bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–07–27
25 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Spatial map of microglial diversity beyond proteopathy.
  2. T cells require mitochondria to proliferate, function and generate memory.
  3. Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections.
  4. Structure of gut microbial glycolipid modulates host inflammatory response.
  5. LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.
  6. Spatial proteomics of Alzheimer's disease-specific human microglial states.
  7. LONP1 loss causes mitochondrial mayhem in β-cells.
  8. Comprehensive interaction modeling with machine learning improves prediction of disease risk in the UK Biobank.
  9. N-acetylaspartate from fat cells regulates postprandial body temperature.
  10. Targeting triglyceride-rich lipoproteins in cardiovascular disease.
  11. Molecule eases neurological symptoms of mitochondrial deficiency in coenzyme Q10.
  12. Regulatory interaction between metabolite transporters coordinates glucose and exometabolite fluxes to drive bioenergetics.
  13. Polygenic prediction of body mass index and obesity through the life course and across ancestries.
  14. Early methionine availability attenuates T cell exhaustion.
  15. Machine learning in Alzheimer's disease genetics.
  16. Hindbrain octadecaneuropeptide gliotransmission as a therapeutic target for energy balance control without nausea or emesis.
  17. The nuclear periphery confers repression on H3K9me2-marked genes and transposons to shape cell fate.
  18. Scavenger receptor CD163 multimerises to allow uptake of diverse ligands.
  19. Systemic cytokines drive conserved severity-associated myeloid responses across bacterial and viral infections.
  20. Single-molecule live imaging of subunit interactions and exchange within cellular regulatory complexes.
  21. Threonine phosphorylation of STAT1 safeguards gut epithelial integrity and restricts interferon-mediated cytotoxicity.
  22. Modulation of metabolic, inflammatory and fibrotic pathways by semaglutide in metabolic dysfunction-associated steatohepatitis.
  23. Evaluation of a Prediction-Based Bedtime Intervention in Reducing Nocturnal Low Glucose in Adults With Type 1 Diabetes: The DailyDose Bedtime Smart Snack Crossover Study.
  24. Cardiomyocyte OTUD1 drives diabetic cardiomyopathy via directly deubiquitinating AMPKα2 and inducing mitochondrial dysfunction.
  25. The antigen presentation landscape of cytokine-stressed human pancreatic islets.
  1. Nat Immunol. 2025 Jul 24.
    Spatial map of microglial diversity beyond proteopathy.
      
    DOI:  https://doi.org/10.1038/s41590-025-02205-8
  2. Nat Immunol. 2025 Jul 22.
    T cells require mitochondria to proliferate, function and generate memory.
      
    DOI:  https://doi.org/10.1038/s41590-025-02226-3
  3. Immunity. 2025 Jul 12. pii: S1074-7613(25)00286-9. [Epub ahead of print]
    Epigenetic silencing of interleukin-10 by host-derived oxidized phospholipids supports a lethal inflammatory response to infections.
    Marco Di Gioia, Valentina Poli, Piao J Tan, Roberto Spreafico, Anne Chu, Alex G Cuenca, Zhongyang Wu, Mehdi Benamar, Laura Pandolfi, Federica Meloni, Fatemeh Askarian, Jason Hsiao, Elizaveata Borroum, Victor Nizet, Philip L S M Gordts, Joseph L Witztum, Talal A Chatila, Janet Chou, Xu Zhou, James R Springstead, Ivan Zanoni.
      Phagocytes initiate immunity to invading microorganisms by detecting pathogen-associated molecular patterns via pattern recognition receptors. Pathogen encounter and consequent activation of the immune system cause tissue damage and the release of host-derived damage-associated molecular patterns, contributing to shape immunity. However, how self-derived factors are sensed by phagocytes and impact the immune response remains poorly understood. Here, we demonstrated that host-derived oxidized phospholipids (oxPLs) are formed after microbial encounter in both mice and humans. oxPLs exacerbated inflammation without affecting pathogen burden. Mechanistically, oxPLs bound and inhibited AKT, potentiating the methionine cycle and the activity of the epigenetic writer EZH2. EZH2 epigenetically dampened the pluripotent anti-inflammatory cytokine IL-10, contributing to the death of the host. Overall, we found that host-derived oxPLs set the balance between protective and detrimental antimicrobial responses and that they can be prophylactically or therapeutically targeted to protect the host against deranged inflammation and immunopathology.
    Keywords:  ARDS; DAMP; PAMP; PRR; damage-associated molecular pattern; epigenetic; macrophages; pathogen-associated molecular pattern; pattern recognition receptor; sepsis
    DOI:  https://doi.org/10.1016/j.immuni.2025.06.017
  4. Cell. 2025 Jul 18. pii: S0092-8674(25)00566-5. [Epub ahead of print]
    Structure of gut microbial glycolipid modulates host inflammatory response.
    Hyoung-Soo Cho, Ji-Sun Yoo, Xinyang Song, Byoungsook Goh, Alos Diallo, Jesang Lee, Sumin Son, Yoon Soo Hwang, Seung Bum Park, Sungwhan F Oh, Dennis L Kasper.
      Commensals are constantly shaping the host's immunological landscape. Lipopolysaccharides found in gram-negative microbes have a terminal lipid A in their outer membrane. Here, we report that structural variations in symbiotic lipid A lead to divergent immune responses with each lipid A structure, eliciting effects distinct from those induced by classical lipid A. Certain lipid A structures can induce a sustained interferon (IFN)-β response orchestrated by Cdc42-facilitated Toll-like receptor 4 (TLR4) endocytosis and lipid droplet (LD) formation. This lipid A-directed IFN-β response is paramount for colon RORγt+ regulatory T cell (Treg) induction while simultaneously suppressing colonic TH17 cells and controlling gut inflammation. Intriguingly, the quantitatively dominant penta-acylated lipid A species in Bacteroidetes fails to elicit an IFN-β response. Instead, a less abundant tetra-acylated lipid A species sustainably induces IFN-β, thereby contributing to RORγt+ Treg homeostasis. Nuances in symbiont lipid A structure contribute to maintaining potent regulation of Tregs to maintain a healthy endobiotic balance.
    Keywords:  Cdc42; IFNAR signaling; RORγt(+) Tregs; TLR4 endocytosis; colonic inflammation; endobiotic balance; lipid droplet; microbiome; symbiotic lipid A; type I IFNs
    DOI:  https://doi.org/10.1016/j.cell.2025.05.016
  5. Nat Metab. 2025 Jul 21.
    LONP1 regulation of mitochondrial protein folding provides insight into beta cell failure in type 2 diabetes.
    Jin Li, Yamei Deng, Marie Gasser, Jie Zhu, Emily M Walker, Vaibhav Sidarala, Emma C Reck, Dre L Hubers, Mabelle B Pasmooij, Chun-Shik Shin, Khushdeep Bandesh, Eftyhmios Motakis, Siddhi Nargund, Romy Kursawe, Venkatesha Basrur, Alexey I Nesvizhskii, Michael L Stitzel, David C Chan, Guy A Rutter, Scott A Soleimanpour.
      Protein misfolding is a contributor to the development of type 2 diabetes (T2D), but the specific role of impaired proteostasis is unclear. Here we show a robust accumulation of misfolded proteins in the mitochondria of human pancreatic islets from patients with T2D and elucidate its impact on β cell viability through the mitochondrial matrix protease LONP1. Quantitative proteomics studies of protein aggregates reveal that islets from donors with T2D have a signature resembling mitochondrial rather than endoplasmic reticulum protein misfolding. Loss of LONP1, a vital component of the mitochondrial proteostatic machinery, with reduced expression in the β cells of donors with T2D, yields mitochondrial protein misfolding and reduced respiratory function, leading to β cell apoptosis and hyperglycaemia. LONP1 gain of function ameliorates mitochondrial protein misfolding and restores human β cell survival after glucolipotoxicity via a protease-independent effect requiring LONP1-mitochondrial HSP70 chaperone activity. Thus, LONP1 promotes β cell survival and prevents hyperglycaemia by facilitating mitochondrial protein folding. These observations provide insights into the nature of proteotoxicity that promotes β cell loss during the pathogenesis of T2D, which could be considered as future therapeutic targets.
    DOI:  https://doi.org/10.1038/s42255-025-01333-7
  6. Nat Immunol. 2025 Jul 22.
    Spatial proteomics of Alzheimer's disease-specific human microglial states.
    Dunja Mrdjen, Bryan J Cannon, Meelad Amouzgar, YeEun Kim, Candace Liu, Kausalia Vijayaragavan, Christine Camacho, Angie Spence, Erin F McCaffrey, Anusha Bharadwaj, Dmitry Tebaykin, Syed Bukhari, Marc Bosse, Felix J Hartmann, Adam Kagel, John Paul Oliveria, Koya Yakabi, Geidy E Serrano, Maria M Corrada, Claudia H Kawas, Robert Tibshirani, Thomas G Beach, M Ryan Corces, Will Greenleaf, R Michael Angelo, Thomas Montine, Sean C Bendall.
      Microglia are implicated in aging, neurodegeneration and Alzheimer's disease (AD). Low-plex protein imaging does not capture cellular states and interactions in the human brain, which differs from rodent models. Here we used multiplexed ion beam imaging to spatially map cellular states and niches in cognitively normal human brains, identifying a spectrum of proteomic microglial profiles. Defined by immune activation states that were skewed across brain regions and compartmentalized according to microenvironments, this spectrum enables the identification of proteomic trends across the microglia of ten cognitively normal individuals and orthogonally with single-nuclei epigenetic analysis, revealing associated molecular functions. Notably, AD tissues exhibit regulatory shifts in the immunologically active cells at the end of the proteomic spectrum, including enrichment of CD33 and CD44 and decreases in HLA-DR, P2RY12 and ApoE expression. These findings establish an in situ, single-cell spatial proteomic framework for AD-specific microglial states.
    DOI:  https://doi.org/10.1038/s41590-025-02203-w
  7. Nat Metab. 2025 Jul 21.
    LONP1 loss causes mitochondrial mayhem in β-cells.
    Kok Lim Kua, Carmella Evans-Molina.
      
    DOI:  https://doi.org/10.1038/s42255-025-01328-4
  8. Nat Commun. 2025 Jul 18. 16(1): 6620
    Comprehensive interaction modeling with machine learning improves prediction of disease risk in the UK Biobank.
    Heli Julkunen, Juho Rousu.
      Understanding how risk factors interact to jointly influence disease risk can provide insights into disease development and improve risk prediction. Here we introduce survivalFM, a machine learning extension to the widely used Cox proportional hazards model that enables scalable estimation of all potential pairwise interaction effects on time-to-event outcomes. The method approximates interaction effects using a low-rank factorization, allowing it to overcome the computational and statistical limitations typically associated with high-dimensional interaction modeling. Applied to the UK Biobank dataset across nine disease examples and diverse clinical and omics risk factors, survivalFM improves prediction performance in terms of discrimination, explained variation, and reclassification in 30.6%, 41.7%, and 94.4% of the scenarios tested, respectively. In a clinical cardiovascular risk prediction scenario using the established QRISK3 model, the method adds predictive value by identifying interactions beyond the age interaction effects currently included. These results demonstrate that comprehensive modeling of interactions can facilitate advanced insights into disease development and improve risk predictions.
    DOI:  https://doi.org/10.1038/s41467-025-61891-y
  9. Nat Metab. 2025 Jul 23.
    N-acetylaspartate from fat cells regulates postprandial body temperature.
    Jessica B Felix, Pradip K Saha, Evelyn L de Groot, Lin Tan, Robert Sharp, Elizabeth S Anaya, Yafang Li, Holly Quang, Nooshin Saidi, Layla Abushamat, Christie M Ballantyne, Christopher I Amos, Philip L Lorenzi, Samuel Klein, Xia Gao, Sean M Hartig.
      N-acetylaspartate (NAA), the brain's second most abundant metabolite, provides essential substrates for myelination through its hydrolysis1. However, the physiological roles of NAA in other tissues remain unknown. Here, we show that aspartoacylase (ASPA) expression in white adipose tissue (WAT) governs blood NAA levels for postprandial body temperature regulation. Genetic ablation of Aspa in mice resulted in systemically elevated NAA levels, and the ensuing accumulation in WAT stimulated pyrimidine production. Stable isotope tracing confirmed higher incorporation of glucose-derived carbon into pyrimidine metabolites in Aspa knockout cells. Additionally, serum NAA levels positively correlated with the abundance of the pyrimidine intermediate orotidine 5'-monophosphate, and this relationship predicted lower body mass index in humans. Using whole-body and tissue-specific knockout mouse models, we observed that fat cells provided plasma NAA and suppressed postprandial body temperature elevation. Moreover, unopposed NAA from adipocytes greatly enhanced whole-body glucose disposal exclusively in WAT. Exogenous NAA also increased plasma pyrimidines and lowered body temperature. These data place WAT-derived NAA as an endocrine regulator of postprandial body temperature and define broader roles for metabolic homeostasis.
    DOI:  https://doi.org/10.1038/s42255-025-01334-6
  10. Nat Med. 2025 Jul 24.
    Targeting triglyceride-rich lipoproteins in cardiovascular disease.
    Archna Bajaj, Daniel J Rader.
      
    DOI:  https://doi.org/10.1038/s41591-025-03845-x
  11. Nature. 2025 Jul 23.
    Molecule eases neurological symptoms of mitochondrial deficiency in coenzyme Q10.
      
    Keywords:  Brain; Diseases; Health care
    DOI:  https://doi.org/10.1038/d41586-025-02289-0
  12. Nat Commun. 2025 Jul 24. 16(1): 6819
    Regulatory interaction between metabolite transporters coordinates glucose and exometabolite fluxes to drive bioenergetics.
    Noa Yehoshua, Ahlam Khamaysi, Liana Shimshilashvili, Aharon Keshet, Mahmoud Taha, Moran Fremder, Hadar Eini-Rider, Ehud Ohana.
      The composition of tricarboxylic acid cycle metabolites in the external environment of cells determines vital physiological functions, including nutrient and mineral absorption, inflammation, and cellular energy management. Here, we study how the transport of external metabolites into the cells functions as an independent metabolic pathway that controls cellular energy. We show that liver cells orchestrate simultaneous fluxes of glucose and the omnipotent metabolite citrate across the cell membrane, acting as a first line metabolic pathway that responds to nutrient availability. Using functional mapping and gene silencing, we delineate the underlying molecular mechanism showing that the liver citrate transporter (NaCT) interacts with glucose transporters (Glut) and the anion transporters. The interaction is mediated by a specific region of the NaCT protein to reciprocally regulate the transport functions. Our findings describe an independent mechanism that coordinates external metabolites and glucose balance, thus driving key energy management processes in response to nutrient availability in the liver.
    DOI:  https://doi.org/10.1038/s41467-025-62103-3
  13. Nat Med. 2025 Jul 21.
    Polygenic prediction of body mass index and obesity through the life course and across ancestries.
    23andMe Research Team
      Polygenic scores (PGSs) for body mass index (BMI) may guide early prevention and targeted treatment of obesity. Using genetic data from up to 5.1 million people (4.6% African ancestry, 14.4% American ancestry, 8.4% East Asian ancestry, 71.1% European ancestry and 1.5% South Asian ancestry) from the GIANT consortium and 23andMe, Inc., we developed ancestry-specific and multi-ancestry PGSs. The multi-ancestry score explained 17.6% of BMI variation among UK Biobank participants of European ancestry. For other populations, this ranged from 16% in East Asian-Americans to 2.2% in rural Ugandans. In the ALSPAC study, children with higher PGSs showed accelerated BMI gain from age 2.5 years to adolescence, with earlier adiposity rebound. Adding the PGS to predictors available at birth nearly doubled explained variance for BMI from age 5 onward (for example, from 11% to 21% at age 8). Up to age 5, adding the PGS to early-life BMI improved prediction of BMI at age 18 (for example, from 22% to 35% at age 5). Higher PGSs were associated with greater adult weight gain. In intensive lifestyle intervention trials, individuals with higher PGSs lost modestly more weight in the first year (0.55 kg per s.d.) but were more likely to regain it. Overall, these data show that PGSs have the potential to improve obesity prediction, particularly when implemented early in life.
    DOI:  https://doi.org/10.1038/s41591-025-03827-z
  14. Nat Immunol. 2025 Jul 23.
    Early methionine availability attenuates T cell exhaustion.
    Piyush Sharma, Ao Guo, Suresh Poudel, Emilio Boada-Romero, Katherine C Verbist, Gustavo Palacios, Kalyan Immadisetty, Mark J Chen, Dalia Haydar, Ashutosh Mishra, Junmin Peng, M Madan Babu, Giedre Krenciute, Evan S Glazer, Douglas R Green.
      T cell receptor (TCR) activation is regulated in many ways, including niche-specific nutrient availability. Here we investigated how methionine (Met) availability and TCR signaling interplay during the earliest events of T cell activation affect subsequent cell fate. Limiting Met during the initial 30 min of TCR engagement increased Ca2+ influx, NFAT1 (encoded by Nfatc2) activation and promoter occupancy, leading to T cell exhaustion. We identified changes in the protein arginine methylome during initial TCR engagement and identified an arginine methylation of the Ca2+-activated potassium transporter KCa3.1, which regulates Ca2+-mediated NFAT1 signaling for optimal activation. Ablation of KCa3.1 arginine methylation increased NFAT1 nuclear localization, rendering T cells dysfunctional in mouse tumor and infection models. Furthermore, acute, early Met supplementation reduced nuclear NFAT1 in tumor-infiltrating T cells and augmented antitumor activity. These findings identify a metabolic event early after T cell activation that affects cell fate.
    DOI:  https://doi.org/10.1038/s41590-025-02223-6
  15. Nat Commun. 2025 Jul 22. 16(1): 6726
    Machine learning in Alzheimer's disease genetics.
    EADB
      Traditional statistical approaches have advanced our understanding of the genetics of complex diseases, yet are limited to linear additive models. Here we applied machine learning (ML) to genome-wide data from 41,686 individuals in the largest European consortium on Alzheimer's disease (AD) to investigate the effectiveness of various ML algorithms in replicating known findings, discovering novel loci, and predicting individuals at risk. We utilised Gradient Boosting Machines (GBMs), biological pathway-informed Neural Networks (NNs), and Model-based Multifactor Dimensionality Reduction (MB-MDR) models. ML approaches successfully captured all genome-wide significant genetic variants identified in the training set and 22% of associations from larger meta-analyses. They highlight 6 novel loci which replicate in an external dataset, including variants which map to ARHGAP25, LY6H, COG7, SOD1 and ZNF597. They further identify novel association in AP4E1, refining the genetic landscape of the known SPPL2A locus. Our results demonstrate that machine learning methods can achieve predictive performance comparable to classical approaches in genetic epidemiology and have the potential to uncover novel loci that remain undetected by traditional GWAS. These insights provide a complementary avenue for advancing the understanding of AD genetics.
    DOI:  https://doi.org/10.1038/s41467-025-61650-z
  16. Sci Transl Med. 2025 Jul 23. 17(808): eadu6764
    Hindbrain octadecaneuropeptide gliotransmission as a therapeutic target for energy balance control without nausea or emesis.
    Caroline E Geisler, Kylie S Chichura, Oleksandr Orativskyi, Jiayin Hu, Drew L Belser, Caitlyn M Pelletier, Tito Borner, Caitlin Baumer-Harrison, Bart C De Jonghe, Richard C Crist, Benjamin C Reiner, Robert P Doyle, Matthew R Hayes.
      Glia play a dynamic role in central nutrient sensing and appetite regulation yet represent underexplored targets in treating dysregulated energy balance. Glia within the dorsal vagal complex of the hindbrain synthesize the anorexigenic peptide octadecaneuropeptide (ODN), the influence and therapeutic potential of which remain to be explored. We demonstrate that hindbrain-targeted ODN induced weight loss, counteracted glucoprivation, and improved glucose clearance in rats. Furthermore, blocking central ODN signaling attenuated the anorectic response to GLP-1R agonists in rats. Peripheral administration of an ODN derivative, TDN, improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamp in obese mice and induced weight loss without pica behavior, a proxy for nausea in rats, or emesis in the musk shrew, a vomiting mammalian model. Central ODN and TDN treatment in rats was not accompanied by changes in core body temperature, physical activity, or heart rate. This work highlights hindbrain ODN signaling as an important modulator of energy balance and demonstrates the potential for targeting this gliopeptide system to treat dysregulated feeding and metabolic activity without side effects.
    DOI:  https://doi.org/10.1126/scitranslmed.adu6764
  17. Nat Cell Biol. 2025 Jul 22.
    The nuclear periphery confers repression on H3K9me2-marked genes and transposons to shape cell fate.
    Harold C Marin, Charlie Allen, Eric Simental, Eric W Martin, Barbara Panning, Bassem Al-Sady, Abigail Buchwalter.
      Heterochromatic loci marked by histone H3 lysine 9 dimethylation (H3K9me2) are enriched at the nuclear periphery in metazoans, but the effect of spatial position on heterochromatin function has not been defined. Here we remove three nuclear lamins and the lamin B receptor (LBR) in mouse embryonic stem cells and show that heterochromatin detaches from the nuclear periphery. Mutant mouse embryonic stem cells sustain naive pluripotency and maintain H3K9me2 across the genome but cannot repress H3K9me2-marked genes or transposons. Further, mutant cells fail to differentiate into epiblast-like cells, a transition that requires the expansion of H3K9me2 across the genome. Mutant epiblast-like cells can silence naive pluripotency genes and activate epiblast-stage genes. However, H3K9me2 cannot repress markers of alternative fates, including primitive endoderm. We conclude that the lamins and LBR control the spatial position, dynamic remodelling and repressive capacity of H3K9me2-marked heterochromatin to shape cell fate decisions.
    DOI:  https://doi.org/10.1038/s41556-025-01703-z
  18. Nat Commun. 2025 Jul 18. 16(1): 6623
    Scavenger receptor CD163 multimerises to allow uptake of diverse ligands.
    Richard X Zhou, Matthew K Higgins.
      CD163 is an archetypal scavenger receptor and mediates detoxification of free haemoglobin. Release of haemoglobin from lysed erythrocytes causes oxidative tissue and organ damage. Detoxification involves haemoglobin binding to the abundant serum protein haptoglobin, followed by CD163-mediated uptake of stoichiometrically diverse haptoglobin-haemoglobin complexes into macrophages for degradation. We show that CD163 adopts dimeric and trimeric assemblies due to calcium-mediated interactions within a membrane-associated base. Arms protrude from this base and create a ligand-binding site. Flexibility within the base, coupled with multiple small ligand-binding surfaces on each arm, allow the receptor to mould around its ligands, resulting in promiscuous uptake of ligands with different structures and stoichiometries. Monomeric CD163 lacks this ability to internalise lower-avidity ligands. Arms from adjacent protomers can also self-associate, blocking ligand-binding surfaces in an autoinhibited state. Therefore, through calcium-dependent multimer formation and flexible ligand binding, CD163 scavenges ligands with different structures and avidities, mediating haemoglobin detoxification.
    DOI:  https://doi.org/10.1038/s41467-025-62054-9
  19. Commun Biol. 2025 Jul 23. 8(1): 1096
    Systemic cytokines drive conserved severity-associated myeloid responses across bacterial and viral infections.
    Kimberly Kajihara, Donghong Yan, Gretchen L Seim, Hannah Little-Hooy, Jing Kang, Cynthia Chen, Marco De Simone, Tim Delemarre, Spyros Darmanis, Haridha Shivram, Rebecca N Bauer, Carrie M Rosenberger, Sharookh B Kapadia, Min Xu, Miguel Reyes.
      Both bacterial and viral infections can trigger an overwhelming host response, leading to immunopathology and organ dysfunction. Multiple studies have reported dysregulated myeloid cell states in patients with bacterial sepsis or severe SARS-CoV-2 infection. However, their relevance to viral infections other than COVID-19, the factors driving their induction, and their role in tissue injury remain poorly understood. Here, we performed a multi-cohort analysis of single cell and bulk transcriptomic data from 1845 patients across 25 studies. Our meta-analysis revealed a conserved severity-associated gene signature pointing to emergency myelopoiesis (EM) and increased IL1R2 expression in monocytes and neutrophils from patients with bacterial sepsis, COVID-19, and influenza. Analysis of tocilizumab-treated COVID-19 patients showed that IL-6 signaling blockade partially reduces this signature and results in a compensatory increase in G-CSF. To validate the role of these cytokines in vivo, we used a mouse model of influenza infection that recapitulates severity-associated increases in IL1R2+ monocytes and IL1R2hi neutrophils, and demonstrate that combined IL-6 and G-CSF blockade inhibits their production. Our study demonstrates the cooperative role of G-CSF and IL-6 in driving the production of severity-associated IL1R2+ myeloid cells and highlights the link between myeloid dysregulation and tissue injury during severe infection.
    DOI:  https://doi.org/10.1038/s42003-025-08407-y
  20. Mol Cell. 2025 Jul 15. pii: S1097-2765(25)00578-7. [Epub ahead of print]
    Single-molecule live imaging of subunit interactions and exchange within cellular regulatory complexes.
    Thomas G W Graham, Claire Dugast-Darzacq, Gina M Dailey, Britney Weng, Sathvik Anantakrishnan, Xavier Darzacq, Robert Tjian.
      Cells are built from vast networks of interdependent molecular interactions. Here, we combine proximity-assisted photoactivation (PAPA) with automated fast single-molecule tracking (fSMT) to probe subunit interactions within endogenous protein complexes in live human cells. PAPA-fSMT revealed that the inactive positive transcription elongation factor b (P-TEFb):7SK ribonucleoprotein complex is predominantly mobile, not tethered to chromatin, and detected interaction of specific heterogeneous nuclear ribonucleoproteins (hnRNPs) with the 7SK complex. Cyclin-dependent kinase 9 (Cdk9) inhibition liberated hnRNP R from large RNAs, increased hnRNP R binding to 7SK, and evicted P-TEFb from 7SK within minutes-consistent with rapid, homeostatic negative feedback regulation of P-TEFb by competing protein-RNA interactions. Association with the coactivator BRD4 increased P-TEFb chromatin binding, which depended on the BRD4 bromodomains. Finally, PAPA detected the release of P-TEFb from 7SK by the HIV transcriptional activator Tat. Our results illuminate aspects of P-TEFb regulation that were previously inaccessible in live cells and open a route to probe subunit interactions and exchange within endogenous regulatory complexes.
    Keywords:  7SK complex; BRD4; HIV Tat; P-TEFb; PAPA; fSMT; fast single-molecule tracking; heterogeneous nuclear ribonucleoproteins; hnRNP R; hnRNPs; positive transcription elongation factor b; protein-protein interactions; proximity-assisted photoactivation; transcriptional regulation
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.028
  21. Proc Natl Acad Sci U S A. 2025 Jul 29. 122(30): e2511957122
    Threonine phosphorylation of STAT1 safeguards gut epithelial integrity and restricts interferon-mediated cytotoxicity.
    Hozaifa Metwally, Maha M Elbrashy, Hisako Kayama, Kazuki Okuyama, Ichiro Taniuchi, Kiyoshi Takeda, Tadamitsu Kishimoto.
      Barrier tissues such as the intestine are constantly challenged by environmental stressors and must adapt to maintain integrity and prevent excessive inflammation. Although traditionally viewed as a proinflammatory effector of interferon (IFN) signaling, STAT1 is shown here to play a protective role in intestinal epithelial cells (IEC) by promoting resilience to damage and restraining IFN-induced cytotoxicity. We identify phosphorylation of threonine 748 (Thr748) on STAT1 as an evolutionarily selected adaptation-highly conserved between humans and mice-that reciprocally regulates IEC integrity and IFN responsiveness. Mice expressing a phospho-deficient T748A Stat1 mutant exhibit severe colitis-induced tissue damage comparable to Stat1-deficient littermates, underscoring the critical role of Thr748 phosphorylation in mediating Stat1-driven protection during intestinal inflammation. Bone marrow transfer experiments further demonstrate that this protective effect is nonhematopoietic. Integrated genomic and transcriptomic analyses reveal that Thr748 phosphorylation modulates STAT1 DNA binding, directly activates the Itgb4 promoter, and enhances integrin β4 expression in IEC following inflammation. In intestinal organoid models, gain- and loss-of-function experiments demonstrate that Thr748 phosphorylation drives integrin β4 expression and epithelial resilience independently of IFN-induced Tyrosine 701 (Tyr701) phosphorylation. In contrast, IFN stimulation via Tyr701 induces Zbp1-a cytotoxic nucleic acid sensor-while repressing integrin β4, resulting in epithelial injury that is mitigated by Thr748 phosphorylation. Together, these findings reveal a modular architecture of STAT1 signaling in which Thr748 phosphorylation functions as a molecular rheostat that safeguards epithelial integrity while tempering IFN-driven cytotoxic responses.
    Keywords:  STAT1; gut epithelium; integrins; interferons; threonine phosphorylation
    DOI:  https://doi.org/10.1073/pnas.2511957122
  22. Nat Med. 2025 Jul 21.
    Modulation of metabolic, inflammatory and fibrotic pathways by semaglutide in metabolic dysfunction-associated steatohepatitis.
    Maximilian Jara, Jenny Norlin, Mette Skalshøi Kjær, Kasper Almholt, Kristian M Bendtsen, Elisabetta Bugianesi, Kenneth Cusi, Elisabeth D Galsgaard, Milan Geybels, Lise L Gluud, Lea M Harder, Rohit Loomba, Gianluca Mazzoni, Philip N Newsome, Louise M Nitze, Mads S Palle, Vlad Ratziu, Anne-Sophie Sejling, Vincent W-S Wong, Quentin M Anstee, Lotte B Knudsen.
      Metabolic dysfunction-associated steatohepatitis (MASH) is a chronic liver disease strongly associated with cardiometabolic risk factors. Semaglutide, a glucagon-like peptide-1 receptor agonist, improves liver histology in MASH, but the underlying signals and pathways driving semaglutide-induced MASH resolution are not well understood. Here we show that, in two preclinical MASH models, semaglutide improved histological markers of fibrosis and inflammation and reduced hepatic expression of fibrosis-related and inflammation-related gene pathways. Aptamer-based proteomic analyses of serum samples from patients with MASH in a clinical trial identified 72 proteins significantly associated with MASH resolution and semaglutide treatment, with most related to metabolism and several implicated in fibrosis and inflammation. An independent real-world cohort verified the pathophysiological relevance of this signature, showing that the same 72 proteins are differentially expressed in patients with MASH relative to healthy individuals. Taken together, these data suggest that semaglutide may revert the circulating proteome associated with MASH to the proteomic pattern observed in healthy individuals.
    DOI:  https://doi.org/10.1038/s41591-025-03799-0
  23. Diabetes Care. 2025 Jul 24. pii: dc250407. [Epub ahead of print]
    Evaluation of a Prediction-Based Bedtime Intervention in Reducing Nocturnal Low Glucose in Adults With Type 1 Diabetes: The DailyDose Bedtime Smart Snack Crossover Study.
    Clara Mosquera-Lopez, Valentina Roquemen-Echeverri, Peter G Jacobs, Katrina Ramsey, Joseph Pinsonault, Jae Eom, Hantao Ling, Daisy Chen, Deborah Branigan, Jessica R Castle, Korey K Hood, Melanie B Gillingham, Diana Aby-Daniel, Leah M Wilson.
       OBJECTIVE: Nocturnal hypoglycemia is challenging for individuals with type 1 diabetes, particularly those who are physically active or using multiple daily injections (MDIs). We hypothesized that adding bedtime decision support to usual care with continuous glucose monitoring (CGM)-augmented MDI therapy could reduce nocturnal hypoglycemia.
    RESEARCH DESIGN AND METHODS: We developed the DailyDose Smart Snack (DDSS) app, which features CGM and physical activity logging and delivers personalized bedtime snack recommendations to help prevent nocturnal hypoglycemia. Recommendations are based on the probability and timing of low-glucose events forecasted by an evidential neural network. We conducted a randomized crossover trial comparing DDSS with CGM-augmented MDI for 4 weeks each under free-living conditions to evaluate the feasibility and effect of DDSS in reducing nocturnal hypoglycemia.
    RESULTS: Twenty participants completed the study (mean ± SD age 39 ± 15 years; 10 women; HbA1c 7.1% ± 1.0% [54 ± 11 mmol/mol]). There was no difference between arms in the proportion of nights with low-glucose events <70 mg/dL lasting 10+ min (control 26.0% ± 14.1% vs. DDSS 23.6% ± 15.6%; odds ratio [OR] 0.83; P = 0.207) or in overnight CGM metrics. A post hoc analysis showed that the proportion of nights with low-glucose events <54 mg/dL lasting 10+ min was significantly reduced in the DDSS arm by 3.5% (11.9% ± 12.9% vs. 8.3% ± 8.8%; OR 0.64; P = 0.040).
    CONCLUSIONS: DDSS did not significantly reduce the proportion of nights with low-glucose events <70 mg/dL lasting 10+ min but reduced nocturnal low glucose <54 mg/dL without compromising other glycemic metrics.
    DOI:  https://doi.org/10.2337/dc25-0407
  24. Nat Commun. 2025 Jul 19. 16(1): 6668
    Cardiomyocyte OTUD1 drives diabetic cardiomyopathy via directly deubiquitinating AMPKα2 and inducing mitochondrial dysfunction.
    Xue Han, Ruyi Zheng, Jiajia Zhang, Yanan Liu, Ze Li, Guoxuan Liu, Jianing Zheng, Weiqi Li, Zijun Liang, Mengyang Wang, Jie Yu, Qiaojuan Shi, Huazhong Ying, Guang Liang.
      Deubiquitinating modification of proteins is involved in the pathogenesis of diseases. Here, we investigated the role and regulating mechanism of a deubiquitinating enzyme (DUB), ovarian tumor domain-containing protein 1 (OTUD1), in diabetic cardiomyopathy (DCM). We find a significantly increased OTUD1 expression in diabetic mouse hearts, and single-cell RNA sequencing shows OTUD1 mainly distributing in cardiomyocytes. Cardiomyocyte-specific OTUD1 knockout prevents cardiac hypertrophy and dysfunction in both type 2 and type 1 diabetic male mice. OTUD1 deficiency restores cardiac AMPK activity and mitochondrial function in diabetic hearts and cardiomyocytes. Mechanistically, OTUD1 binds to AMPKα2 subunit, deubiquitinates AMPKα2 at K60/K379 sites, and then inhibits AMPKT172 phosphorylation through impeding the interaction of AMPKα2 and its upstream kinase CAMKK2. Finally, silencing AMPKα2 in cardiomyocytes abolishes the cardioprotective effects of OTUD1 deficiency in diabetic mice. In conclusion, this work identifies a direct regulatory DUB of AMPK and presents a OTUD1-AMPK axis in cardiomyocytes for driving DCM.
    DOI:  https://doi.org/10.1038/s41467-025-61901-z
  25. Cell Rep. 2025 Jul 18. pii: S2211-1247(25)00698-9. [Epub ahead of print]44(8): 115927
    The antigen presentation landscape of cytokine-stressed human pancreatic islets.
    Padma P Nanaware, J Mauricio Calvo-Calle, Sambra D Redick, Mason W Tarpley, John Cruz, Cristina C Clement, Anthony Manganaro, Erandi E Velarde de la Cruz, Khaja Muneeruddin, Melissa Faulkner, Jennifer P Wang, Scott A Shaffer, David M Harlan, Laura Santambrogio, Sally C Kent, Lawrence J Stern.
      Type 1 diabetes (T1D) arises from T cell-mediated destruction of insulin-secreting pancreatic β cells. Inflammatory triggers have been hypothesized to induce presentation of new epitopes for pathogenic T cells, but the naturally processed MHC-bound peptides presented by primary human islet β cells are largely unknown. We used mass spectrometry to identify native and post-translationally modified self-peptides presented by MHC proteins from human cadaveric islet samples treated in vitro with cytokines to identify epitopes in an inflamed pancreas. Of >4,300 islet peptides presented by 60 different MHC molecules, we identified 28 autoimmune epitopes targeted by T cells from patients with T1D, 31 additional epitopes from previously identified autoantigens, and 100 additional candidate autoantigens. The epitopes derive from inflammation, unfolded protein response, and secretory hormone processing pathways. These results identify naturally processed islet peptides targeted by autoimmune T cells in T1D and provide a resource for investigating T1D etiology and progression.
    Keywords:  CP: Immunology; CP: Metabolism; MHC protein; T cell epitope discovery; autoimmunity; immunopeptidome; islets of Langerhans; peptide elution; type 1 diabetes
    DOI:  https://doi.org/10.1016/j.celrep.2025.115927
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