bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–05–17
nineteen papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Even mild blows to the head disrupt the microbiome.
  2. Tissue softness unlocks regeneration.
  3. Somatic variants in microglia-like cells linked to Alzheimer's disease pathology.
  4. PRECISE-seq reveals disease-relevant TCR repertoires with phenotypic plasticity.
  5. Immune cells in the blood drive cognitive ageing - blocking them improves memory.
  6. Macrophages sample the living self.
  7. Whole-blood NAD+ levels do not reflect healthy ageing.
  8. A Krüppel of factors regulate T cell residency and exhaustion.
  9. Inter-organ metabolic feedback via BCAA catabolism regulates glucagon-like hormone secretion in Drosophila.
  10. Network topology of the gut microbiome associates with metabolic health in obesity.
  11. Adipokine IL-11/IL-11Ra constrains sphingolipid metabolism to limit the thermogenic capacity of beige adipocytes.
  12. SIRT6 overexpression counteracts chromatin aging in the male murine liver.
  13. ART Interrupted: Insights into ART-free HIV remission.
  14. Gpnmb defines a phagocytic state of microglia linked to cell death in prion disease mouse model.
  15. CD8+ T cells turn resilient under stress.
  16. Are we closer to surpassing residual renal risk in type 2 diabetes?
  17. A tissue-intrinsic mechanism sensitizes HIV-1 particles for TLR-triggered innate immune responses.
  18. Deep peptide recognition profiling decodes TCR specificity and enables disease-associated antigen discovery.
  19. Aged circulating CD8+ T cells and their secreted factors drive cognitive decline.
  1. Nature. 2026 May 15.
    Even mild blows to the head disrupt the microbiome.
      
    Keywords:  Microbiome
    DOI:  https://doi.org/10.1038/d41586-026-01504-w
  2. Nat Aging. 2026 May 12.
    Tissue softness unlocks regeneration.
    Anna Kriebs.
      
    DOI:  https://doi.org/10.1038/s43587-026-01134-x
  3. Nat Aging. 2026 May 12.
    Somatic variants in microglia-like cells linked to Alzheimer's disease pathology.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-026-01135-w
  4. J Exp Med. 2026 Jun 01. pii: e20251779. [Epub ahead of print]223(6):
    PRECISE-seq reveals disease-relevant TCR repertoires with phenotypic plasticity.
    Shibo Liu, Guanghao Liang, Yayun Yang, Yanyang Shi, Lihui Dong, Yue Zhao, Boyuan Mei, Jun Wang, Feng Lin, Yilin Li, Wenxin Dong, Chengyang Liu, Yuhui Cao, Dali Han, Peng R Chen, Meng Michelle Xu.
      Linking T cell phenotypes with antigen specificity and functional avidity is critical for understanding in vivo immune responses in infection and cancer. Here, we develop PRECISE-seq, a method that integrates multi-omics T cell analysis with contact-dependent proximity labeling for rapid screening of disease-relevant T cell repertoires, and for linking the relative TCR avidity with T cell phenotypes at single-cell resolution. PRECISE-seq accurately retrieves CMV-specific clonotypes from human peripheral blood and quantitatively measures functional avidity in physiological contexts. We find that high-potency CMV-specific T cells preferentially acquire an exhausted phenotype. In tumors, polyclonal tumor-reactive CD8+ T cells predominantly differentiate into a protumor Ly49+ regulatory state (TLy49), characterized by inhibitory killer cell lectin-like receptor expression and originating from effector memory T cells along a trajectory distinct from exhaustion. Notably, PD-1 blockade reduces TLy49 formation and promotes effector revival, which correlates with responsiveness to immunotherapy. Together, PRECISE-seq enables high-resolution mapping of TCR potency and T cell phenotype, revealing a regulatory axis shaping T cell fate in tumors.
    DOI:  https://doi.org/10.1084/jem.20251779
  5. Nature. 2026 May 14.
    Immune cells in the blood drive cognitive ageing - blocking them improves memory.
    Claudia Steiner.
      
    Keywords:  Ageing; Brain; Immunology
    DOI:  https://doi.org/10.1038/d41586-026-01531-7
  6. Nat Rev Immunol. 2026 May 11.
    Macrophages sample the living self.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-026-01311-4
  7. Nat Metab. 2026 May 14.
    Whole-blood NAD+ levels do not reflect healthy ageing.
      
    DOI:  https://doi.org/10.1038/s42255-026-01540-w
  8. Immunity. 2026 May 12. pii: S1074-7613(26)00169-X. [Epub ahead of print]59(5): 1168-1170
    A Krüppel of factors regulate T cell residency and exhaustion.
    Dominic S Albao, Shashank D Nagaraja, Matthew E Pipkin.
      CD8+ T cells responding to chronic infections are functionally and spatially heterogeneous. In this issue of Immunity, Shen et al. and Geng et al. demonstrate that the transcription factors KLF2 and KLF3 have integrated but opposing roles in regulating tissue residency and terminal exhaustion.
    DOI:  https://doi.org/10.1016/j.immuni.2026.04.007
  9. Nat Commun. 2026 May 09.
    Inter-organ metabolic feedback via BCAA catabolism regulates glucagon-like hormone secretion in Drosophila.
    Takashi Nishimura, Chisei Arakawa, Yuto Yoshinari.
      Metabolic homeostasis regulated by nutrient-responsive endocrine hormones is essential for organismal survival. In insects, lipid and carbohydrate mobilization is controlled by adipokinetic hormone (Akh), a glucagon-like peptide secreted from neuroendocrine cells. However, whether Akh secretion is subject to negative feedback via its downstream catabolic effects remains unclear. Here, we develop a quantitative assay for Akh using tandem mass spectrometry and show that inter-organ metabolic communication regulates Akh secretion during starvation in Drosophila. Metabolic profiling reveals that Akh signaling in the fat body promotes branched-chain amino acid (BCAA) catabolism by inducing BCAA transaminase (Bcat). Loss of Akh signaling impairs clearance of BCAAs derived from fat body autophagy, resulting in Akh hypersecretion. BCAA catabolism is coupled to glutathione biosynthesis and redox homeostasis during nutrient stress. Our findings reveal a feedback mechanism in which Akh signaling regulates its own secretion via amino acid catabolism, linking energy mobilization to redox homeostasis during starvation.
    DOI:  https://doi.org/10.1038/s41467-026-72677-1
  10. Nat Commun. 2026 May 13. pii: 4113. [Epub ahead of print]17(1):
    Network topology of the gut microbiome associates with metabolic health in obesity.
    Blanca Lacruz-Pleguezuelos, Alba Pérez-Cuervo, Diego Coleto-Checa, Guadalupe X Bazán, Sergio Romero-Tapiador, Gala Freixer, Jorge Fernández-Cabezas, Elena Aguilar-Aguilar, Adrián Martín-Segura, Nicolás Cárdenas-Roig, Lucía Carrasco-Guijarro, Lara P Fernández, Isabel Espinosa-Salinas, Ana Ramírez de Molina, Aythami Morales, Ruben Tolosana, Javier Ortega-Garcia, Vera Pancaldi, Laura Judith Marcos-Zambrano, Enrique Carrillo de Santa Pau.
      Obesity is a heterogeneous condition comprising a continuum of phenotypes with various metabolic and inflammatory profiles. Metabolically healthy obesity (MHO) identifies individuals with obesity but a relatively preserved metabolic state, although little is known about the gut microbiome features underlying this phenotype. Here, we analyzed gut microbial network structures of 931 individuals living with metabolically healthy non-obesity (MHNO), MHO, metabolically unhealthy non-obesity (MUNO), and metabolically unhealthy obesity (MUO), performing cross-sectional analyses on feces shotgun metagenomics data. Individuals with MHNO and MHO harbor more robust and functionally cohesive microbial networks, while communities from MUO and MUNO phenotypes exhibit a potentially dysbiotic state with reduced connectivity. A nutritional intervention cohort showed an improvement in network connectivity in parallel with metabolic improvements. Our findings show differences in microbial connectivity and association patterns across metabolic and obesity phenotypes, shedding light on how distinct microbial network structures may associate with host metabolic health and disease.
    DOI:  https://doi.org/10.1038/s41467-026-72588-1
  11. Cell Metab. 2026 May 14. pii: S1550-4131(26)00151-8. [Epub ahead of print]
    Adipokine IL-11/IL-11Ra constrains sphingolipid metabolism to limit the thermogenic capacity of beige adipocytes.
    Jiadai Liu, Ronghui Gao, Qianqian Kang, Zhihan Wang, Xuemin Peng, Jing Ge, Wenshe Wang, Hongyan Deng, Yuyu Xie, Zengzhe Zhu, Min Yang, Rui He, Huanyu Wang, Yulian Liu, Pema Maretich, Yongsheng Chang, Jichun Yang, Shingo Kajimura, Ruping Pan, Yong Chen.
      Adipocytes exhibit cellular plasticity by secreting pro-inflammatory cytokines in response to an energy excess. Here, we identify that interleukin (IL)-11 is robustly induced and secreted from adipocytes, especially beige adipocytes upon adrenergic stimulation. IL-11 inhibits adipocyte thermogenesis through binding to IL-11 receptor a (IL-11Ra) and serves as a "brake" to maintain energy homeostasis. Adipocyte-specific IL-11Ra-knockout mice exhibit enhanced whole-body energy consumption and improved glucose and lipid metabolism under a high-fat diet (HFD). Inhibition of IL-11/IL-11Ra signaling enhances sphingosine kinase 1 (Sphk1)-driven production of sphingosine-1-phosphate (S1P), thus remodeling intracellular calcium cycling in beige adipocytes. Notably, treatment with a designed peptide against IL-11Ra in obese mice effectively alleviates fat accumulation and obesity-associated disorders. Taken together, our study defines a physiological and noncanonical mechanism of beige adipocyte-derived IL-11 in energy metabolism, which may serve as a promising target for the treatment of obesity.
    Keywords:  adipokine; calcium signaling; obesity; sphingolipid metabolism; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.013
  12. Nat Commun. 2026 May 14.
    SIRT6 overexpression counteracts chromatin aging in the male murine liver.
    Ron Nagar, Zacharia Schwartz, Almog Katz, Noga Touitou, Efrat Sharon, Kobi Tzdaka, Odeya Waner, Noam Shalev, Rotem Clo, Leah Weiss, Benjamin Epstein, Michel Bernier, Roni B Shtark, Nirad Banskota, Kwan-Wood G Lam, Supriyo De, Nathan L Price, Batia Lerrer, Daniel Z Bar, Rafael de Cabo, Haim Y Cohen.
      Aging is associated with detrimental changes in chromatin structure and gene expression, contributing to inflammation, metabolic decline and tissue dysfunction. SIRT6, a histone deacetylase, plays a key role in maintaining chromatin integrity and promoting longevity. Our multi-omics approach, combining ATAC-seq, methylome and RNA-seq shows that aging leads to increased chromatin accessibility in the male murine liver, accompanied by upregulation of inflammation and downregulation of metabolic pathways. Remarkably, SIRT6 overexpression reverses these changes in chromatin structure, reducing inflammation and enhancing metabolic function. Notably, ETS family members and liver-enriched transcription factors are enriched in regions with increased and reduced accessibility during aging, respectively. ChIP-seq shows that H3K9ac, but not H3K56ac, is associated with increased accessibility during aging, and that SIRT6 can reverse this effect. Furthermore, AAV-mediated SIRT6 overexpression in aged male mice demonstrates that SIRT6 not only slows age-related chromatin changes but can also reverse them, rejuvenating chromatin accessibility to a youthful state.
    DOI:  https://doi.org/10.1038/s41467-026-73115-y
  13. Immunity. 2026 May 12. pii: S1074-7613(26)00173-1. [Epub ahead of print]59(5): 1174-1176
    ART Interrupted: Insights into ART-free HIV remission.
    Ramon A Lujan, Eli A Boritz.
      Defining correlates of HIV rebound upon antiretroviral therapy (ART) interruption can advance HIV cure research. In this issue of Immunity, Ma et al. analyze immunophenotypes and transcriptomes from multiple clinical trials, linking T and NK cell subsets to delayed rebound and identifying DDIT4 and ZNF254 as HIV silencing factors. The antidiabetic drug metformin induces DDIT4 and silences HIV in vitro.
    DOI:  https://doi.org/10.1016/j.immuni.2026.04.011
  14. Nat Commun. 2026 May 12.
    Gpnmb defines a phagocytic state of microglia linked to cell death in prion disease mouse model.
    Davide Caredio, Giovanni Mariutti, Lisa Polzer, Beatrice Gatta, Martina Cerisoli, Yasmine Laimeche, Giulia Miracca, Jeanne Droux, Mohamad El Amki, Marc Emmenegger, Marian Hruska-Plochan, Susanne Wegener, Magdalini Polymenidou, Matthias Schmitz, Inga Zerr, Elena De Cecco, Adriano Aguzzi.
      Neurodegenerative disorders display brain region tropism accompanied by the emergence of distinct cellular states that contribute to disease pathogenesis, with molecular alterations occurring predominantly in glial cells. Here we show the emergence of a microglial state with distinct spatial distribution in the brains of terminally sick prion-infected mice characterized by high expression of Gpnmb (glycoprotein non-metastatic melanoma protein B), transcriptional signatures consistent with phagocytic activity, and increased expression of lysosomal genes in regions undergoing pronounced cell death. We find that this cellular state is not induced by pathological protein aggregates but by soluble factors released by dying cells regardless of the initiating insult. This work defines Gpnmb⁺ microglia as a distinct phagocytic state that links cell death to microglial activation and reveals a generalizable mechanism by which microglia respond to cell loss.
    DOI:  https://doi.org/10.1038/s41467-026-73003-5
  15. Immunity. 2026 May 12. pii: S1074-7613(26)00168-8. [Epub ahead of print]59(5): 1171-1173
    CD8+ T cells turn resilient under stress.
    Daniele C Nascimento, Luciana Berod.
      Tumors present metabolic challenges for T cells. In this issue of Immunity, Scaglione et al. show that CD8+ T cells adapt to nutrient stress through biosynthetic plasticity, coupling translational reprioritization to metabolic reprogramming, preserving effector function and supporting antitumor immunity.
    DOI:  https://doi.org/10.1016/j.immuni.2026.04.006
  16. Lancet Diabetes Endocrinol. 2026 May 11. pii: S2213-8587(26)00101-4. [Epub ahead of print]
    Are we closer to surpassing residual renal risk in type 2 diabetes?
    Janaka Karalliedde.
      
    DOI:  https://doi.org/10.1016/S2213-8587(26)00101-4
  17. Nat Commun. 2026 05 09. pii: 4209. [Epub ahead of print]17(1):
    A tissue-intrinsic mechanism sensitizes HIV-1 particles for TLR-triggered innate immune responses.
    Samy Sid Ahmed, Liv Zimmermann, Andrea Imle, Katrin Wuebben, Nadine Tibroni, Lena Rauch-Wirth, Jan Münch, Petr Chlanda, Frederik Graw, Oliver T Fackler.
      In vivo, HIV-1 replicates within tissues, yet the impact of three-dimensional (3D) environments on viral spread remains unclear. Our laboratory previously showed that collagen-rich 3D extracellular matrix (ECM) imposes an Environmental Restriction to cell-free Virus Infectivity (ERVI). Here, we demonstrate that ERVI is mediated by adhesive ECM components assembled into tissue-like scaffolds. Transient interactions with collagen fibers rapidly diminish virion infectivity across diverse primary strains by impairing virus fusogenicity. Notably, collagen-experienced particles also induce a distinct antiviral transcriptional program and strong pro-inflammatory cytokine secretion in monocyte-derived macrophages. Mechanistically, collagen contact induces conformational changes in the viral glycoprotein Env, enhances its interaction with toll-like receptor 2 (TLR2), and promotes trafficking into TLR8-positive endosomes, thereby amplifying innate immune sensing. Thus, ERVI functions through a dual mechanism: reducing virion fusogenicity while increasing innate immune detection. These findings identify the biophysical properties of the ECM as a tissue-intrinsic arm of antiviral innate immunity.
    DOI:  https://doi.org/10.1038/s41467-026-72586-3
  18. Nat Biotechnol. 2026 May 13.
    Deep peptide recognition profiling decodes TCR specificity and enables disease-associated antigen discovery.
    Nan Wang, Hugh Yeh, Ben Lai, Jason Perera, Kevin M Jude, Isabel Risch, Joy Um, Xiaojing Chen, Xinyu Xiang, Chunyu Wang, Liu Daisy Liu, Xinbo Yang, Michael A Paley, Aly A Khan, K Christopher Garcia.
      Predicting T cell receptor (TCR) specificity on the basis of sequence is challenging because TCRs of similar sequence can recognize entirely different antigens, whereas TCRs of different sequence can recognize the same antigens. Here we present a system that integrates high-throughput yeast display with fine-tuned protein language models (pLMs) to generate deep peptide recognition profiles (PRPs) for individual TCRs, each detailing binding against millions of peptides. We provide detailed PRPs for a panel of HLA-B*27:05-restricted TCRs from persons with ankylosing spondylitis and acute anterior uveitis that almost exclusively recognize peptides through CDR3β. pLMs trained on these PRPs outperform AlphaFold3 and tFold-TCR in predicting T cell activation. We discover and validate novel candidate autoantigens, demonstrate that model generalization to new TCRs correlates with functional distance (PRP divergence) rather than sequence similarity and introduce a model-intrinsic uncertainty metric to quantify prediction confidence. This system and its associated PRP datasets offer a scalable approach to mapping TCR recognition, accelerating antigen discovery and guiding TCR engineering.
    DOI:  https://doi.org/10.1038/s41587-026-03128-x
  19. Immunity. 2026 May 14. pii: S1074-7613(26)00176-7. [Epub ahead of print]
    Aged circulating CD8+ T cells and their secreted factors drive cognitive decline.
    Juliana Sucharov, Gregor Bieri, Karishma J B Pratt, Amber R Philp, Turan Aghayev, Shanan Sahota, Laura Remesal, Adam B Schroer, Cedric E Snethlage, Rebecca Chu, Zachary J Holmes, Julien Couthouis, Saul A Villeda.
      Changes in peripheral CD8+ T cells are a hallmark of immune aging. However, the role of aged non-infiltrating CD8+ T cells in brain aging remains to be fully defined. Here, we showed that aged circulating CD8+ T cells and their secreted factors drove hippocampal-dependent cognitive decline. Using heterochronic parabiosis and transcriptomics analysis, we observed that peripheral CD8+ T cells maintained properties intrinsic to their age. Systemic exposure of young mice to aged CD8+ T cells elicited synaptic-related hippocampal changes and impaired cognition, and inhibiting activation, but not infiltration, mitigated their pro-aging effects. Conversely, targeting aged circulating CD8+ T cells restored youthful signatures and rescued cognition. Mechanistically, we identified granzyme K (GZMK) as a secreted pro-aging CD8+ T cell-derived factor in plasma, and GZMK inhibition rescued cognition in aged animals. Together, our data identified activated aged CD8+ T cell-derived circulating factors as potential therapeutic targets to rescue cognition in old age.
    Keywords:  brain aging; cognitive decline; hippocampus; immune aging; parabiosis; peripheral immune brain cross-talk; rejuvenation
    DOI:  https://doi.org/10.1016/j.immuni.2026.04.014
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