bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–08–23
thirteen papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
  2. Living in the age of inflammation: the reverse hygiene hypothesis.
  3. A proteomic atlas of obesity and weight loss.
  4. Functional role of skull lymphoid structures in CNS immunosurveillance.
  5. GLP-1 Drugs Linked to Lower Fracture Risk in People With Type 2 Diabetes.
  6. RAD51 stabilizes neutrophil extracellular traps to compartmentalize inflammation.
  7. Multi-organ proteomic atlas of obesity regression in male mice.
  8. Dissociation of the Glucose and Lipid Regulatory Functions of FoxO1 by Targeted Knockin of Acetylation-Defective Alleles in Mice.
  9. Why adaptive immunity?
  10. Microglia activation by derepression of endogenous retroviruses drives inflammation and cellular senescence.
  11. A lipid kinase joins the transcriptional machinery.
  12. Regulatory CD8+ T lymphocytes control intestinal inflammation.
  13. Macrophages diverge into profibrotic SAMs and proresolving ReM2 cells to regulate liver fibrosis.
  1. Sci Adv. 2026 Aug 21. 12(34): eaed6318
    Mitochondrial profiling across macrophage states reveals inhibition of IL-4/IL-13 reprogramming by the integrated stress response.
    Joan Blanco-Fernandez, Miriam Lisci, Mads M Foged, Chloé Chapuis, Tim Pflästerer, Tatjana Kleele, Alexis A Jourdain.
      Mitochondria drive cellular reprogramming by integrating metabolism and signaling. In macrophages, mitochondria are central to immunometabolic responses to external cues, but the extent to which they are remodeled and participate in macrophage reprogramming remains unclear. Here, we integrate transcriptomics with whole-cell and purified mitochondrial proteomics to profile lipopolysaccharide (LPS)/interferon-γ (IFN-γ)- and interleukin-4 (IL-4)/IL-13-stimulated macrophages. We reveal a notable disconnect between mitochondrial transcript and protein levels following either stimulus and a signal transducer and activator of transcription 6 (STAT6)-dependent increase in mitochondrial DNA (mtDNA) expression and intramitochondrial translation in IL-4/IL-13 macrophages. We demonstrate that pharmacological inhibition of mitochondrial translation or individual respiratory chain complexes variably impairs reprogramming, whereas ATP synthase inhibition uniquely triggers a heme-regulated inhibitor (HRI)-dependent integrated stress response (ISR) through mitochondrial hyperpolarization, thereby preventing IL-4/IL-13 reprogramming. Mechanistically, we show that restoring mitochondrial membrane potential or inhibiting the ISR rescues IL-4/IL-13-mediated reprogramming. Together, we identify mtDNA expression, intramitochondrial translation, and mitochondrial membrane potential as critical, drug-sensitive determinants of the IL-4/IL-13 response.
    DOI:  https://doi.org/10.1126/sciadv.aed6318
  2. Nat Rev Immunol. 2026 Aug 19.
    Living in the age of inflammation: the reverse hygiene hypothesis.
    Luke A J O'Neill.
      
    DOI:  https://doi.org/10.1038/s41577-026-01349-4
  3. Nat Metab. 2026 Aug 21.
    A proteomic atlas of obesity and weight loss.
    Natasha D Suriani, Matthew J Watt.
      
    DOI:  https://doi.org/10.1038/s42255-026-01601-0
  4. Nature. 2026 Aug 19.
    Functional role of skull lymphoid structures in CNS immunosurveillance.
    Jang Hyun Park, Daviti Abramishvili, Gustavo Gastão Davanzo, Ruben Silva, Xingxing Gu, Siling Du, Daniel D Lee, Bernd H Zinselmeyer, Jackson S Turner, Gwendalyn J Randolph, Igor Smirnov, Jonathan Kipnis.
      Accumulating evidence demonstrates that the central nervous system (CNS) is not disconnected from the peripheral immune system; however, precisely how the adaptive immune system surveils the CNS remains a critical question. Recent findings reveal that channels between the skull and the dura mater facilitate the exchange of cerebrospinal fluid and immune cells between the CNS and skull bone marrow of mice under both homeostatic and disease conditions1-6. Skull bone marrow functions as a source of immune cells for the CNS5, yet its role in CNS antigen-specific adaptive immune responses remains unclear. Here we identify lymphoid structures within the skull bone marrow, featuring germinal-centre-like formations and containing a distinct population of follicular-helper-like T cells that promote B cell activation and humoral immunity through CD40L, IL-21 and IFNγ signalling. Adaptive immune cells within these skull bone marrow lymphoid structures surveil and respond to CNS-derived antigens and contribute to anti-tumour immune responses in mouse brain cancer models. Together, our findings show that the skull bone marrow is a site of CNS immunosurveillance that may influence immune responses across diverse neurological diseases.
    DOI:  https://doi.org/10.1038/s41586-026-10951-4
  5. JAMA. 2026 Aug 21.
    GLP-1 Drugs Linked to Lower Fracture Risk in People With Type 2 Diabetes.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2026.12059
  6. Science. 2026 Aug 20. 393(6813): eaed9286
    RAD51 stabilizes neutrophil extracellular traps to compartmentalize inflammation.
    Lorenza Iolanda Tsansizi, Sophie Yihan Guan, Iker Valle Aramburu, Rajvee Shah Punatar, Thomas J Williams, Yihe E Qiao, Anna Reed, Darius Armstrong-James, Stephen C West, Venizelos Papayannopoulos.
      Neutrophil extracellular traps (NETs) feature a branched chromatin architecture whose origin and function remain unknown. We found that NET branching is mediated by RAD51, a protein generating DNA junctions during DNA recombination repair. Pharmacological inhibition, RAD51 knockdown, or GEN1 and RuvC resolvase treatment reduced branching and destabilized NETs, whereas RAD51 up-regulation by different stimuli generated NETs with variable stability. RAD51 inhibition during murine pulmonary Aspergillus fumigatus infection dismantled NETs and reduced lung cytokines. However, the increased accumulation of NET components in the circulation led to interleukin-6 (IL-6) induction in circulating monocytes that exacerbated type 2 inflammation and asthma. Extracellular plasma DNA correlated with IL-6 and eotaxin in human aspergillosis. By structurally stabilizing NETs, RAD51 compartmentalizes inflammation to thwart aberrant systemic immune activation, linking DNA repair to inflammation.
    DOI:  https://doi.org/10.1126/science.aed9286
  7. Nat Metab. 2026 Aug 21.
    Multi-organ proteomic atlas of obesity regression in male mice.
    Felix Boel, Ellen Gammelmark Klinggaard, Vyacheslav Akimov, Daniel Hansen, M L Uthpala, Babukrishna Maniyadath, Flora Reincke Fuglsang, Marc Pielies Avellí, Simon Rasmussen, Kim Ravnskjær, Susanne Mandrup, Blagoy Blagoev.
      Obesity drives systemic metabolic dysfunction, yet how the body adapts and recovers at a system-wide level remains unclear. Here we generate a multi-organ proteomic atlas of diet-induced obesity and its regression in male mice. Using a standardized, semi-automated sample preparation workflow, we quantify 12,936 unique proteins across 15 organs and four timepoints. We find proteomic changes to be highly tissue-dependent, with a small number of proteins displaying shared changes across multiple tissues. While proteomes of most tissues revert to lean levels after weight loss, white adipose tissue retains strong phagocytic and inflammatory responses, and the brain, kidney, bone, thymus and spleen display delayed obesity-induced alterations. We map the adipose tissue-specific immune regulators using ligand-target inference and show reduced expression of proteasomal subunits in brown adipose tissue, resulting in stalled ubiquitin turnover. Finally, we make all datasets open access and create an interactive webtool to facilitate further community-driven discovery.
    DOI:  https://doi.org/10.1038/s42255-026-01599-5
  8. Cell Metab. 2026 Aug 20. pii: S1550-4131(26)00337-2. [Epub ahead of print]
    Dissociation of the Glucose and Lipid Regulatory Functions of FoxO1 by Targeted Knockin of Acetylation-Defective Alleles in Mice.
    Alexander S Banks, Ja Young Kim-Muller, Teresa L Mastracci, Natalie M Kofler, Li Qiang, Rebecca A Haeusler, Michael J Jurczak, Dina Laznik, Garrett Heinrich, Varman T Samuel, Gerald I Shulman, Virginia E Papaioannou, Domenico Accili.
      
    DOI:  https://doi.org/10.1016/j.cmet.2026.08.012
  9. Nat Rev Immunol. 2026 Aug 18.
    Why adaptive immunity?
    Caetano Reis E Sousa.
      
    DOI:  https://doi.org/10.1038/s41577-026-01350-x
  10. Nat Neurosci. 2026 Aug 17.
    Microglia activation by derepression of endogenous retroviruses drives inflammation and cellular senescence.
    Xin Yan, Christina Georgopoulou, Hang-Mao Lee, Ala Ahrari, Jenny Russ, Vijay Chandrasekar, Tim Ducksch, Giuliano Crispatzu, Valentina Talevi, Liang Qiao, Shobhit Agrawal, Sophie Crux, Andrew W Daman, Lena Wischhof, Miriam Stork, Margit Zweyer, Emma Dorotea Zanfi, Manon Chevallot-Beroux, Yunxiao Li, Elena De-Domenico, Dina Hüsson, Lorenzo Bonaguro, Yuanfang Li, Jonas Schulte-Schrepping, Qingyi Liang, Ketty Kessler, Dan Ehninger, Shahin Rafii, Jiankai Luo, Andreas Hermann, Annett Halle, Ying Liu, Elvira Mass, Melania Capasso, Hiroki Kato, Joachim L Schultze, Pierluigi Nicotera, Daniele Bano, Steven Zvi Josefowicz, Martin Fuhrmann, Thomas Ulas, Marc Beyer, Juntang Lin, Monique M B Breteler, N Ahmad Aziz, Paolo Salomoni.
      Aging-associated loss of chromatin compaction is linked to derepression of retrotransposable elements (RTEs) in mouse and human tissues. Whether such RTE transcription contributes to the microglia activation that is common in aged brains is unknown. Here, we show that DAXX, a histone chaperone and RTE repressor, is downregulated during aging, preserves microglia homeostasis and inhibits cellular senescence. Loss of Daxx in young-adult microglia drives a reactive phenotype marked by chromatin decompaction at RTEs, loss of homeostatic markers, cell cycle re-entry and behavioral changes. This state leads to DNA damage and microglial depletion, followed by replacement with DAXX-deficient/Apoehigh microglia displaying features of senescence. Sustained induction of senescence relies on promyelocytic leukemia protein, a DAXX-interacting factor and interferon target. Together, these findings highlight the importance of heterochromatin maintenance in preserving adult microglial identity and plasticity, with broader implications for brain homeostasis, healthy aging and behavior.
    DOI:  https://doi.org/10.1038/s41593-026-02404-y
  11. Nat Cell Biol. 2026 Aug 20.
    A lipid kinase joins the transcriptional machinery.
    Fernanda Rezende Pabst, Daphne Selvaggia Cabianca.
      
    DOI:  https://doi.org/10.1038/s41556-026-02046-z
  12. Nat Immunol. 2026 Aug 20.
    Regulatory CD8+ T lymphocytes control intestinal inflammation.
    Holm H Uhlig.
      
    DOI:  https://doi.org/10.1038/s41590-026-02627-y
  13. Proc Natl Acad Sci U S A. 2026 Aug 25. 123(34): e2611441123
    Macrophages diverge into profibrotic SAMs and proresolving ReM2 cells to regulate liver fibrosis.
    Dezhen Zhang, Xinjie Liu, Dong Ma, Lingling Liao, Fugang Duan, Yiming Wang, Tongzhen Zhang, Jiang Liu, Wei Dong, Junfei Jin, Zhenhua Luo, Haining Zhou.
      A central question in liver fibrosis is how macrophages, key regulators of inflammation and tissue repair, are divergently programmed to either promote scar formation or drive its resolution. Here, we identify a macrophage axis that governs this balance. While scar-associated macrophages (SAMs) promote fibrogenesis through cytokine-mediated activation of hepatic stellate cells, a previously uncharacterized macrophage subset, termed ReM2, orchestrates fibrosis regression. ReM2 arises from circulating monocytes following liver injury, accumulates during fibrogenesis, and peaks during the resolution phase. Mechanistically, ReM2-dependent fibrosis regression requires the expression of specific receptors, including FCGR4 and ITGA4, which may mediate this effect by enabling direct recognition and phagocytic clearance of collagen I and fibronectin from the extracellular matrix. These findings reveal a functional divergence of monocyte-derived macrophages that governs fibrosis progression vs. resolution and suggest that therapeutic rebalancing of the SAM-ReM2 axis may represent a promising strategy for treating liver fibrosis.
    Keywords:  FCGR4; ITGA4; fibrosis regression; liver fibrosis; regression-related macrophage
    DOI:  https://doi.org/10.1073/pnas.2611441123
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