bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–08–30
sixteen papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Microglia effects.
  2. Aging by impaired efferocytosis.
  3. Breg cells to the rescue.
  4. β-cell FMO3-produced TMAO prevents NF-κB-mediated senescence and inflammation in ageing and diabetic conditions.
  5. Mutation-resolved single-cell transcriptomics reveals enhanced β-amyloid clearance in TET2-mutant human monocytes.
  6. Altered bone marrow niche forms central innate immune memory driving cardiac dysfunction.
  7. Excessive EFHD1-dependent ER-mitochondrial contacts drive a maladaptive antiviral response in metabolic liver disease.
  8. Transcriptomic profiling of human brown and white adipose tissue depots.
  9. ACSS2-KAT5 complex-driven histone crotonylation orchestrates a pro-inflammatory program to promote the transition from MASLD to MASH.
  10. A multimodal, all-optical platform for linking cell identity to metabolic function in intact tissues.
  11. cGAS-deficient mice display premature aging associated with derepression of LINE1 elements and inflammation.
  12. Dynamic remodeling of the pancreas immune landscape in obesity.
  13. Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits.
  14. The brain struggles to make new neurons in people with depression.
  15. London's clean air zone benefits child health.
  16. Leaky oocytes propagate cGAS-STING signaling.
  1. Nat Immunol. 2026 Sep;27(9): 1772
    Microglia effects.
    Ioana Staicu.
      
    DOI:  https://doi.org/10.1038/s41590-026-02649-6
  2. Nat Immunol. 2026 Sep;27(9): 1772
    Aging by impaired efferocytosis.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-026-02647-8
  3. Nat Immunol. 2026 Sep;27(9): 1772
    Breg cells to the rescue.
    Laurie A Dempsey.
      
    DOI:  https://doi.org/10.1038/s41590-026-02648-7
  4. Nat Commun. 2026 07 27. pii: 9112. [Epub ahead of print]17(1):
    β-cell FMO3-produced TMAO prevents NF-κB-mediated senescence and inflammation in ageing and diabetic conditions.
    Baomin Wang, Yumei Yang, Yuen Man Ho, Huige Lin, Juntao Yuan, Kekao Long, Kenneth King Yip Cheng, Xiaomu Li.
      Human cells utilize gut microbiota-derived metabolites to control systemic metabolism. Trimethylamine N-oxide (TMAO) is traditionally considered a hepatocyte-derived metabolite from microbial trimethylamine. Here we show that pancreatic β-cells also produce TMAO as an autocrine and intracellular metabolite to maintain β-cell function. β-cells synthesize TMAO via flavin-containing monooxygenase 3 (FMO3), but this machinery deteriorates in humans and rodents under diabetic and ageing conditions. β-cell-specific deletion of FMO3 depletes intracellular TMAO, leading to senescence, inflammation, and defective glucose-stimulated insulin secretion, causing age-dependent glucose intolerance in mice. Loss of FMO3 triggers nuclear factor kappa-B (NF-κB) activation, promoting senescent and inflammatory responses. Mechanistically, TMAO binds to inhibitor of kappa B alpha (IκBα), which inhibits IκBα degradation and NF-κB nuclear translocation, thereby blocking NF-κB-mediated transcription of senescent and inflammatory programs. Replenishment of FMO3 reduces NF-κB activation and senescence in aged human islets. Our findings reveal a protective role of β-cell-derived TMAO against ageing-related β-cell dysfunction.
    DOI:  https://doi.org/10.1038/s41467-026-76075-5
  5. JCI Insight. 2026 Aug 24. pii: e208804. [Epub ahead of print]11(16):
    Mutation-resolved single-cell transcriptomics reveals enhanced β-amyloid clearance in TET2-mutant human monocytes.
    Xiao Yang, Sameen Fatima, Salvador Sampere-Birlanga, Akshay Ware, Mariana Shumliakivska, Lukas Zanders, Srisurekha Radhakrishnan, Guillermo Luxán, David John, Stefan Günther, Silvia Mas-Peiro, Stefanie Dimmeler, Andreas M Zeiher, Wesley T Abplanalp.
      TET2-driven clonal hematopoiesis has been associated with reduced Alzheimer's disease risk, but mechanisms in humans remain unclear. Using mutation-resolved single-cell transcriptomics, we distinguished TET2-mutant and wild-type monocytes within the same aged individuals and identified enrichment of phagocytosis and complement programs in mutant cells. TET2 silencing in human monocytes and macrophages recapitulated this phenotype and enhanced β-amyloid uptake, indicating mutation-specific bias of innate immunity toward aggregate clearance.
    Keywords:  Aging; Alzheimer disease; Immunology; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.208804
  6. Nat Commun. 2026 08 26. pii: 8261. [Epub ahead of print]17(1):
    Altered bone marrow niche forms central innate immune memory driving cardiac dysfunction.
    Kohsaku Goto, Yukiteru Nakayama, Junichi Sugita, Tsukasa Oshima, Kunihito Kani, Atsushi Kobayashi, Naoto Setoguchi, Yuxiang Liu, Yiyi Yang, Jiaxin Ku, Ryoko Uchida, Eriko Hasumi, Takashi Nagasawa, Issei Komuro, Norihiko Takeda, Ichiro Manabe, Katsuhito Fujiu.
      We previously showed that heart failure induces innate immune memory in hematopoietic stem and progenitor cells, which contributes to recurrence of heart failure and impaired stress responses in multiple organs. While the bone marrow microenvironment maintains blood cell formation, its role in this memory remains poorly understood. Here we show that bone marrow mesenchymal stromal cells expressing the leptin receptor influence hematopoietic stem and progenitor cells to promote cardiac pathology. Transplanting these stromal cells from mice with heart failure together with healthy hematopoietic cells caused inflammatory macrophages to accumulate in the heart and worsened cardiac remodeling. Mechanistically, heart failure reduced a stromal subpopulation producing heparin-binding epidermal growth factor and suppressed growth factor signaling in hematopoietic cells. Heart failure also activated a fat-forming program in stromal cells. Notably, an equivalent stromal subpopulation exists in human bone marrow, and heart failure was associated with increased bone marrow fat in humans, identifying the bone marrow microenvironment as a regulator of innate immune memory.
    DOI:  https://doi.org/10.1038/s41467-026-76178-z
  7. J Clin Invest. 2026 Sep 01. pii: e204023. [Epub ahead of print]
    Excessive EFHD1-dependent ER-mitochondrial contacts drive a maladaptive antiviral response in metabolic liver disease.
    David R Eberhardt, Emma C Rekate, Yasmin B Masini, Hannah E Duron, David Mollinedo, Adrian M Velarde, Devorah Stucki, Tara R Price, Sandra Hj Lee, Enrique Balderas, Neeraj K Rai, Ashley R Bratt, Anthony M Balynas, Chris J Stubben, Ryan Bia, Sudipa Maity, Nicolas Hartel, Xue Yin, Andrea Corbin, Anshu Kumari, Dung M Nguyen, Daisuke Shimura, Vu D Nguyen, Vishaka Vinod, Kamrul H Chowdhury, Francisco Verdeguer, Joel Zvick, Patrice N Mimche, Sihem Boudina, Stavros G Drakos, Ademuyiwa S Aromolaran, Sarah Franklin, Vivek Garg, Robin M Shaw, William L Holland, Scott A Summers, Marcus G Pezzolesi, Jared Rutter, Kimberley J Evason, Dipayan Chaudhuri.
      Metabolic-associated steatohepatitis (MASH) involves hepatocyte damage that cannot be explained solely by lipid accumulation. Here, to discover injury-specific pathways, we focused on a gene of uncertain function, EF-Hand Domain Family Member D1 (EFHD1), identified in human genome-wide association studies of liver injury but not liver fat. We show that EFHD1, a Ca2+-dependent actin crosslinker, stabilizes endoplasmic reticulum-mitochondria contact sites (ERMCS), detecting spatiotemporal coincidence of inter-organellar proximity and ER Ca2+ release. During MASH, EFHD1 upregulation drives pathological mitochondrial fragmentation via excessive contact persistence. This structural failure promotes mitochondrial double-stranded RNA escape and activation of a maladaptive antiviral PKR-associated stress response, a causal relationship also supported by Mendelian randomization in humans. Consequently, inhibiting EFHD1 in human and mouse models blunts hepatocyte damage. These findings identify EFHD1 as a Ca2+-dependent ERMCS stabilizer, reveal a hepatocyte-intrinsic injury pathway, and suggest EFHD1 inhibition as a therapeutic strategy.
    Keywords:  Calcium signaling; Cell biology; Cellular immune response; Hepatology; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1172/JCI204023
  8. Nat Commun. 2026 Jul 29. pii: 9181. [Epub ahead of print]17(1):
    Transcriptomic profiling of human brown and white adipose tissue depots.
    Nhuquynh Nguyen, Cheryl Cero, Adrienne R Guarnieri, Ju Hee Kim, Kelly T Long, Jurgen Heymann, Sahara L Ali, Emily V Leary, Aaron M Cypess.
      Human adipose tissues are solid organs distributed throughout the body in specific locations and are thought to have dichotomous functions: white adipose tissue stores triglycerides as an energy reservoir, and brown adipose tissue uses metabolic fuels to generate heat. To define the transcriptional profile of six principal adipose depots, we analyze tissue from 11 autopsies (3 F/8 M, 16-71 y) of patients who had different underlying diseases. Despite global similarities in terms of cell type proportions, each depot has a distinct transcriptomic signature and functional profile. Each human's adipose tissues are more similar to each other than to the anatomically and functionally matching depots in other patients. The transcriptomic pattern of subcutaneous white adipose tissue can even be used to predict the human donor. This pattern suggests that individualized factors such as genetics, age, environment, diet, and disease play impactful roles in coordinating the behavior of the whole-body adipose tissue depot.
    DOI:  https://doi.org/10.1038/s41467-026-76065-7
  9. Nat Commun. 2026 07 25. pii: 9071. [Epub ahead of print]17(1):
    ACSS2-KAT5 complex-driven histone crotonylation orchestrates a pro-inflammatory program to promote the transition from MASLD to MASH.
    Xiao Wen, Keyan Wu, Mengyao Wang, Zihan Ma, Tao Wang, Jing Zhang, Bei Wang, Siyuan Chen, Jingyi Wang, Siyue Chen, Fan Yang, Chuwei Liu, Xianyang Chen, Lu Deng, Yafan Cheng, Qing Robert Miao, Baofa Sun, Xiongzhong Ruan, Kai Li, Yajun Duan, Wenquan Hu.
      Inflammation is a pivotal driver of the progression from metabolic dysfunction-associated steatotic liver disease (MASLD) to metabolic dysfunction-associated steatohepatitis (MASH), an aggressive form associated with substantial liver-related mortality. However, the molecular mechanisms underlying the initiation and persistence of liver inflammation remain poorly defined. Here, we demonstrated a previously unrecognized role for hepatic acetyl-CoA synthetase short-chain family member 2 (ACSS2) in MASH, showing that ACSS2 upregulation in patients exacerbates MASH progression by functioning as an epigenetic regulator, independent of its canonical lipogenic role. Mechanistically, ACSS2, in complex with lysine acetyltransferase 5 (KAT5), upregulates allograft inflammatory factor-1 (AIF1) transcription via histone crotonylation, thereby inducing liver inflammation and subsequently resulting in the aberrant accumulation of senescent hepatocytes, which further enhances proinflammatory cytokine production. This ultimately initiates a vicious cycle of chronic inflammation, which directly promotes the progression from simple steatosis to MASH. Thus, our work reveals a mechanistically defined and pivotal role for ACSS2 in promoting the MASLD-to-MASH transition, highlighting its potential as a compelling therapeutic target.
    DOI:  https://doi.org/10.1038/s41467-026-75819-7
  10. Nat Methods. 2026 Aug 27.
    A multimodal, all-optical platform for linking cell identity to metabolic function in intact tissues.
      
    DOI:  https://doi.org/10.1038/s41592-026-03181-z
  11. Nat Aging. 2026 Aug 25.
    cGAS-deficient mice display premature aging associated with derepression of LINE1 elements and inflammation.
    John C Martinez, Francesco Morandini, Cheyenne Rechsteiner, Lucinda Fitzgibbons, Natasha Sieczkiewicz, Xiaoyan Liao, Weijie He, Sung Jae Bae, Michael E Meadow, Eric Hillpot, Joseph Cutting, Victoria Paige, Max Zacher, Seyed Ali Biashad, Matthew Simon, Ines Meula-Zarzuela, Mario D Cordero, Martin S Taylor, John M Sedivy, Andrei Seluanov, Vera Gorbunova.
      Aging-associated inflammation is a driver of multiple age-associated diseases. Cyclic GMP-AMP synthase (cGAS) contributes to inflammaging by responding to endogenously-derived cytoplasmic DNA in aged cells. Although cGAS-knockout (KO) mice are viable, their aging has not been characterized. Unexpectedly, we found that cGAS KO mice exhibit an accelerated-aging phenotype, with induction of inflammation in multiple organs. cGAS KO mice display shortened median lifespan and increased frailty relative to wild-type mice. They show increased transcription of long interspersed nuclear element 1 (LINE1) retrotransposons, decreased DNA methylation on LINE1 elements and high levels of cytoplasmic LINE1 complementary DNA, which triggers inflammation, and this phenotype is recapitulated by cGAS knockdown in vitro. Furthermore, cells from cGAS KO mice show a smoothed H3K9me3 chromatin landscape and increased chromatin accessibility. In summary, our results show that cGAS functions to maintain heterochromatin organization in the nucleus, independent of its cytoplasmic role as a DNA sensor or its catalytic activity, with implications for geroprotective strategies targeting this pathway.
    DOI:  https://doi.org/10.1038/s43587-026-01206-y
  12. Nat Commun. 2026 Jul 28. pii: 9205. [Epub ahead of print]17(1):
    Dynamic remodeling of the pancreas immune landscape in obesity.
    Alexey Koshkin, Kranthi Kiran Kishore Tanagala, Anna Eichinger, Michael Chait, Aoife Young, Shanila Shakil, Junichi Yoshikawa, Yosuke Sakamoto, Steven B Wells, Ladan Fazlollahi, Xiaojuan Chen, Boris Reizis, Donna L Farber, Stuart P Weisberg.
      Obesity is a known risk factor for diseases of the pancreas, including diabetes, pancreatic cancer and pancreatitis, but mechanisms remain unclear. Here we show by spatial, transcriptomic and functional profiling of human pancreatic immune cells from obese and non-obese organ donors that obesity profoundly impacts pancreatic immune homeostasis. Obesity is associated with higher density of tissue resident memory T-cells (TRM) in the exocrine pancreas which are characterized by high cytotoxic functions, and aggregate around macrophages. Single cell sequencing of pancreatic macrophages distinguishes two main subsets - FOLR2 + CD11c- foetal-derived macrophages with pro-repair and immunoregulatory function and FOLR2- CD11c+ lipid-associated macrophages with greater T-cell interactions and pro-inflammatory function. In obesity, the pancreatic macrophage landscape shifts to lower predominance of FOLR2 + CD11c- macrophages and expansion of FOLR2- CD11c+ macrophages, which interact selectively with the TRM and inflamed exocrine epithelium. Together, these results identify macrophage-T cell circuits and immune epithelial interactions that might lead to chronic pancreatic inflammation in obesity and might contribute to obesity-related pancreatic diseases.
    DOI:  https://doi.org/10.1038/s41467-026-75090-w
  13. Cell. 2026 Aug 28. pii: S0092-8674(26)00929-3. [Epub ahead of print]
    Genome-scale perturb-seq in primary human CD4+ T cells maps context-specific regulators of T cell programs and human immune traits.
    Ronghui Zhu, Emma Dann, Jun Yan, Justine Reyes Retana, Ryunosuke Goto, Reese C Guitche, Lillian Brixi, Mineto Ota, Austin Hartman, Theodore L Roth, Ansuman T Satpathy, Jonathan K Pritchard, Alexander Marson.
      Gene regulatory networks encode the fundamental logic of cellular functions, but systematic network mapping remains challenging, especially in cell states relevant to human biology and disease. Here, we perturbed all expressed genes across 22 million primary human CD4+ T cells from four donors and developed a probe-based perturb-seq platform to measure the transcriptome effects in cells at rest and after stimulation. These data allowed us to map genes regulating immune pathways, including previously uncharacterized regulators of cytokine production. Importantly, active regulators and the gene programs they control changed dramatically across stimulation conditions. Perturbation signatures enabled us to model T cell states observed in population-scale transcriptomic atlases, nominating regulators of T cell polarization and of age-related phenotypes. Finally, we leveraged perturb-seq to implicate context-specific gene regulatory pathways in autoimmune disease risk. Our study provides a foundational resource and new approaches to decode T cell function and human immune traits.
    Keywords:  CD4(+) T cell polarization; CD4(+) T cells; CRISPR; CRISPR interference; CRISPRi; T cell aging; cell fate decision; functional genomics; gene regulatory networks; human T cells; human genetics; perturb-seq; perturbation signatures; primary human cells; probe-based perturb-seq
    DOI:  https://doi.org/10.1016/j.cell.2026.08.002
  14. Nature. 2026 Aug 25.
    The brain struggles to make new neurons in people with depression.
    Mariana Lenharo.
      
    Keywords:  Brain; Depression; Neuroscience; Stem cells
    DOI:  https://doi.org/10.1038/d41586-026-02661-8
  15. Nat Med. 2026 Aug 28.
    London's clean air zone benefits child health.
    Karen O'Leary.
      
    Keywords:  Paediatrics; Policy; Public health
    DOI:  https://doi.org/10.1038/d41591-026-00043-1
  16. Nat Aging. 2026 Aug 28.
    Leaky oocytes propagate cGAS-STING signaling.
    Subhasri Biswas, Michael B Stout.
      
    DOI:  https://doi.org/10.1038/s43587-026-01153-8
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