bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–04–12
twenty-one papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Haem from stressed mitochondria can drive T cell exhaustion.
  2. Mitochondrial iNOS blocks itaconate production by interacting with IRG1.
  3. Kupffer cells in liver homeostasis and disease: from immune sentinels to metabolic gatekeepers.
  4. Fat bursts T cells to drive joint inflammation.
  5. Biological sex shapes divergent trajectories of immune aging.
  6. Non-necroptotic MLKL function damages mitochondria and promotes hematopoietic stem cell aging.
  7. Genetics reveal why people respond differently to GLP-1 weight-loss drugs.
  8. Single-cell analysis of the human immune system reveals sex-specific dynamics of immunosenescence.
  9. Luminal surface proteome of the brain vasculature uncovers blood-brain barrier regulators.
  10. Mapping the maternal-fetal interface through pregnancy in high resolution.
  11. Vitamin C slows primate aging by targeting iron-driven lipid peroxidation.
  12. Clotting the Gap Between Mitochondria-Mediated Immunity and Mitochondrial Transfer.
  13. The rise of spatial TCR profiling: Emerging technologies and open challenges.
  14. Microglia RANK as fertility regulators.
  15. Exposome-wide patterns predict brain health in aging.
  16. SETDB1 and HUSH modulate Xist RNA levels during establishment of X chromosome inactivation.
  17. Female mice grow testes after this single DNA tweak.
  18. Single-cell spatiotemporal dissection of the human maternal-fetal interface.
  19. Healthy Lifestyle Lowers Cardiometabolic Risk in People With Hypertension.
  20. Mechanisms of human mitochondrial leaderless mRNA translation initiation.
  21. Phage display-mediated immuno-PCR to detect low-abundance secreted proteins in Drosophila.
  1. Nat Rev Immunol. 2026 Apr 07.
    Haem from stressed mitochondria can drive T cell exhaustion.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-026-01301-6
  2. Nat Metab. 2026 Apr 10.
    Mitochondrial iNOS blocks itaconate production by interacting with IRG1.
    Tomas Paulenda, Maxim N Artyomov.
      
    DOI:  https://doi.org/10.1038/s42255-026-01493-0
  3. Nat Rev Immunol. 2026 Apr 08.
    Kupffer cells in liver homeostasis and disease: from immune sentinels to metabolic gatekeepers.
    Bruna Araujo David, Francesco Andreata, Camille Blériot, Florent Ginhoux, Paul Kubes, Matteo Iannacone.
      The liver, a key metabolic organ, has a central role in maintaining systemic homeostasis but is vulnerable to numerous diseases. Its metabolic functions are mainly carried out by hepatocytes; however, the liver also harbours diverse non-parenchymal cell populations, including immune cells. Among these, Kupffer cells, the resident macrophages of the liver, are critical modulators of liver function and immunity. Emerging research highlights their dynamic roles throughout life, from maintaining tissue homeostasis to shaping the balance between immune tolerance and activation in adulthood. Kupffer cells are located in liver sinusoids, where they act as frontline defenders, clearing pathogens and cellular debris from the circulation. Beyond their established phagocytic and immune regulatory functions, Kupffer cells influence metabolic processes, tissue repair and oncogenesis. Moreover, they shape the response of the liver to metabolic disorders such as metabolic dysfunction-associated steatohepatitis, infections and malignancies, including hepatocellular carcinoma. Here we explore Kupffer cell biology, focusing on the development, heterogeneity and multifaceted roles of these cells in liver health and disease. We further discuss how advances in imaging, transcriptomics and macrophage-targeted therapies can inform future strategies to combat liver-associated health challenges.
    DOI:  https://doi.org/10.1038/s41577-026-01288-0
  4. Cell Metab. 2026 Apr 07. pii: S1550-4131(26)00050-1. [Epub ahead of print]38(4): 641-642
    Fat bursts T cells to drive joint inflammation.
    Wei Li, George C Tsokos.
      Chronic autoimmune inflammation is increasingly understood to be shaped by the tissue metabolic environment. Weyand and colleagues show that lipid-rich tissues trigger lipid droplet-dependent, gasdermin D-mediated pyroptosis in metabolically exhausted CD4+ T cells, thereby sustaining inflammatory pathology.
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.007
  5. Nat Aging. 2026 Apr 10.
    Biological sex shapes divergent trajectories of immune aging.
      
    DOI:  https://doi.org/10.1038/s43587-026-01110-5
  6. Nat Commun. 2026 Apr 06. pii: 2798. [Epub ahead of print]17(1):
    Non-necroptotic MLKL function damages mitochondria and promotes hematopoietic stem cell aging.
    Yuta Yamada, Jinjing Yang, Akiho Saiki-Tsuchiya, Yuji Watanabe, Shuhei Koide, Shin Murai, Yuriko Sorimachi, Yu Fukuda, Kenta Sumiyama, Hiroshi Sagara, Hiroyasu Nakano, Keiyo Takubo, Atsushi Iwama, Masayuki Yamashita.
      Hematopoietic stem cells (HSCs) survive many types of cellular stress but often lose their regenerative and lymphopoietic capacities as a result. Such functional decline also occurs with age, and dysfunctional HSCs with impaired mitochondria accumulate during aging. However, the molecular link between HSC stress response and age-related functional decline remains poorly understood. Here we show that multiple stress responses converge on the RIPK3-MLKL axis to induce age-related changes in HSCs. The necroptosis effector MLKL is readily activated by inflammation and replication stress and accumulates in HSC mitochondria. Consequently, activated MLKL does not cause cell death but impairs HSC self-renewal and lymphoid differentiation. Such MLKL-mediated functional decline also occurs in HSCs during organismal aging, with activated MLKL primarily mediating age-related mitochondrial damage and reduced glycolytic flux. Collectively, our results establish the RIPK3-MLKL axis as a key mediator of HSC aging and identify a necroptosis-independent role of MLKL in mitochondrial damage.
    DOI:  https://doi.org/10.1038/s41467-026-71060-4
  7. Nature. 2026 Apr 08.
    Genetics reveal why people respond differently to GLP-1 weight-loss drugs.
    Ruth J F Loos.
      
    Keywords:  Genetics; Genomics; Obesity
    DOI:  https://doi.org/10.1038/d41586-026-00905-1
  8. Nat Aging. 2026 Apr 10.
    Single-cell analysis of the human immune system reveals sex-specific dynamics of immunosenescence.
    Maria Sopena-Rios, Aida Ripoll-Cladellas, Fatemeh Omidi, Sara Ballouz, Jose Alquicira-Hernandez, Roy Oelen, Alex W Hewitt, Lude Franke, Monique G P van der Wijst, Joseph E Powell, Marta Melé.
      Immunosenescence, the progressive aging of the immune system, is characterized by changes in immune cell composition and function that increase susceptibility to disease. However, how biological sex shapes immune aging at the cellular level remains poorly understood. Here, we analyze single-cell RNA sequencing data from the peripheral blood mononuclear cells of 982 female and male donors across adulthood. We find that aging drives sexually dimorphic compositional and transcriptional changes, with female individuals exhibiting stronger immune remodeling. Female-specific changes include the expansion of cytotoxic CD8⁺ effector memory T cell subsets and inflammatory monocytes, and age-related shifts in the CD4⁺ central memory T cell populations involved in autoimmunity. In contrast, a subset of male participants shows an age-associated expansion of a B cell population linked to an asymptomatic precursor state of chronic lymphocytic leukemia. Together, these findings reveal sex-specific hallmarks of immunosenescence and highlight the importance of incorporating biological sex into strategies aimed at promoting healthy immune aging.
    DOI:  https://doi.org/10.1038/s43587-026-01099-x
  9. Science. 2026 Apr 09. 392(6794): eaea2100
    Luminal surface proteome of the brain vasculature uncovers blood-brain barrier regulators.
    Zijian Zhu, Zuzhi Jiang, Yupu Wang, Khanh Nguyen, Yuxiang Zhang, Cameron Genxuan Lian, D R Mani, Jun Zheng, Lang Ding, Shihong Max Gao, Ruyue Alps Xia, Anne Kuszpit, Sarah Lindo, Crystall Lopez, Catherine Lindsey, Brooke Groff, Xinhong Chen, Jiahui Wu, Weiliang Xia, Wei Li, Xiaorong Liu, Viviana Gradinaru, Steven A Carr, Namrata D Udeshi, Jiefu Li.
      At the blood-tissue interface, vasculature luminal surface is critical for molecular transport, signaling transduction, and cell extravasation. Here, we present a method for proteomic profiling of the vasculature luminal surface in vivo, broadly applicable to any vertebrate. Quantitative mass spectrometry revealed the luminal surface proteome of the mouse brain vasculature and its temporal evolution from development to aging. In vivo genetic perturbation found that the arginine transporter SLC7A1 and the nitric oxide synthase NOS3 are needed for blood-brain barrier integrity in neonatal but not adult mice, whereas the hyaluronan degradation enzyme HYAL2 safeguards the barrier throughout the lifespan. By characterizing the proteomic dynamics of the vasculature luminal surface, the study links the metabolism of nitric oxide and hyaluronan to blood-brain barrier integrity.
    DOI:  https://doi.org/10.1126/science.aea2100
  10. Nature. 2026 Apr 08.
    Mapping the maternal-fetal interface through pregnancy in high resolution.
      
    Keywords:  Databases; Developmental biology; Transcriptomics
    DOI:  https://doi.org/10.1038/d41586-026-01037-2
  11. Cell Metab. 2026 Apr 07. pii: S1550-4131(26)00054-9. [Epub ahead of print]38(4): 635-637
    Vitamin C slows primate aging by targeting iron-driven lipid peroxidation.
    Pei-Long Yu, Cheng-Ran Xu.
      Aging has long been associated with oxidative stress, yet its underlying metabolic drivers remain unclear. Liu et al. identify a conserved, iron-driven lipid peroxidation of primate aging mediated by ACSL4 and demonstrate that vitamin C directly suppresses this process, offering a translatable strategy to mitigate age-associated functional decline.
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.011
  12. Circ Res. 2026 Apr 10. 138(8): e326987
    Clotting the Gap Between Mitochondria-Mediated Immunity and Mitochondrial Transfer.
    Florian Tupin, Jorge A Gonzalez-Chapa, Jay H Chung, Christian Lood, Eric Boilard.
      Mitochondria are organelles that orchestrate numerous cell functions in addition to providing energy. During viral infection or in case of defects in mitochondrial replication, an intricate mechanism of self-destruction is engaged through the formation of mitochondrial pores. This leads to the release of mitochondrial DNA into the cytoplasm, where it triggers innate immune responses. Platelets constitute the principal source of circulating mitochondria, and increasing evidence demonstrates that they actively release mitochondria, some of which are enclosed within extracellular vesicles. This process is enhanced in autoimmune conditions, occurs in platelet storage, and has been linked to adverse reactions after platelet transfusion. Extracellular mitochondria act as carriers of damage-associated molecular patterns and are targets of antibodies in various pathologies, including antiphospholipid syndrome and cardiomyopathies. Moreover, elevated levels of antimitochondria antibodies have also been associated with increased mortality and cardiovascular risk in systemic lupus erythematosus. Mitochondrial transplantation, a process by which defective mitochondria in a tissue or organ may be replaced by healthy mitochondria, is receiving growing therapeutic interest. Thus, understanding how extracellular mitochondria interact with the immune system is increasingly important. This review summarizes current knowledge on the multifaceted roles of mitochondria in immunity, with a particular focus on platelets and platelet-derived mitochondria as a key biological context.
    Keywords:  DNA, mitochondrial; autoantibodies; immunity, adaptive; immunity, innate; mitochondria
    DOI:  https://doi.org/10.1161/CIRCRESAHA.125.326987
  13. Sci Immunol. 2026 Apr 10. 11(118): eaeg7517
    The rise of spatial TCR profiling: Emerging technologies and open challenges.
    Yinglu Tang, Tao Wang.
      High-definition spatial TCR profiling illuminates how clonal identity and T cell state are coordinated in the tumor microenvironment (see related Research Article by McCord et al.).
    DOI:  https://doi.org/10.1126/sciimmunol.aeg7517
  14. Nat Neurosci. 2026 Apr;29(4): 772
    Microglia RANK as fertility regulators.
    Ioana A Marin.
      
    DOI:  https://doi.org/10.1038/s41593-026-02274-4
  15. Nat Commun. 2026 Apr 10. pii: 3409. [Epub ahead of print]17(1):
    Exposome-wide patterns predict brain health in aging.
    Mostafa Mahdipour, Somayeh Maleki Balajoo, Federico Raimondo, Jianxiao Wu, Eliana Nicolaisen-Sobesky, Shammi More, Felix Hoffstaedter, Holger Schwender, Masoud Tahmasian, Simon B Eickhoff, Sarah Genon.
      Promoting brain health is vital for well-being and reducing healthcare burdens. Brain health as measured with the Brain Age Gap (BAG) - the difference between chronological and predicted brain age- relates to many factors. However, a holistic view, integrating the range of factors an individual brain is exposed to, is missing for understanding how the exposome shapes brain health. After computing BAG as an indicator of grey matter (GM) health, we predicted it using machine learning based on 261 exposome variables (spanning biomedical, environmental, lifestyle, socio-affective, and early life domains) in UK Biobank participants. Exposome data can predict GM health with factors pertaining to cardiovascular and bone health, along with alcohol and smoking, nutrition and diabetes showing greater contribution to the prediction. In such domains, life period and duration of exposure appeared crucial. These findings call for early prevention in cardiovascular and metabolic health to promote life-long brain health.
    DOI:  https://doi.org/10.1038/s41467-026-71271-9
  16. Nat Commun. 2026 Apr 09.
    SETDB1 and HUSH modulate Xist RNA levels during establishment of X chromosome inactivation.
    Mafalda Almeida, Guifeng Wei, Adam D Cawte, Tatyana B Nesterova, Neil Brockdorff.
      The non-coding RNA Xist mediates X chromosome inactivation (XCI) in mammals, functioning in cis to direct heterochromatin formation over a single X chromosome in cells of early female embryos. Prior studies have determined that Xist transcription and turnover are modulated to maintain the correct level of Xist RNA to inactivate a single X chromosome. The underlying molecular mechanisms are poorly understood. In this study we demonstrate that RNA-dependent recruitment of the H3K9me3 methyltransferase SETDB1 and the HUSH complex across the transcribed Xist locus functions to suppress Xist transcription during establishment of XCI. Thus, degron-mediated acute depletion of SETDB1 or core HUSH subunits abrogates allelic H3K9me3 deposition, increasing Xist transcription, accumulation of Xist RNA, and the rate of X-linked gene silencing. Our findings support a model in which the SETDB1/HUSH pathway coordinates Xist transcription rates to maintain optimal Xist RNA levels, ensuring the silencing of a single X chromosome.
    DOI:  https://doi.org/10.1038/s41467-026-71569-8
  17. Nature. 2026 Apr 09.
    Female mice grow testes after this single DNA tweak.
    Rachel Fieldhouse.
      
    Keywords:  Genetics; Genomics
    DOI:  https://doi.org/10.1038/d41586-026-01120-8
  18. Nature. 2026 Apr 08.
    Single-cell spatiotemporal dissection of the human maternal-fetal interface.
    Cheng Wang, Yan Zhou, Yuejun Wang, Tuhin Kumar Guha, Zhida Luo, Anxhela Mustafaraj, Tara I McIntyre, Marisa E Schwab, Brittany R Davidson, Gabriella C Reeder, Ronald J Wong, Sarah K England, Juan M Gonzalez, Robert Blelloch, Alexis J Combes, Linda C Giudice, Adrian Erlebacher, Tippi C MacKenzie, David K Stevenson, Gary M Shaw, Michael P Snyder, Xiaofei Sun, Virginia D Winn, Susan J Fisher, Jingjing Li.
      The human maternal-fetal interface is characterized by mosaic intermingling of maternal and fetal cells1. Yet the underlying cellular, molecular and spatial programmes remain incompletely defined. Here we generate a comprehensive atlas of the human maternal-fetal interface across normal pregnancies from early gestation to term by integrating large-scale paired single-nucleus transcriptomic and chromatin accessibility profiling with submicrometre-resolution spatial transcriptomics and CODEX multiplex protein imaging2, substantially boosting the spatiotemporal resolution of prior research3. This framework delineates common and transient cell types, states and spatial niches across the fetal and maternal compartments, reconstructs transcriptional programmes that guide cytotrophoblast and decidual stromal cell differentiation, and resolves recurrent architecture structural units that build this interface. We identify previously unrecognized arterial endothelial state transitions during cytotrophoblast-mediated spiral artery remodelling and develop a machine learning model that predicts cytotrophoblast invasiveness from transcriptomic signatures. We further discover a decidual stromal cell subtype that suppresses cytotrophoblast invasion via endocannabinoid signalling at the human maternal-fetal interface. By integrating the atlas with genome-wide association data, we pinpoint maternal and fetal cells that are most vulnerable to pre-eclampsia, preterm birth or miscarriage. This resource provides a comprehensive spatially resolved single-cell multiomic reference of the human placenta and decidua and offers a framework for decoding their normal and disordered development.
    DOI:  https://doi.org/10.1038/s41586-026-10316-x
  19. JAMA. 2026 Apr 10.
    Healthy Lifestyle Lowers Cardiometabolic Risk in People With Hypertension.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2026.2110
  20. Nat Commun. 2026 Apr 04.
    Mechanisms of human mitochondrial leaderless mRNA translation initiation.
    Shuangjie Shen, Yinghua Xu, Daniel L Kober, Jinfan Wang.
      Mitochondrial translation is essential for cellular function, and its dysregulation is associated with mitochondrial disorders and cancer. However, the mechanisms by which human mitochondrial ribosomes initiate translation remain poorly understood, particularly because mitochondrial mRNAs generally lack the 5' untranslated regions that guide translation initiation in bacterial and cytoplasmic systems. Using real-time single-molecule fluorescence measurements, biochemical assays, and cryo-EM analysis, we show that human mitochondrial translation initiation occurs through two parallel pathways. In one pathway, leaderless mRNA first loads onto the 28S small subunit, followed by recruitment of the 39S large subunit to form the 55S initiation complex. In the second pathway, a preassembled 55S monosome directly loads onto leaderless mRNA. Both pathways require recruitment of mtIF2 and fMet-tRNAMet before mRNA binding. However, the monosome-loading pathway tolerates non-formylated Met-tRNAMet and is suppressed by mtIF3. Together, these findings define the heterogeneous pathways of human mitochondrial translation initiation on leaderless mRNAs.
    DOI:  https://doi.org/10.1038/s41467-026-71535-4
  21. Proc Natl Acad Sci U S A. 2026 Apr 14. 123(15): e2531777123
    Phage display-mediated immuno-PCR to detect low-abundance secreted proteins in Drosophila.
    Myeonghoon Han, Baolong Xia, Ah-Ram Kim, Elizabeth Filine, Emily Stoneburner, Ting Miao, Ying Liu, Jonathan Zirin, Norbert Perrimon.
      Circulating hormones, that mediate communications across organs to maintain physiological balance, are commonly detected and quantified using enzyme-linked immunosorbent assays (ELISAs). However, while ELISA is well suited for organisms where sample blood can be readily obtained, its application is considerably more challenging in smaller organisms, particularly Drosophila, which has gained widespread use in recent years for physiological studies. Here, we present sensitive phage display-mediated immuno-PCR (PD-iPCR) to detect Drosophila hemolymph proteins via two approaches: 1) by identifying high-affinity nanobodies through phage display library screening and subsequent affinity maturation and 2) by generating a knock-in fly line producing secreted proteins tagged with tandem NanoTags composed of VHH05 and 127D01. Using these approaches, we successfully established PD-iPCR to detect insulin-binding ImpL2 protein in fly hemolymph. Notably, the tandem NanoTag-based sandwich PD-iPCR enabled highly sensitive detection of tagged antigens, allowing us to quantify elevated ImpL2 levels in the hemolymph of starved flies and those bearing Yki-induced gut tumors. Collectively, our results demonstrate that PD-iPCR enables detection of endogenous, low-abundance circulating hormones in Drosophila, providing a powerful tool for studying interorgan communication.
    Keywords:  gene-editing; hormone; immuno-PCR; inter-organ communications; nanobody screen
    DOI:  https://doi.org/10.1073/pnas.2531777123
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