imaging, we show that ensemble activity in the BNST encodes stimulus identity and the animal's internal state. Finally, we demonstrate that manipulating BNST activity can bidirectionally transform consummatory responses. Together, these findings illustrate how the internal state modulates sensory responses, characterize a general brain dial for consumption, and provide fresh insights into sites of action of GLP1R agonists and a strategy to help promote weight gain in pathological states.
    Keywords:  GLP1R; brain circuits; cachexia; consummatory behaviors; internal state; sweet, salt, and food; taste; weight loss
    DOI:  https://doi.org/10.1016/j.cell.2025.08.021
  8. Nat Cell Biol. 2025 Sep;27(9): 1387-1388
    RNA-binding proteins pull in chromatin loops.
    Ann Dean.
      
    DOI:  https://doi.org/10.1038/s41556-025-01743-5
  9. Nat Commun. 2025 Sep 10. 16(1): 8049
    Dysregulated RNA splicing impairs regeneration in alcohol-associated liver disease.
    Ullas V Chembazhi, Sushant Bangru, Rajesh Kumar Dutta, Diptatanu Das, Brandon Peiffer, Subhashis Natua, Katelyn Toohill, Aurelia Leona, Ishita Purwar, Anuprova Bhowmik, Yogesh Goyal, Zhaoli Sun, Anna Mae Diehl, Auinash Kalsotra.
      Individuals with progressive liver failure risk dying without liver transplantation. However, our understanding of why regenerative responses are disrupted in failing livers is limited. Here, we perform multiomic profiling of healthy and diseased human livers using bulk and single-nucleus RNA- and ATAC-seq. We report that in alcohol-associated liver disease, alterations in the hepatic immune milieu prevent hepatocytes from transitioning to proliferative progenitors. We also find differences in RNA binding protein expression, particularly of the ESRP, PTBP, and SR families, leading to misregulation of developmentally controlled RNA splicing. Our data pinpoint ESRP2 as a disease-sensitive splicing factor and support a causal role for its deficiency in the pathogenesis of severe alcoholic hepatitis. Notably, splicing defects in Tcf4 and Slk, two ESPR2 targets, alter their nuclear localization and activities, disrupting WNT and Hippo signaling pathways that are critical for normal liver regeneration. We further demonstrate that changes in stromal cell populations enrich failing livers with TGF-β, which suppresses the ESRP2-driven epithelial splicing program and replaces functional parenchyma with quasi-progenitor-like cells lacking liver-specific functions. Taken together, these findings indicate that misspliced RNAs are effective biomarkers for alcohol-associated liver disease, and targeting them could improve recovery in affected individuals.
    DOI:  https://doi.org/10.1038/s41467-025-63251-2
  10. Nature. 2025 Sep 10.
    ABCA7 variants impact phosphatidylcholine and mitochondria in neurons.
    Djuna von Maydell, Shannon E Wright, Ping-Chieh Pao, Colin Staab, Oisín King, Andrea Spitaleri, Julia Maeve Bonner, Liwang Liu, Chung Jong Yu, Ching-Chi Chiu, Daniel Leible, Aine Ni Scannail, Mingpei Li, Carles A Boix, Hansruedi Mathys, Guillaume Leclerc, Gloria Suella Menchaca, Gwyneth Welch, Agnese Graziosi, Noelle Leary, George Samaan, Manolis Kellis, Li-Huei Tsai.
      Loss-of-function variants in the lipid transporter ABCA7 substantially increase the risk of Alzheimer's disease1,2, yet how they impact cellular states to drive disease remains unclear. Here, using single-nucleus RNA-sequencing analysis of human brain samples, we identified widespread gene expression changes across multiple neural cell types associated with rare ABCA7 loss-of-function variants. Excitatory neurons, which expressed the highest levels of ABCA7, showed disrupted lipid metabolism, mitochondrial function, DNA repair and synaptic signalling pathways. Similar transcriptional disruptions occurred in neurons carrying the common Alzheimer's-associated variant ABCA7 p.Ala1527Gly3, predicted by molecular dynamics simulations to alter the ABCA7 structure. Induced pluripotent stem (iPS)-cell-derived neurons with ABCA7 loss-of-function variants recapitulated these transcriptional changes, displaying impaired mitochondrial function, increased oxidative stress and disrupted phosphatidylcholine metabolism. Supplementation with CDP-choline increased phosphatidylcholine synthesis, reversed these abnormalities and normalized amyloid-β secretion and neuronal hyperexcitability-key Alzheimer's features that are exacerbated by ABCA7 dysfunction. Our results implicate disrupted phosphatidylcholine metabolism in ABCA7-related Alzheimer's risk and highlight a possible therapeutic approach.
    DOI:  https://doi.org/10.1038/s41586-025-09520-y
  11. Nat Commun. 2025 Sep 10. 16(1): 8255
    Integrated single-cell atlas of human atherosclerotic plaques.
    Korbinian Traeuble, Matthias Munz, Jessica Pauli, Nadja Sachs, Eshan Vafadarnejad, Tania Carrillo-Roa, Lars Maegdefessel, Peter Kastner, Matthias Heinig.
      Atherosclerosis, a major cause of cardiovascular diseases, is characterized by the buildup of lipids and chronic inflammation in the arteries, leading to plaque formation and potential rupture. Despite recent advances in single-cell transcriptomics (scRNA-seq), the underlying immune mechanisms and transformations in structural cells driving plaque progression remain incompletely defined. Existing datasets often lack comprehensive coverage and consistent annotations, limiting the utility of downstream analyses. Here, we present an integrated single-cell atlas of human atherosclerotic plaques, covering roughly 250k high-quality annotated cells. We achieve robust cell type annotations validated by expert consensus and surface protein measurements. Using this atlas, we introduce distinct markers for plaque neutrophils, identify a proangiogenic endothelial cell cluster enriched in advanced lesions, and specialized macrophage subsets. We also establish that fibromyocytes are exclusive to vascular tissue. This comprehensive atlas enables accurate automatic cell type annotation of new datasets, improves experimental design by guiding sample size and detection power, and supports the deconvolution of bulk RNA-seq data. An interactive WebUI makes these resources widely accessible.
    DOI:  https://doi.org/10.1038/s41467-025-63202-x
  12. Nat Aging. 2025 Sep 09.
    Towards a personalized approach in senolytic trials.
    Sundeep Khosla, David G Monroe, Joshua N Farr.
      
    DOI:  https://doi.org/10.1038/s43587-025-00964-5
  13. Nature. 2025 Sep 03.
    Daily briefing: How bad are ultra-processed foods, really?
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-025-02842-x
  14. J Exp Med. 2025 Nov 03. pii: e20250185. [Epub ahead of print]222(11):
    Autoimmune disease risk gene ANKRD55 promotes TH17 effector function through metabolic modulation.
    Jinjin Xu, Lingjia Kong, Elizabeth A Creasey, Sneha Rath, Lei Deng, Julian Avila-Pacheco, Chenhao Li, Blayne A Oliver, Tyler T Dao, Angela R Shih, Mark J Daly, Alex K Shalek, Clary B Clish, Daniel B Graham, Jacques Deguine, Ramnik J Xavier.
      Genome-wide association studies (GWAS) have linked the locus encoding ankyrin repeat domain 55 (ANKRD55) with numerous autoimmune diseases; however, its biological function and role in inflammation are unclear. Here, we demonstrate that Ankrd55-deficient mice are protected from T cell-mediated colitis but are more susceptible to Citrobacter rodentium infection. Mechanistically, Ankrd55 deletion impairs CD4+ T cell proliferation and reduces effector cytokine production in T helper 17 (TH17) cells in a cell-intrinsic manner. ANKRD55 is associated with mitochondria, and its loss is associated with impaired mitochondrial respiration and activation of the LKB1 pathway. Consistently, IL-17 production can be rescued by the deletion of LKB1 in Ankrd55-deficient T cells. Altogether, our study implicates the protein ANKRD55 as a functional modulator of T cell metabolism that directly impacts TH17 responses, highlighting it as a potential target across multiple autoimmune diseases.
    DOI:  https://doi.org/10.1084/jem.20250185
  15. Nature. 2025 Sep 10.
    Structure and mechanism of the mitochondrial calcium transporter NCLX.
    Minrui Fan, Chen-Wei Tsai, Jinru Zhang, Jianxiu Zhang, Aswini R Krishnan, Tsung-Yun Liu, Yu-Lun Huang, Deniz Aydin, Siyuan Du, Briana L Sobecks, Madison X Rodriguez, Andrew H Reiter, Carolyn R Bertozzi, Ron O Dror, Ming-Feng Tsai, Liang Feng.
      As a key mitochondrial Ca2+ transporter, NCLX regulates intracellular Ca2+ signalling and vital mitochondrial processes1-3. The importance of NCLX in cardiac and nervous-system physiology is reflected by acute heart failure and neurodegenerative disorders caused by its malfunction4-9. Despite substantial advances in the field, the transport mechanisms of NCLX remain unclear. Here we report the cryo-electron microscopy structures of NCLX, revealing its architecture, assembly, major conformational states and a previously undescribed mechanism for alternating access. Functional analyses further reveal an unexpected transport function of NCLX as a H+/Ca2+ exchanger, rather than as a Na+/Ca2+ exchanger as widely believed1. These findings provide critical insights into mitochondrial Ca2+ homeostasis and signalling, offering clues for developing therapies to treat diseases related to abnormal mitochondrial Ca2+.
    DOI:  https://doi.org/10.1038/s41586-025-09491-0
  16. Proc Natl Acad Sci U S A. 2025 Sep 16. 122(37): e2516103122
    Microglia-to-neuron signaling links APOE4 and inflammation to enhanced neuronal lipid metabolism and network activity.
    Ana P Verduzco Espinoza, Na Na, Loraine Campanati, Priscilla Ngo, Kristin K Baldwin, Hollis T Cline.
      Microglia regulate neuronal circuit plasticity. Disrupting their homeostatic function has detrimental effects on neuronal circuit health. Neuroinflammation contributes to the onset and progression of neurodegenerative diseases, including Alzheimer's disease (AD), with several microglial activation genes linked to increased risk for these conditions. Inflammatory microglia alter neuronal excitability, inducing metabolic strain. Interestingly, expression of APOE4, the strongest genetic risk factor for AD, affects both microglial activation and neuronal excitability, highlighting the interplay between lipid metabolism, inflammation, and neuronal function. It remains unclear how microglial inflammatory state is conveyed to neurons to affect circuit function and whether APOE4 expression alters this intercellular communication. Here, we use a reductionist model of human iPSC-derived microglial and neuronal monocultures to dissect how the APOE genotype in each cell type independently contributes to microglial regulation of neuronal activity during inflammation. Conditioned media (CM) from LPS-stimulated microglia increased neuronal network activity, assessed by calcium imaging, with APOE4 microglial CM driving greater neuronal activity than APOE3 CM. Both APOE3 and APOE4 neurons increase network activity in response to CM treatments, while APOE4 neurons uniquely increase presynaptic puncta in response to APOE4 microglial CM. CM-derived exosomes from LPS-stimulated microglia can mediate increases to network activity. Finally, increased network activity is accompanied by increased lipid droplet (LD) metabolism, and blocking LD metabolism abolishes network activity. These findings illuminate how microglia-to-neuron communication drives inflammation-induced changes in neuronal circuit function, demonstrate a role for neuronal LDs in network activity, and support a potential mechanism through which APOE4 increases neuronal excitability.
    Keywords:  APOE4; Alzheimer’s disease; exosomes; lipid droplets; microglia
    DOI:  https://doi.org/10.1073/pnas.2516103122
  17. Nature. 2025 Sep;645(8080): 322-323
    How did the oldest star clusters form?
    Natalia Lahén.
      
    Keywords:  Astronomy and astrophysics; Cosmology
    DOI:  https://doi.org/10.1038/d41586-025-02598-4
  18. Sci Transl Med. 2025 Sep 10. 17(815): eadv2106
    Impaired TIM4-mediated efferocytosis by liver macrophages contributes to fibrosis in metabolic dysfunction-associated steatohepatitis.
    Hongxue Shi, Xiaobo Wang, Christopher Sloas, Brennan Gerlach, Arif Yurdagul, Mary P Moore, Eui Jung Jung, Faridoddin Mirshahi, Luisa Ronzoni, Arun J Sanyal, Luca Valenti, Chyuan-Sheng Lin, James Montgomery, Bradley Zinker, Michael Klichinsky, Ira Tabas.
      Hepatocyte apoptosis is a key feature of metabolic dysfunction-associated steatohepatitis (MASH), but the fate of apoptotic hepatocytes in MASH is poorly understood. Here, we explore the hypotheses that clearance of dead hepatocytes by liver macrophages (efferocytosis) is impaired in MASH because of low expression of the efferocytosis receptor T cell immunoglobulin and mucin domain containing 4 (TIM4; gene Timd4) by MASH liver macrophages, which then drives liver fibrosis in MASH. We show that apoptotic hepatocytes accumulate in human and experimental MASH, using mice fed the fructose-palmitate-cholesterol (FPC) diet or the high-fat, choline-deficient amino acid-defined (HF-CDAA) diet. Apoptotic hepatocyte accumulation is associated with impaired efferocytosis and loss of TIM4. Administration of neutralizing anti-TIM4 antibodies or genetic deletion of Timd4 in Kupffer cells of FPC and HF-CDAA diet-fed mice decreased efferocytosis by liver macrophages, increased profibrotic activation of collagen-producing hepatic stellate cells (HSCs), and accelerated the progression to fibrotic MASH. Genetic restoration of macrophage Timd4 in FPC and HF-CDAA diet-fed MASH mice or cell therapy with TIM4+ macrophages enhanced apoptotic hepatocyte clearance and decreased HSC activation and liver fibrosis. Studies using an ex vivo macrophage HSC cross-talk model and the HF-CDAA MASH model revealed that inactivation of HSCs by efferocytosing macrophages involved macrophage reprogramming to secrete interleukin-10 (IL-10), which activated the IL-10 receptor on HSCs to dampen their profibrotic activation. These findings reveal a key process in the progression from hepatic steatosis to early MASH fibrosis and identify a mechanism-based therapeutic strategy to prevent fibrotic MASH progression.
    DOI:  https://doi.org/10.1126/scitranslmed.adv2106
  19. Cell. 2025 Sep 11. pii: S0092-8674(25)00979-1. [Epub ahead of print]
    Immunometabolic defects of CD8+ T cells disrupt gut barrier integrity in people with HIV.
    Upasana Das Adhikari, Leah M Froehle, Alexandra N Pipkin, Heeva Baharlou, Alice H Linder, Palak Shah, Amanda Hussey, Qiming Zhang, Sarah Nyquist, Saleh Khwaled, Fangtao Chi, Swagata Goswami, Sabhyata Sedhain, Salina Hussain, Thomas J Diefenbach, Benjamin J Read, Byungji Kim, Darrell Irvine, Osaretin Asowata, Mark Ladinsky, Pamela Bjorkman, Fusi Madela, Shakeel Kader, Alex K Shalek, Musie Ghebremichael, Henrik Kloverpris, Alison E Ringel, Ömer H Yilmaz, Douglas S Kwon.
      A hallmark of HIV infection is disruption of intestinal barrier integrity that persists in people with HIV (PWH) despite treatment with antiretroviral therapy (ART). This disruption is central to HIV disease progression, yet the causes remain incompletely understood. We report a mechanism by which immunometabolic defects in colon-resident CD8+ T cells in PWH lead to intestinal epithelial apoptosis and disruption of intestinal barrier integrity. We show that in PWH, these cells downregulate the lipid sensor peroxisome proliferator-activated receptor-γ (PPARγ), which results in reduced intracellular lipid droplets, impaired fatty acid oxidation, and acquisition of lipids by CD8+ T cells from intestinal epithelial cells, which then contributes to epithelial cell death. Our findings indicate that HIV-associated immunometabolic dysregulation of colon CD8+ T cells leads to loss of intestinal epithelial homeostasis. These results identify potential strategies to reduce comorbidities in PWH and other disorders with disrupted intestinal barrier integrity.
    Keywords:  HIV; gut barrier integrity; immune-epithelial interaction; immunometabolism; intestinal epithelial cells; tissue resident CD8+T cells
    DOI:  https://doi.org/10.1016/j.cell.2025.08.024
  20. Nat Genet. 2025 Sep;57(9): 2083
    A bivalent chromatin state regulates the function of composite transposons.
    Chiara Anania.
      
    DOI:  https://doi.org/10.1038/s41588-025-02337-5
  21. Nat Rev Immunol. 2025 Sep 08.
    Metabolic control of innate-like T cells.
    Thomas Riffelmacher, Mitchell Kronenberg.
      Immunometabolism, the intersection of cellular metabolism and immune function, has revolutionized our understanding of T cell biology. Changes in cellular metabolism help guide the development of thymocytes and the transition of T cells from naive to effector, memory and tissue-resident states. Innate-like T cells are a unique group of T cells with special characteristics. They respond rapidly, reside mainly in tissues and express T cell receptors with limited diversity that recognize non-peptide antigens. This group includes invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells and some populations of γδ T cells. Different subsets of innate-like T cells rely on specific metabolic pathways that influence their differentiation and function and distinguish them from conventional CD4+ and CD8+ T cells. Although there are differences between innate-like T cell types, they share metabolic and functional features. In this Review, we highlight recent research in this emerging field. Understanding how metabolic programmes differ between innate-like T cells and other T cells may open opportunities for tailoring innate-like T cell responses and adoptive T cell therapies for use in cancer, metabolic and autoimmune diseases.
    DOI:  https://doi.org/10.1038/s41577-025-01219-5
  22. Nature. 2025 Sep 10.
    Myeloid progenitor dysregulation fuels immunosuppressive macrophages in tumours.
    Samarth Hegde, Bruno Giotti, Brian Y Soong, Laszlo Halasz, Jessica Le Berichel, Maximilian M Schaefer, Benoit Kloeckner, Raphaël Mattiuz, Matthew D Park, Assaf Magen, Adam Marks, Meriem Belabed, Pauline Hamon, Theodore Chin, Leanna Troncoso, Juliana J Lee, Kaili Fan, Dughan Ahimovic, Michael J Bale, Kai Nie, Grace Chung, Darwin D'souza, Krista Angeliadis, Seunghee Kim-Schulze, Raja M Flores, Andrew J Kaufman, Florent Ginhoux, Jason D Buenrostro, Steven Z Josefowicz, Alexander M Tsankov, Thomas U Marron, Sai Ma, Brian D Brown, Miriam Merad.
      Monocyte-derived macrophages (mo-macs) often drive immunosuppression in the tumour microenvironment (TME)1 and tumour-enhanced myelopoiesis in the bone marrow fuels these populations2. Here we performed paired transcriptome and chromatin accessibility analysis over the continuum of myeloid progenitors, circulating monocytes and tumour-infiltrating mo-macs in mice and in patients with lung cancer to identify myeloid progenitor programs that fuel pro-tumorigenic mo-macs. We show that lung tumours prime accessibility for Nfe2l2 (NRF2) in bone marrow myeloid progenitors as a cytoprotective response to oxidative stress, enhancing myelopoiesis while dampening interferon response and promoting immunosuppression. NRF2 activity is amplified during monocyte differentiation into mo-macs in the TME to regulate stress and drive immunosuppressive phenotype. NRF2 genetic deletion and pharmacological inhibition significantly reduced the survival and immunosuppression of mo-macs in the TME, restoring natural killer and T cell anti-tumour immunity and enhancing checkpoint blockade efficacy. Our findings identify a targetable epigenetic node of myeloid progenitor dysregulation that sustains immunoregulatory mo-macs in the lung TME and highlight the potential of early interventions to reprogram macrophage fate for improved immunotherapy outcomes.
    DOI:  https://doi.org/10.1038/s41586-025-09493-y
  23. Nat Aging. 2025 Sep 10.
    Mitochondria-associated condensates maintain mitochondrial homeostasis and promote lifespan.
    Yan Bai, Tengfei Ma, Shan Zhao, Shalan Li, Xin Wang, Jingyang Li, Wenhao Sun, Yang Yang, Fenglian Liu, Qian Shan, Zizhen Qin, Nan Liu, Jie Zhang, Fei Tian, Mei Duan, Shunkai Chen, Fan Lai, Qingfeng Chen, Xuna Wu, Chonglin Yang.
      Membraneless organelles assembled by liquid-liquid phase separation interact with diverse membranous organelles to regulate distinct cellular processes. It remains unknown how membraneless organelles are engaged in mitochondrial homeostasis. Here we demonstrate that mitochondria-associated translation organelles (MATOs) mediate local synthesis of proteins required for structural and functional maintenance of mitochondria. In Caenorhabditis elegans, the RNA-binding protein LARP-1 (La-related protein 1) orchestrates coalescence of translation machinery and multiple RNA-binding proteins via liquid-liquid phase separation into MATOs that associate with mitochondria in a translocase of the outer membrane complex-dependent manner. LARP-1 deficiency markedly reduces mitochondrial protein levels, impairing cristae organization and ATP production. Specifically, we show that the membrane-shaping MICOS subunit IMMT-1(MIC60) and the ATP synthase β subunit ATP-2, both being important for cristae organization, are synthesized in LARP-1 MATOs. During aging and starvation, LARP-1 MATOs dissociate from mitochondria; however, mitochondrion-persistent LARP-1 MATOs protect mitochondrial health and greatly extend lifespan. These findings suggest an important mitochondrion-regulating mechanism in aging and stress.
    DOI:  https://doi.org/10.1038/s43587-025-00942-x
  24. Aging Cell. 2025 Sep;24(9): e70162
    SIRT2 and NAD+ Boosting Broadly Suppress Aging-Associated Inflammation.
    Marine Barthez, Zehan Song, Yufan Feng, Yifei Wang, Chih-Ling Wang, Danica Chen.
      Aging leads to chronic inflammation that is linked to aging-associated conditions and diseases. Multiple immune pathways become activated during aging, posing a challenge to effectively reduce aging-associated inflammation. SIRT2, an NAD+-dependent deacetylase, suppresses several immune pathways that become activated during aging and may represent an attractive target to broadly dampen aging-associated inflammation. Here, we show that SIRT2 deficiency leads to increased inflammation governed by multiple immune pathways and tissue function decline at an old age, while NAD+ boosting with 78c suppresses aging-associated inflammation and improves tissue function. These findings highlight SIRT2 as a master regulator of aging-associated inflammation and support NAD+ boosting as an effective strategy to counteract aging-associated inflammation and tissue function decline.
    DOI:  https://doi.org/10.1111/acel.70162
This page is being maintained by Thomas Krichel. It was last updated on 2025‒09‒14 at 7:12.