bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–06–07
nineteen papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. OXPHOS fuels cDC1s.
  2. Integrative analyses elucidate transcriptional regulatory functions of risk alleles for metabolic liver disease.
  3. Taming the inflamed heart.
  4. Obesity doesn't equate to ill health: why the 'disease' label doesn't always fit.
  5. The immune engram: a spatial model of immunological memory.
  6. Decreased degree of adipocyte differentiation in visceral adipose tissue contributes to metabolic dysfunction-associated steatotic liver disease.
  7. Explosive cytotoxicity of ruptoblasts bridges hormone surveillance and immune defense.
  8. Environmental regulation of mucosal-associated invariant T cells: Adding food for thought.
  9. Electric vehicles cut pollution in China - and prevent 260,000 premature deaths.
  10. Mitochondria across the globe: Diverse voices, shared energy.
  11. Epigenetic landscapes in human pancreatic islets reveal distinct drivers for adaptation to age and type 2 diabetes.
  12. Targeting hypothalamic SIK3 to promote weight loss and improve glycemic control in mice.
  13. Why Celebrate?
  14. Hepatic Lipoprotein Production, Cardiometabolic Phenotypes, and Subtypes of Steatotic Liver Disease.
  15. Inference of spatial chromatin accessibility via integration of spatial transcriptomics and single-cell multi-omics data.
  16. Blood Pressure Above Goal Among Adults With Hypertension in the US.
  17. scMEDAL: interpretable single-cell transcriptomics analysis with batch effect visualization via deep mixed-effects autoencoder.
  18. CIDEB and CGI-58 differentially regulate liver lipid-droplet cholesterol to modulate metabolic dysfunction-associated steatohepatitis severity.
  19. Triglyceride-Rich Lipoprotein Metabolism and Cardiovascular Risk in Diabetes: Bedside to Bench to Bedside.
  1. Nat Immunol. 2026 Jun;27(6): 1085
    OXPHOS fuels cDC1s.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-026-02551-1
  2. Nat Genet. 2026 Jun 02.
    Integrative analyses elucidate transcriptional regulatory functions of risk alleles for metabolic liver disease.
    VA Million Veteran Program
      Genome-wide association studies have identified >100 loci associated with metabolic dysfunction-associated steatotic liver disease (MASLD), yet the mechanisms by which noncoding variants alter disease risk remain unclear. Here we map chromatin accessibility in human MASLD liver nuclei, revealing enrichment of risk variants within cell-type-specific regulatory elements bound by lineage-determining transcription factors. Using a massively parallel reporter assay, we identified hundreds of differential activity variants (DAVs) that act in a cell-type-dependent and stimulus-dependent manner and perturb transcriptional regulatory networks linked to liver pathology. Integration of liver expression quantitative trait loci, chromatin looping and single-cell CRISPR interference screening assigns target genes to these DAVs. Importantly, DAVs at numerous loci, including SLC22A3 and key triglyceride metabolism regulators (APOA5, ANGPTL3 and LPL), modulate gene expression, lipid metabolism and hepatic stellate cell activation. Moreover, these DAVs allow improved prediction of MASLD risk. These results define a regulatory framework linking noncoding genetic variation to MASLD pathogenesis.
    DOI:  https://doi.org/10.1038/s41588-026-02617-8
  3. Nat Med. 2026 Jun 05.
    Taming the inflamed heart.
    Charlotte Harrison.
      
    DOI:  https://doi.org/10.1038/d41591-026-00030-6
  4. Nature. 2026 Jun;654(8117): 33-36
    Obesity doesn't equate to ill health: why the 'disease' label doesn't always fit.
    Francesco Rubino.
      
    Keywords:  Medical research; Obesity; Policy
    DOI:  https://doi.org/10.1038/d41586-026-01729-9
  5. Nat Rev Immunol. 2026 Jun 04.
    The immune engram: a spatial model of immunological memory.
    Hiroyuki Takaba.
      
    DOI:  https://doi.org/10.1038/s41577-026-01320-3
  6. Nat Commun. 2026 Jun 03.
    Decreased degree of adipocyte differentiation in visceral adipose tissue contributes to metabolic dysfunction-associated steatotic liver disease.
    Kyla Z Gelev, Seung Hyuk T Lee, Marcus Alvarez, Rosellina M Mancina, Federica Tavaglione, Oveis Jamialahmadi, Umberto Vespasiani-Gentilucci, Asha Kar, Zitian Wang, Dorota Kaminska, Minna U Kaikkonen, Ville Männistö, Sini Heinonen, Tuure Saarinen, Anne Juuti, Kirsi H Pietiläinen, Jussi Pihlajamäki, Stefano Romeo, Päivi Pajukanta.
      The mechanisms connecting the human fat depots, subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), to metabolic dysfunction-associated steatotic liver disease (MASLD) remain elusive. We hypothesize that in individuals with obesity, a decreased degree of adipocyte differentiation may contribute to ectopic fat accumulation in the liver, seen in MASLD. Here we show, using single nucleus RNA-sequencing from adipose tissue biopsies, that the predicted degree of VAT adipocyte differentiation is decreased in individuals with MASLD, with an attenuated impact observed in SAT adipocytes. Next, we discover that regional variants of the VAT adipocyte differentiation gene set explain a substantial proportion (17%) of MASLD heritability. These genes largely overlap (>50%) with adipocyte genes differentially expressed by MASLD, regulated by variants in cis. Finally, we show that these genes are linked to smaller adipocyte size. Together, our findings reveal that a decreased predicted degree of VAT adipocyte differentiation contributes to MASLD.
    DOI:  https://doi.org/10.1038/s41467-026-73660-6
  7. Cell. 2026 Jun 02. pii: S0092-8674(26)00567-2. [Epub ahead of print]
    Explosive cytotoxicity of ruptoblasts bridges hormone surveillance and immune defense.
    Chew Chai, Eliya Sultan, Souradeep R Sarkar, Lihan Zhong, Dania Nanes Sarfati, Orly Gershoni-Yahalom, Christine Jacobs-Wagner, Hawa Racine Thiam, Benyamin Rosental, Bo Wang.
      Current understanding of cytotoxic immunity is shaped by hematopoietic-derived cells-T cells, natural killer cells, and neutrophils. Here, we identify "ruptoblasts," a previously unknown cytotoxic glandular cell type in regenerative planarian flatworms. Ruptoblasts undergo an explosive cell death, "ruptosis," triggered by activin, a multifunctional hormone acting as an inflammatory cytokine. Excessive activin-induced through protein injection, genetic chimerism, or bacterial infection-initiates ruptosis, discharging potent diffusible cytotoxic agents capable of eliminating nearby cells, bacteria, and even mammalian cells within minutes. Ruptoblast ablation suppresses inflammation but compromises bacterial clearance, highlighting their broad-spectrum immune functions. Mechanistically distinct from known cytotoxic and cell death mechanisms, the explosive nature of ruptosis relies on endoplasmic reticulum (ER)-derived calcium and cytoskeleton-dependent signal amplification. Ruptoblast-like cells appear conserved in diverse basal bilaterians, implying an ancient evolutionary origin. These findings unveil a strategy coupling hormonal regulation with immune defense and expand the landscape of evolutionary immune innovations.
    Keywords:  activin signaling; cell death/destruction; cytotoxicity; evolution of immune system; extreme cell biology; genetic chimeras; glandular/secretory cell types; hormonal surveillance; planarian
    DOI:  https://doi.org/10.1016/j.cell.2026.05.008
  8. Sci Signal. 2026 Jun 02. 19(940): eaec6992
    Environmental regulation of mucosal-associated invariant T cells: Adding food for thought.
    Eimear K Ryan, Linda V Sinclair, Andrew E Hogan.
      Mucosal-associated invariant T (MAIT) cells are a population of innate-like, unconventional T cells characterized by the expression of a semi-invariant, non-MHC-restricted T cell receptor (TCR), which play an important role in mediating innate immune responses to bacterial and viral pathogens. Emerging research continues to describe the many environmental signals that influence the types of responses elicited downstream of MAIT cell activation. In this Review, we highlight five key factors that determine the metabolic and functional responses of MAIT cells, including TCR engagement, costimulation, chemokine signaling, cytokine stimulation, and nutrient availability. We further define the importance of optimal nutrient availability as "signal 5" in promoting MAIT cell fitness and in governing their capacity to respond appropriately to challenge. In understanding the ways in which MAIT cells are influenced by their microenvironment, we can continue to identify the potential factors that drive dysregulated responses in hostile circumstances, enabling restoration of their protective nature in the context of infection or in the tumor microenvironment.
    DOI:  https://doi.org/10.1126/scisignal.aec6992
  9. Nature. 2026 Jun 05.
    Electric vehicles cut pollution in China - and prevent 260,000 premature deaths.
    Claudia Steiner.
      
    Keywords:  Energy; Government; Public health
    DOI:  https://doi.org/10.1038/d41586-026-01781-5
  10. Cell Metab. 2026 Jun 02. pii: S1550-4131(26)00153-1. [Epub ahead of print]38(6): 1075-1078
    Mitochondria across the globe: Diverse voices, shared energy.
    Ichitaro Abe, Alejandro Failde Fiestras, Maia Hjerting Ekstrand, Nahid A Khan, Kenneth Bowitz Larsen, Jason Maynes, Agata M Rudolf, Francois Singh.
      Like mitochondria themselves, research on the organelle can take many shapes and sizes. This month, to coincide with the Cell Press Symposia: Multifaceted mitochondria, we are highlighting the diversity of the global mitochondria community with contributions from researchers at all career stages published across Cell Metabolism, Molecular Cell, Cell Reports, and Trends in Endocrinology & Metabolism. Together, these voices showcase the central role of mitochondrial research in metabolism, inflammation, cell biology, and much more.
    DOI:  https://doi.org/10.1016/j.cmet.2026.04.015
  11. Nat Commun. 2026 Jun 03. pii: 4811. [Epub ahead of print]17(1):
    Epigenetic landscapes in human pancreatic islets reveal distinct drivers for adaptation to age and type 2 diabetes.
    Lucas Maurin, Lorella Marselli, Mathilde Boissel, Vincent Pascat, Mara Suleiman, Emma Henriques, Carmela De Luca, Lijiao Ning, Marie Fourcot, Marta Tesi, Bénédicte Toussaint, Souhila Amanzougarene, Mehdi Derhourhi, Frédérik Oger, Frederic Burdet, Mickael Canouil, Miriam Cnop, Mark Ibberson, Amélie Bonnefond, Piero Marchetti, Philippe Froguel, Amna Khamis.
      Age is the strongest risk factor for type 2 diabetes, yet their independent contribution to pancreatic islet dysfunction remains unclear. We integrate DNA methylation, transcriptomic, and genotyping data from 144 islet donors. We identify 996 age- and 902 T2D-associated CpGs with minimal overlap, and 251 age- and 310 diabetes CpG target genes, usually distant from the CpG. Age-linked CpGs are enriched in promoters, form co-regulated gene modules, link to beta-cell function, including insulin secretion. Diabetes-associated CpGs are enriched in enhancer/non-regulatory regions, and modules suggest stress-induced epigenetic drift. CpG-gene associations are independent of genetic variation. Mendelian randomisation supports a causal role for age-associated CpGs regulating KLHL42, a T2D GWAS locus. A blood-based methylation risk score based on age-linked CpGs correlates with insulin secretion and improves diabetes classification when combined with genetic risk (AUC = 0.91). Altogether, age is associated with a coordinated epigenetic programme, whereas diabetes links to a heterogeneous, stress-related epigenetic signature.
    DOI:  https://doi.org/10.1038/s41467-026-73222-w
  12. Nat Commun. 2026 Jun 02.
    Targeting hypothalamic SIK3 to promote weight loss and improve glycemic control in mice.
    Danise Ann Onda, Chieh-Hsin Yang, Callen Goldsmith, Cait A Beddows, Rui Qi Teo, Lei Zhang, XiaoZhuo Yuan, Yifei Zhu, Man Ks Lee, Ashley J Ovens, Dingyi Yu, Kei Sakamoto, John W Scott, Andrew J Murphy, Noriyuki Tsumaki, Herbert Herzog, Garron T Dodd, Kim Loh.
      Salt-Inducible Kinase 3 (SIK3) has emerged as a key regulator of peripheral metabolism, however its cellular and molecular function in regulating body weight and energy metabolism, particularly in hypothalamic neurons, remains unclear and largely unexplored. Here, we demonstrate that SIK3 expression is elevated in the hypothalamus of obese mice. Inactivation of SIK3 specifically in orexigenic NPY neurons reduces food intake, increases energy expenditure, and enhances white adipose tissue browning, resulting in resistance to high-fat diet-induced obesity in mice. Pharmacological inhibition of SIK3 with the inhibitor GLPG3970 in diet-induced obese mice led to significant reductions in body weight and adiposity, primarily due to decreased energy intake, with notable improvements in metabolic health. These effects are linked to enhanced central leptin and insulin signaling, and the dephosphorylation and nuclear translocation of key transcriptional metabolic regulators, CRTC1 and HDAC5. These findings reveal a previously unidentified SIK3-mediated pathway that promotes positive energy balance and suggests SIK3 inhibition may offer therapeutic potential for treating obesity and metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-026-73649-1
  13. JAMA. 2026 Jun 04.
    Why Celebrate?
      
    DOI:  https://doi.org/10.1001/jama.2025.15962
  14. Circ Res. 2026 Jun 05. 138(12): e327269
    Hepatic Lipoprotein Production, Cardiometabolic Phenotypes, and Subtypes of Steatotic Liver Disease.
    Nicholas O Davidson.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) impacts more than a third of adults worldwide. The burgeoning epidemic of MASLD has led to increases in atherosclerotic cardiovascular disease (CVD), which is the leading cause of morbidity and mortality among affected individuals, particularly those with type 2 diabetes. Subsets of patients with MASLD will develop progressive liver disease, including metabolic dysfunction-associated steatohepatitis, advanced fibrosis, cirrhosis, and hepatocellular cancer. The association of progressive forms of MASLD with cardiometabolic disease has spurred interest in understanding how distinct pathways in hepatic lipid and lipoprotein metabolism may identify candidate therapeutic targets to mitigate CVD risk. A deeper understanding of hepatic lipid and lipoprotein homeostasis in MASLD is a pressing need for several reasons connected with some of the molecular and signaling adaptations occurring in obesity and type 2 diabetes. First, because these conditions individually and in combination accelerate the onset and progression of MASLD; second, because progressive MASLD may promote insulin resistance and type 2 diabetes; and third, because some CVD risk factors (dyslipidemia, obesity, type 2 diabetes) overlap with those for MASLD. Evidence suggests a multifactorial cause for MASLD, including genetic factors that either promote or mitigate liver disease progression and which, along with environmental modifiers (diet, obesity) and insulin resistance, contribute to CVD risk. Segregating these causes of MASLD by phenotype/metabotype reveals a systemic metabolic dysfunction (obesity, insulin resistance) dominant subtype, which is associated with increased CVD, and a second dominant subtype where familial and genetic factors predominate, which reflects impaired VLDL (very low-density lipoprotein) secretion and is associated with reduced CVD risk. Further study of these distinctive subtypes of MASLD may identify new, tailored approaches to prevent cardiometabolic disease.
    Keywords:  cardiovascular diseases; insulin resistance; lipoproteins; obesity; phenotype
    DOI:  https://doi.org/10.1161/CIRCRESAHA.126.327269
  15. Nat Commun. 2026 Jun 04.
    Inference of spatial chromatin accessibility via integration of spatial transcriptomics and single-cell multi-omics data.
    Ishita Debnath, Zhana Duren.
      Integrating spatial transcriptomics, which maps gene expression location within tissues, with single-cell multi-omics data, profiling gene expression and chromatin accessibility (or other epigenomic data) for the same cell, offers powerful insights into gene regulation. However, commercially available kits for simultaneous spatial multi-omics profiling are currently unavailable, hindering widespread data generation. Here, we present ISON (Integrated Spatial Omics Network), a unified computational method for integrative spatial multi-omics analysis from single cell multiome data and spatial transcriptomics data. ISON accurately predicts chromatin accessibility profiles for spatial spots and reconstructs spatially resolved gene regulatory networks, demonstrating scalability in both time and memory. Importantly, ISON's chromatin accessibility prediction captures patterns consistent with cis- and trans- regulatory information and enables estimation of transcription factor (TF) activity at the spot level, distinguishing between TFs even within the same family, which is unique and is not present in approaches relying solely on chromatin accessibility data. The application of ISON to Alzheimer's disease data reveals disease- and age-specific spatially variable gene regulatory modules, highlighting its potential to uncover spatially organized mechanisms driving complex biological processes.
    DOI:  https://doi.org/10.1038/s41467-026-73948-7
  16. JAMA. 2026 Jun 01.
    Blood Pressure Above Goal Among Adults With Hypertension in the US.
    Donald E Casey, Stephen D Persell, Gregory Wozniak.
      
    DOI:  https://doi.org/10.1001/jama.2026.5310
  17. Nat Commun. 2026 Jun 02.
    scMEDAL: interpretable single-cell transcriptomics analysis with batch effect visualization via deep mixed-effects autoencoder.
    Aixa X Andrade, Son N Nguyen, Austin Marckx, Albert A Montillo.
      Single-cell RNA sequencing enables high-resolution analysis of cellular heterogeneity, yet disentangling biological signal from batch effects remains challenging. Existing batch-correction algorithms suppress or discard batch-related variation rather than modeling it. We propose scMEDAL-single-cell Mixed Effects Deep Autoencoder Learning-a framework that separately and independently models batch-invariant and batch-specific effects. The principal innovation, scMEDAL-RE, is a random-effects Bayesian autoencoder that learns batch-specific representations while preserving biologically meaningful information confounded with batch effects, signal often lost under standard correction. Across diverse conditions (autism, leukemia, cardiovascular), cell types, and technical and biological effects, scMEDAL-RE produces interpretable, batch-specific embeddings that complement multiple batch correction methods, improving prediction of disease status, donor group, and tissue. scMEDAL also provides generative visualizations-including counterfactual reconstructions of a cell's expression as if acquired in another batch. Overall, scMEDAL is a versatile, interpretable framework that complements existing correction, providing insight into cellular heterogeneity and data acquisition.
    DOI:  https://doi.org/10.1038/s41467-026-72666-4
  18. Cell Rep. 2026 Jun 02. pii: S2211-1247(26)00447-X. [Epub ahead of print]45(6): 117369
    CIDEB and CGI-58 differentially regulate liver lipid-droplet cholesterol to modulate metabolic dysfunction-associated steatohepatitis severity.
    Ikki Sakuma, Rafael C Gaspar, Henrique N Morgan, Jie Zheng, Ali R Nasiri, Sylvie Dufour, Mario Kahn, Mateus T Guerra, Yuki Taki, Yusuke Kawashima, Dean Yimlamai, Mark Perelis, Daniel F Vatner, Kitt Falk Petersen, Varman T Samuel, Tomoaki Tanaka, Gerald I Shulman.
      Metabolic dysfunction-associated steatohepatitis (MASH) increases liver-related mortality, and new therapies targeting its underlying mechanisms are warranted. We examined whether two lipid-droplet proteins, CIDEB and CGI-58, exert opposing control over MASH by altering cholesterol in liver lipid droplets. Using antisense oligonucleotides, we silenced CIDEB or CGI-58 in the livers of C57BL/6J mice fed a choline-deficient, L-amino acid-defined high-fat diet. CIDEB silencing decreased both triglyceride and cholesterol levels in liver lipid droplets and lowered plasma transaminases and the number of crown-like structures. These protective effects were abrogated by cholesterol supplementation. Conversely, CGI-58 knockdown raised triglyceride and cholesterol levels and exacerbated MASH; bempedoic acid, a cholesterol-synthesis inhibitor, reversed these changes. Dual CIDEB/CGI-58 silencing confirmed that CGI-58 loss abrogated the protective effects of CIDEB knockdown. Our data establish liver lipid-droplet cholesterol as a critical determinant in MASH mediated by CIDEB and CGI-58 and demonstrate that CIDEB knockdown confers protection by enhancing CGI-58-dependent lipolysis.
    Keywords:  ATGL; CGI-58/ABHD5; CIDEB; CP: metabolism; antisense oligonucleotide; cholesterol; choline-deficient, L-amino acid-defined high-fat diet; lipid droplet protein; lipid-droplet cholesterol; metabolic dysfunction-associated steatohepatitis
    DOI:  https://doi.org/10.1016/j.celrep.2026.117369
  19. Circ Res. 2026 Jun 05. 138(12): e327267
    Triglyceride-Rich Lipoprotein Metabolism and Cardiovascular Risk in Diabetes: Bedside to Bench to Bedside.
    Henry N Ginsberg, Karin E Bornfeldt.
      Type 1 diabetes and type 2 diabetes are associated with an increased risk of atherosclerotic cardiovascular disease (ASCVD), manifested as myocardial infarction, ischemic stroke, and peripheral artery disease. The increased ASCVD risk in diabetes cannot be fully explained by traditional risk factors. This review highlights the dysregulation of TRLs (triglyceride-rich lipoproteins; VLDL [very low-density lipoprotein] and chylomicrons), and their remnants, as contributors to ASCVD risk in diabetes by examining 6 typical clinical cases integrated with mechanistic data obtained in preclinical models. Type 2 diabetes is often associated with insulin resistance and increased hepatic secretion of VLDL particles, which are enlarged by an increased lipid load, increased intestinal secretion of chylomicrons, and reduced hepatic clearance of both VLDL and chylomicron remnants. The increased levels of TRLs in turn contribute to the predominance of smaller, denser LDL (low-density lipoprotein) particles and smaller cholesterol-depleted HDL (high-density lipoprotein) particles compared with people without diabetes. When type 2 diabetes occurs in individuals with genetic variants causing altered function of proteins stimulating TRL clearance (LPL, APOC2, APOA5, GPIHBP1, LMF1, or LDLR) or suppressing TRL clearance (APOC3, ANGPTL3, ANGPTL4, ANGPTL8), the result is a compounded accumulation of TRLs and their remnants in plasma and an associated increased ASCVD risk. VLDL secretion is usually unaltered in individuals with well-controlled type 1 diabetes, but ASCVD risk is increased when insulin resistance and defects in TRL clearance are also present. Mechanistically, TRLs enhance ASCVD risk at least in part by exacerbating local vascular inflammation caused by the accumulation of free cholesterol and triglyceride lipolysis products. Because cardiovascular outcome trials targeting triglyceride levels to date have been mostly futile, the field is now focused on trials targeting proteins involved in TRL clearance. Carefully determining inclusion and exclusion criteria for such trials will be critical for advancing our understanding of how to better prevent ASCVD in individuals living with diabetes.
    Keywords:  apolipoproteins; chylomicron remnants; dyslipidemias; insulin resistance; lipoproteins
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.327267
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