bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–09–27
twenty-two papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Autoantibody source.
  2. Surprising protein links dietary restriction to increased lifespan in flies.
  3. Landmark map of human brain's gene activity holds clues to Alzheimer's disease and more.
  4. Remodeling of a distal IRF4 element spurs human regulatory T cell instability under inflammatory conditions.
  5. Lipoprotein(a)-Lowering Agent Fails to Reduce Cardiovascular Events.
  6. The predicted interactome of the human mitochondrial proteome.
  7. Deletion of a distal IRF4 element prevents inflammation-induced reprogramming of human regulatory T cell fate.
  8. Combinatorial targeting of the miR-379/miR-410 cluster normalizes glucose and lipid homeostasis in male models of diabetes and obesity.
  9. Integrated single-cell multiomics reveals neutrophil-driven immune-metabolic reprogramming of Kupffer cells via thrombospondin-1/CD36 after surgical stress.
  10. Alternative immunity.
  11. Genetic architecture of cytokine autoantibodies and associated risk of common diseases.
  12. How some brain macrophages go with the flow.
  13. A cross-species single-cell kidney epigenome atlas reveals epithelial-dominant aging-like states in disease.
  14. Timed metabolic repair after myocardial infarction.
  15. Deep learning aging marker from retinal images unveils sex-specific clinical and genetic signatures.
  16. The next big questions in immunology.
  17. Short-chain fatty acids and blood pressure.
  18. Shared non-HLA genetic architecture across diverse ancestries links insulin secretion and resistance to type 1 diabetes.
  19. Continuous Glucose Monitoring Alert Settings and Glycemic Control in People With Diabetes.
  20. Transcriptional and epigenomic analysis of insulin sensitivity in human adipocytes.
  21. Hepatocyte Growth Hormone Receptor Ablation Is Associated With Aging Phenotypes and Hepatic Mitochondrial Dysfunction.
  22. High-Mobility Group Box 1 Is Essential for Mitochondrial Quality Control.
  1. Nat Immunol. 2026 Sep 25.
    Autoantibody source.
    Ioana Staicu.
      
    DOI:  https://doi.org/10.1038/s41590-026-02676-3
  2. Nature. 2026 Sep 23.
    Surprising protein links dietary restriction to increased lifespan in flies.
    Linda Partridge.
      
    Keywords:  Ageing; Cell biology; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-026-02774-0
  3. Nature. 2026 Sep 23.
    Landmark map of human brain's gene activity holds clues to Alzheimer's disease and more.
    Amanda Heidt.
      
    Keywords:  Alzheimer's disease; Brain; Neurodegeneration; Neuroscience; Psychiatric disorders
    DOI:  https://doi.org/10.1038/d41586-026-02947-x
  4. Nat Immunol. 2026 Sep 24.
    Remodeling of a distal IRF4 element spurs human regulatory T cell instability under inflammatory conditions.
      
    DOI:  https://doi.org/10.1038/s41590-026-02663-8
  5. JAMA. 2026 Sep 25.
    Lipoprotein(a)-Lowering Agent Fails to Reduce Cardiovascular Events.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2026.14725
  6. Nat Commun. 2026 Aug 25. pii: 10162. [Epub ahead of print]17(1):
    The predicted interactome of the human mitochondrial proteome.
    Abhinav B Swaminathan, Mohammad Zulkifli, Rachel M Guerra, Sofia M Calabrese, Dimitris T Kalafatis, David J Pagliarini, Vishal M Gohil.
      Despite the fundamental importance of mitochondria in cellular metabolism, the molecular function(s) of many mitochondrial proteins remain unknown. Since protein function can be inferred from their interacting partners, we repurpose the protein structure prediction algorithm AlphaFold Multimer (AFM) as a classification model to predict protein-protein interactions of the entire human mitochondrial proteome. By screening 630,003 protein pairs, we create a compendium of 2,895 previously known and newly observed interactions, which include the interacting partner(s) of 85 uncharacterized mitochondrial proteins, thereby linking them to a known biochemical pathway. Extending the AFM-based analysis to 11 diverse eukaryotes identifies evolutionarily conserved interactions among human hits, including regulators of core bioenergetic pathways. Our experiments, guided by these predictions, nominate protein interactions that form the coenzyme Q metabolon and define the mitochondrial copper delivery pathway to cytochrome c oxidase. Our compendium represents a powerful resource for the systematic, structure-based functionalization of the human mitochondrial proteome.
    DOI:  https://doi.org/10.1038/s41467-026-77112-z
  7. Nat Immunol. 2026 Sep 21.
    Deletion of a distal IRF4 element prevents inflammation-induced reprogramming of human regulatory T cell fate.
    Patrick Ho, Alexander Vu, Joey Leung, Wendy Rosenthal, Vasilis Ntranos, Jeffrey A Bluestone, Qizhi Tang.
      Regulatory T (Treg) cells in mice can lose lineage identity and acquire proinflammatory functions, but whether human Treg cells are similarly susceptible to cytokine-driven destabilization remains unclear. Here we established an in vitro model of human Treg cell destabilization defined by silencing of the lineage-specifying transcription factor FOXP3, loss of suppressive function and acquisition of proinflammatory activity. Single-cell chromatin accessibility and transcriptomic profiling revealed a genome-wide increase in accessibility at AP-1-binding sites, including a putative regulatory element distal to IRF4. Increased accessibility at this element correlated with increased IRF4 expression during Treg cell destabilization, and its excision conferred resistance to inflammatory cytokine-induced reprogramming. Conversely, forced expression of IRF4 together with BATF promoted Treg cell destabilization. These data identify a distal IRF4 regulatory element as a critical node enabling heightened AP-1-IRF4 cooperative activity to drive Treg cell destabilization, with implications for the design of more stable and effective Treg cell-based therapies.
    DOI:  https://doi.org/10.1038/s41590-026-02655-8
  8. Nat Commun. 2026 Sep 21. pii: 10014. [Epub ahead of print]17(1):
    Combinatorial targeting of the miR-379/miR-410 cluster normalizes glucose and lipid homeostasis in male models of diabetes and obesity.
    Manuel Gil-Lozano, Estefanía Simoes, Moya Wu, Tobias Wiedemann, Yun Kwon, Revathi Sekar, Pauline Morigny, Maria Troullinaki, Juliane Merl-Pham, Michael Buettner, Annette Feuchtinger, Celine Jouffe, Adriano Maida, Daniela Hass, Daniel Samaga, Gretchen Wolff, Juliano Machado, Maude Giroud, Katarina Klepac, Carolyn L Cummins, Marcos Ríos García, Peter Weber, Anja Zeigerer, N Henriette Uhlenhaut, Julia Szendroedi, Matthias Blüher, Stephan Herzig.
      Non-coding RNAs from the Dlk1-Dio3 locus are critical for the maturation of metabolic tissues in early stages of postnatal development; however, their role in the mature organs remains elusive. Herein, we show that microRNAs from the miR-379/miR-410 cluster are robustly upregulated in livers of subjects with obesity and various mouse models of metabolic dysfunction. Adult-onset, combinatorial inhibition of this miRNA cluster by hepatocyte-specific expression of a decoy sequence reduces triglyceride, total and LDL cholesterol circulating levels, decreases basal glycemia and improves glucose tolerance and insulin sensitivity irrespective of sex. Consistent with the decoy-triggered enhancement of PI3K/mTOR signaling in these mice, hepatocytes expressing the combinatorial decoy show augmented mitochondrial mass and function. Notably, decoy therapy also ameliorates glucose and lipid homeostasis in both type 1 diabetic and diet-induced, type 2 pre-diabetic, obese male animals. Collectively, our results demonstrate that microRNAs from the miR-379/miR-410 cluster are critical regulators of metabolic homeostasis in the mature liver. Given the preservation of miRNA dysfunction in human obesity, hepatocyte-specific combinatorial inhibition of a large miRNA cluster represents an approach towards multi-parameter improvements in diabetes and obesity.
    DOI:  https://doi.org/10.1038/s41467-026-77808-2
  9. JCI Insight. 2026 Sep 22. pii: e203495. [Epub ahead of print]11(18):
    Integrated single-cell multiomics reveals neutrophil-driven immune-metabolic reprogramming of Kupffer cells via thrombospondin-1/CD36 after surgical stress.
    Hongji Zhang, Xingping Huang, Preethi Jayakumar, Yunwei Zhang, Ti Yang, Xiaorong Guo, Grace Wu, Amrendra Kumar, Vijaya Bharti, Amblessed Onuma, Chengli Shen, Dequan Lou, Patricia S Latham, James M Crawford, Kong Chen, Anna E Vilgelm, Lopa Mishra, Allan Tsung, Meihong Deng, Hai Huang.
      Surgical stress, such as liver ischemia/reperfusion (I/R) injury characterized by robust neutrophil infiltration and immune activation, induces sterile inflammation that reshapes tissue immunity and contributes to organ dysfunction, yet the intercellular circuits that spatially orchestrate these responses within the hepatic immune microenvironment remain incompletely defined. Here, we integrate single-cell RNA sequencing, spatial transcriptomics, high-dimensional spectral flow cytometry, and metabolomics to resolve the hepatic immune landscape following I/R at cellular and spatial resolution. While confirming extensive immune remodeling, we identify a dominant neutrophil-Kupffer cell communication axis mediated by neutrophil-derived thrombospondin-1 (TSP-1), which selectively engages CD36 on Kupffer cells. This interaction drives coordinated immune-metabolic reprogramming in Kupffer cells, characterized by suppression of oxidative phosphorylation, enhanced glycolysis, and remodeling of sphingolipid metabolism, including accumulation of hexosylceramides. Spatial analyses reveal preferential neutrophil-Kupffer cell colocalization within necrotic niches, and cross-species integration with human liver transplant datasets demonstrates conserved upregulation of the TSP-1/CD36 axis following reperfusion. Pharmacologic inhibition of TSP-1 attenuates liver injury and inflammatory responses in vivo. Together, these findings define a spatially organized, neutrophil-driven immune-metabolic circuit that governs functional reprogramming of Kupffer cells during surgical stress and identify the TSP-1/CD36 pathway as a conserved and targetable mediator of sterile liver injury.
    Keywords:  Adaptive immunity; Hepatology; Immunology; Inflammation; Innate immunity; Surgery
    DOI:  https://doi.org/10.1172/jci.insight.203495
  10. Science. 2026 09 24. 393(6818): 1292-1295
    Alternative immunity.
    Mitch Leslie.
      A little-known arm of the immune system respond to lipids, with a protein called CD1 driving reactions to bee stings, bacteria, and possibly poison ivy.
    DOI:  https://doi.org/10.1126/science.aem6505
  11. Nat Commun. 2026 Aug 22. pii: 10053. [Epub ahead of print]17(1):
    Genetic architecture of cytokine autoantibodies and associated risk of common diseases.
    DBDS Genomic Consortium
      Anti-cytokine autoantibodies are increasingly recognized as modulators of immune function and determinants of disease risk, yet their genetic basis and population-level impact remain unclear. Here we perform genome-wide association studies of autoantibodies against IL-1α, IL-6, IL-10, IFN-α, IFN-β, IFN-γ and GM-CSF in 15,000 individuals from the Danish Blood Donor Study. We identify 52 genome-wide significant loci, implicating genes enriched in antigen-presentation pathways. Using these data, we derive cytokine-specific polygenic risk scores and evaluate their associations across 300,000 individuals in the Copenhagen Hospital Biobank. Genetic predisposition to IL-1α autoantibodies is associated with reduced risk of rheumatoid arthritis and certain cancers, whereas genetic predisposition to IL-6 autoantibodies is associated with increased risk of diabetes, mirroring prior clinical observations. These findings define the genetic architecture of anti-cytokine autoantibodies and indicate their divergent effects on human disease risk at population scale, providing a framework for mechanistic investigation and potential clinical stratification.
    DOI:  https://doi.org/10.1038/s41467-026-76394-7
  12. Sci Signal. 2026 Sep 22. 19(956): eaem4471
    How some brain macrophages go with the flow.
    Wei Wong.
      cMAF drives the identity and signaling of a brain macrophage subset involved in vascular homeostasis.
    DOI:  https://doi.org/10.1126/scisignal.aem4471
  13. Nat Aging. 2026 Sep 24.
    A cross-species single-cell kidney epigenome atlas reveals epithelial-dominant aging-like states in disease.
    Hyeonsoo Jeong, Blue B Lake, Dinh Diep, Xuwen Li, Qi Yan, Debora L Gisch, Madhurima Kaushal, Stephanie Reinert, Michael T Eadon, Joseph P Gaut, Sanjay Jain, Kun Zhang.
      Epigenetic aging is a hallmark of chronic diseases. While such epigenetic changes can arise following tissue injury, the cell types most affected remain largely unknown. Here we built a cross-species single-cell multiomics atlas of DNA methylation, chromatin accessibility and transcription profiles from healthy, injured (human) and aged (mouse) kidneys. We found that tubular epithelial cells in diseased kidneys exhibit pronounced accelerated epigenetic aging and showed that this pathological state mirrors transcriptional trajectories observed during aging, driven by preferential dysregulation of lineage-specific genes lacking CpG islands. Spatially, these epigenetic changes mapped to pathological niches of unresolved repair. Co-profiling single-cell DNA methylation and 3D genome architecture revealed that epithelial repair states in disease undergo significant higher-order genome reorganizations, alongside activation of genes associated with renal decline. Together, our findings characterize a loss of epigenetic repression within coordinated three-dimensional chromatin structures and reduced local methylome integrity, which compromises epithelial cell identity during aging and impedes repair.
    DOI:  https://doi.org/10.1038/s43587-026-01221-z
  14. Nat Cardiovasc Res. 2026 Sep 22.
    Timed metabolic repair after myocardial infarction.
    Chak Kwong Cheng, Yu Huang.
      
    DOI:  https://doi.org/10.1038/s44161-026-00873-9
  15. Nat Commun. 2026 Aug 26. pii: 10185. [Epub ahead of print]17(1):
    Deep learning aging marker from retinal images unveils sex-specific clinical and genetic signatures.
    VascX Consortium
      Retinal fundus images offer a non-invasive window into systemic aging. Here, we fine-tune a foundation model (RETFound) to predict chronological age from color fundus images in 71,343 participants from the UK Biobank, achieving a mean absolute error of 2.85 years. The resulting retinal age gap, i.e. the difference between predicted and chronological age, is associated with cardiometabolic traits, inflammation, cognitive performance, all-cause mortality, dementia, cancer, and incident cardiovascular disease. Genome-wide analyses identify genes related to longevity, metabolism, neurodegeneration, and age-related eye diseases. Sex-stratified models reveal consistent performance but divergent biological signatures: males have stronger links to metabolic syndrome, while in females, both model attention and genetics point to a greater involvement of retinal vasculature. Additional analyses indicate that retinal aging patterns in females vary across the menopausal transition, with postmenopausal females exhibiting higher retinal age gap values and clinical associations that more closely resemble those observed in males. Our study positions the retinal age gap as a biologically relevant and sex-specific phenotype associated with multiple aging-related diseases and outcomes beyond conventional risk factors, including chronological age.
    DOI:  https://doi.org/10.1038/s41467-026-77102-1
  16. Nat Rev Immunol. 2026 Oct;26(10): 707-708
    The next big questions in immunology.
      
    DOI:  https://doi.org/10.1038/s41577-026-01353-8
  17. Nat Metab. 2026 Sep 25.
    Short-chain fatty acids and blood pressure.
    Rikeish R Muralitharan, Francine Z Marques.
      
    DOI:  https://doi.org/10.1038/s42255-026-01641-6
  18. Diabetologia. 2026 Sep 22.
    Shared non-HLA genetic architecture across diverse ancestries links insulin secretion and resistance to type 1 diabetes.
    Qi Fu, Keyao Wang, Min Shen, Sipeng Shen, Jinglan Dai, Xiaoyan Yi, Yu Qian, Wenkai Duan, Jie Zhang, Liying Jiang, Hao Dai, Heng Chen, Tao Yang, Miriam Cnop, Decio L Eizirik, Kuanfeng Xu.
       AIMS/HYPOTHESIS: Type 1 diabetes is an autoimmune disease with a strong genetic component. Nevertheless, the genetic underpinnings linking type 1 diabetes susceptibility to both insulin secretion and insulin resistance across diverse ancestries have yet to be fully characterised.
    METHODS: We performed a multi-ancestry type 1 diabetes genome-wide association study meta-analysis comprising 26,198 cases and 36,733 control individuals to identify risk regions across diverse ancestral populations. We further evaluated their associations with clinical traits, integrated epigenetic profiles, mapped candidate genes to define tissue and cell type specificity, and conducted pathway enrichment analyses to elucidate the genetic links between type 1 diabetes and both insulin secretion and insulin resistance.
    RESULTS: We observed 69 non-HLA regions for type 1 diabetes risk, including three novel genome-wide association study signals: rs2179781 in AHI1 (OR 1.074, p=1.19×10-8), rs10117059 near TRAF1 (OR 1.074, p=3.95×10-8) and rs7184802 near ADCY7 (OR 1.089, p=4.12×10-8). Notably, over one-third (26/69) of these variants were associated with insulin secretion or resistance indices. Using Bayesian fine-mapping integrated with three complementary annotation strategies, we prioritised 136 putative functional variants. Integrative analysis leveraging Roadmap Epigenomics data revealed that these variants exhibited elevated regulatory potential, as evidenced by DNase I hypersensitivity, characteristic H3 histone modifications and active chromatin states in key metabolic tissues (pancreatic islets, liver, skeletal muscle and adipose). Computational mapping and annotation of these variants implicated 447 candidate genes, which showed metabolic tissue-specific expression, and were enriched in pathways related to insulin secretion and resistance (p=5.41×10-4 and 2.10×10-5, respectively), a pattern not evident for HLA risk genes. Subsequent functional characterisation identified ADCY7, regulated by functional variant rs1872691, as the probable causal gene at the novel 16q12.1 locus. In pancreatic beta cells, proinflammatory cytokines downregulated Adcy7 expression and Adcy7 perturbation bidirectionally modulated both insulin secretion and cytokine-induced apoptosis. Conversely, Adcy7 knockdown in adipocytes augmented lipogenesis and enhanced insulin sensitivity.
    CONCLUSIONS/INTERPRETATION: Our findings support the existence of a shared non-HLA genetic architecture that may link type 1 diabetes susceptibility to both impaired insulin secretion and insulin resistance, providing preliminary genetic evidence for their convergent pathogenic mechanisms.
    Keywords:   ADCY7 ; GWAS; Insulin resistance; Insulin secretion; Non-HLA risk; Type 1 diabetes
    DOI:  https://doi.org/10.1007/s00125-026-06865-5
  19. JAMA Netw Open. 2026 Sep 01. 9(9): e2635687
    Continuous Glucose Monitoring Alert Settings and Glycemic Control in People With Diabetes.
    Yaguang Zheng, Stephen B Johnson, Eduardo Iturrate, Bei Wu, Heng Huang, William Small, Susan Zweig, Rozalina G McCoy.
      
    DOI:  https://doi.org/10.1001/jamanetworkopen.2026.35687
  20. Cell Rep. 2026 Sep 25. pii: S2211-1247(26)01120-4. [Epub ahead of print]45(10): 118042
    Transcriptional and epigenomic analysis of insulin sensitivity in human adipocytes.
    Qianbin Zhang, Audrey Zhou, Adam G Maynard, Margo P Emont, Christopher Jacobs, Soumya Nagesh, Thiago M Batista, Renee M Gibson, Yi Huang, Rama Kaalia, Joaquín Pérez-Schindler, Bellis Min, Anna Lyubetskaya, Brian Dawes, Anlu Chen, Danielle Tenen, Eleanna De Filippis, Erin Merkel, Rachael Ivison, Amrita Kar, Hesam Dashti, Melina Claussnitzer, Linus Tsai, Evan D Rosen.
      Insulin resistance is a key feature of type 2 diabetes (T2D) and is also associated with a wide variety of other disease states. We isolated adipocytes from subjects with and without insulin resistance and subjected them to transcriptional and epigenomic profiling, allowing us to identify genes, cis-regulatory elements, and pathways that associate with insulin resistance in this critical cell type. We focused on several differentially enriched regions near the IRS1 gene that were close to, but distinct from, single-nucleotide polymorphisms associated with T2D and insulin resistance. CRISPR interference (CRISPRi)-mediated repression of these elements identified two major enhancer regions that regulate IRS1 expression in a cell-state-dependent manner. Finally, we identified specific transcription factors that act through these sites to enhance IRS1 gene expression. These studies help to define the molecular events that characterize, and potentially determine, human insulin sensitivity and resistance.
    Keywords:  CP: metabolism; CP: molecular biology; CRISPRi; H3K27ac; IRS1; RNA-seq; adipocyte; epigenomics; human; insulin resistance; insulin sensitivity
    DOI:  https://doi.org/10.1016/j.celrep.2026.118042
  21. Aging Cell. 2026 Oct;25(10): e70741
    Hepatocyte Growth Hormone Receptor Ablation Is Associated With Aging Phenotypes and Hepatic Mitochondrial Dysfunction.
    Kangkang Yang, Yuli Jian, Fusheng Pang, Ming Ying, Qian Yang, Nian Liu, Shujing Wang, Yingjie Wu.
      Aging drives physiological decline and predisposes individuals to multiple age-related pathologies, constituting a major global health challenge. Growth hormone receptor (GHR), a critical regulator of growth, development, and metabolism, has emerged as a potential therapeutic target. However, its precise role in aging and age-related diseases remains incompletely defined. Here, we demonstrate that hepatocyte-specific GHR knockout mice display accelerated aging-related phenotypes, characterized by shortened lifespan, enhanced cellular senescence, reduced metabolic stress resilience, cognitive decline, impaired bone mineralization, and exacerbated inflammaging. Elevated circulating GH following hepatocyte-specific GHR ablation mediates adipose-liver crosstalk that promotes adipose lipolysis and CD36-dependent hepatic steatosis. Hepatocyte-specific GHR deficiency also promotes liver aging and aggravates age-related hepatic pathologies in both naturally aged and high-fat diet (HFD)-fed mice. Mechanistically, loss of hepatic GHR impairs STAT5b phosphorylation while upregulating PPARγ expression. Enhanced nuclear translocation of PPARγ activates transcription of Pdk4 and Cd36, leading to mitochondrial damage and ectopic lipid accumulation. Together, dysregulated lipid metabolism and mitochondrial dysfunction establish a self-amplifying vicious cycle that accelerates aging and its pathophysiology. Pharmacological inhibition of PDK4 in vivo effectively ameliorates the age-related pathologies induced by hepatocyte-specific GHR ablation. These findings identify hepatic GHR signaling as an important contributor to age-related hepatic pathology and a candidate node within the broader network of factors driving systemic aging phenotypes, highlighting hepatocyte GHR signaling as a promising therapeutic target for age-related liver disorders.
    Keywords:  GH‐GHR; age‐related pathologies; aging; ectopic lipid accumulation; mitochondrial dysfunction
    DOI:  https://doi.org/10.1111/acel.70741
  22. Cell Metab. 2026 08 04. pii: S1550-4131(26)00282-2. [Epub ahead of print]38(8): 1722
    High-Mobility Group Box 1 Is Essential for Mitochondrial Quality Control.
    Daolin Tang, Rui Kang, Kristen M Livesey, Guido Kroemer, Timothy R Billiar, Bennett Van Houten, Herbert J Zeh, Michael T Lotze.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.07.009
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