bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–08–17
24 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Obesity-associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating mitochondrial fragmentation.
  2. Circadian circuits control plasticity of group 3 innate lymphoid cells by sustaining epigenetic configuration of RORγt.
  3. Genetic architecture of bone marrow fat fraction implies its involvement in osteoporosis risk.
  4. TNF and type I interferon crosstalk controls the fate and function of plasmacytoid dendritic cells.
  5. Platelets sequester extracellular DNA, capturing tumor-derived and free fetal DNA.
  6. The liver metabolizes dietary galactose to fuel antitumour T cell immunity.
  7. Dysregulation of GTPase-activating protein-binding protein1 in the pathogenesis of metabolic dysfunction-associated steatotic liver disease.
  8. Dual-targeted siRubicon delivery strategy triggers hepatocellular lipophagy for mitigating liver steatosis.
  9. How Paris dealt with lightning in the Age of Enlightenment.
  10. Cross-species analysis of adult hippocampal neurogenesis reveals human-specific gene expression but convergent biological processes.
  11. T cells fast-track gut signals to the brain.
  12. Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy.
  13. No STINGs attached: How APOE-Christchurch dampens Alzheimer's pathology.
  14. Clock genes tune plasticity of group 3 innate lymphoid cells.
  15. Glucose-dependent insulinotropic polypeptide receptor signaling in oligodendrocytes increases the weight-loss action of GLP-1R agonism.
  16. MacroD1 sustains mitochondrial integrity and oxidative metabolism.
  17. Metabolic regulation of immunological aging.
  18. Fbxo42 promotes the degradation of Ataxin-2 granules to trigger terminal Xbp1 signaling.
  19. A reconceptualized framework for human microbiome transmission in early life.
  20. European and African ancestry-specific plasma protein-QTL and metabolite-QTL analyses identify ancestry-specific T2D effector proteins and metabolites.
  21. A continuously oxygenated macroencapsulation system enables high-density packing and delivery of insulin-secreting cells.
  22. Breast cancer induces CD62L+ Kupffer cells via DMBT1 to promote neutrophil extracellular trap formation and liver metastasis.
  23. Astrocyte priming enhances microglial Aβ clearance and is compromised by APOE4.
  24. Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age.
  1. Nat Commun. 2025 Aug 14. 16(1): 7564
    Obesity-associated macrophages dictate adipose stem cell ferroptosis and visceral fat dysfunction by propagating mitochondrial fragmentation.
    Yan Tao, Jinhao Zang, Tianci Wang, Peixuan Song, Zixin Zhou, Huijie Li, Yalin Wang, Yiyang Liu, Haipeng Jie, Mei Kuang, Hui Zhao, Fuwu Wang, Shen Dai, Chun Guo, Faliang Zhu, Haiting Mao, Fengming Liu, Lining Zhang, Qun Wang.
      Morbid obesity induces adipose stem cell (ASC) shortage that impairs visceral adipose tissue (VAT) homeostasis. Macrophages cooperate with ASCs to regulate VAT metabolism, their impact on ASC shortage remains elusive. TNF-α-induced protein 8-like 2 (TIPE2) is an important regulator in immune cells, its expression in VAT macrophages and function in macrophage-ASC crosstalk are largely unknown. Here, TIPE2 loss in VAT macrophages promotes ASC ferroptosis to aggravate diet-induced obesity and metabolic disorders in male mice, which can be corrected by macrophage-specific TIPE2 restoration in VAT. Mechanistically, TIPE2-deficient macrophages propagate mitochondrial fragmentation and reduce delivery of exosomal ferritin toward ASCs, resulting in mitochondrial ROS and Fe2+ overload that dictates ASC ferroptosis. TIPE2 interacts with IP3R to constrain IP3R-Ca2+-Drp1 axis, thereby preventing excessive mitochondrial fission and enabling macrophages to protect against ASC ferroptosis. This study reveals distinct obesity-associated macrophages that dictate ASC ferroptosis, and proposes macrophage TIPE2 as therapeutic target for obesity-related diseases.
    DOI:  https://doi.org/10.1038/s41467-025-62690-1
  2. Nat Immunol. 2025 Aug 13.
    Circadian circuits control plasticity of group 3 innate lymphoid cells by sustaining epigenetic configuration of RORγt.
    Bishan Bhattarai, Alina Ulezko Antonova, Jose L Fachi, Leone S Hopkins, Matthew V D McCullen, Ankita Saini, Sarah de Oliveira, Wandy L Beatty, Erik S Musiek, Vijay K Kuchroo, Mitchell A Lazar, Eugene M Oltz, Marco Colonna.
      The gut experiences daily fluctuations in microbes and nutrients aligned with circadian rhythms that regulate nutrient absorption and immune function. Group 3 innate lymphoid cells (ILC3s) support gut homeostasis through interleukin-22 (IL-22) but can convert into interferon-γ-producing ILC1s. How circadian proteins control this plasticity remains unclear. Here we showed that the circadian proteins REV-ERBα and REV-ERBβ maintain ILC3 identity. Their combined deletion promoted ILC3-to-ILC1 conversion, reduced energy metabolism and IL-22 production, increased interferon-γ production, and heightened susceptibility to Citrobacter rodentium infection. Single-cell multiomics and gene editing revealed that REV-ERBα/REV-ERBβ deficiency upregulated the transcription factor NFIL3, which repressed the expression of RORγt via a -2-kb cis-regulatory element in the Rorc gene, shifting cells toward a T-bet-driven state. Chromatin and metabolic analyses indicated that REV-ERBα/REV-ERBβ loss reprogrammed regulatory and metabolic circuits. Thus, REV-ERBα/REV-ERBβ safeguard gut integrity by regulating clock genes that control RORγt expression and preserve ILC3 identity and resistance to intestinal inflammation.
    DOI:  https://doi.org/10.1038/s41590-025-02240-5
  3. Nat Commun. 2025 Aug 12. 16(1): 7490
    Genetic architecture of bone marrow fat fraction implies its involvement in osteoporosis risk.
    Zuyou Wu, Yang Yang, Caibo Ning, Jiali Li, Yimin Cai, Yanmin Li, Zilong Cao, Shuangshuang Tian, Jingyi Peng, Qianying Ma, Chunyi He, Shuting Xia, Jun Chen, Xiaoping Miao, Zhen Li, Ying Zhu, Qian Chu, Jianbo Tian.
      Bone marrow adipose tissue, as a distinct adipose subtype, has been implicated in the pathophysiology of skeletal, metabolic, and hematopoietic disorders. To identify its underlying genetic factors, we utilized a deep learning algorithm capable of quantifying bone marrow fat fraction (BMFF) in the vertebrae and proximal femur using magnetic resonance imaging data of over 38,000 UK Biobank participants. Genome-wide association analyses uncovered 373 significant BMFF-associated variants (P-value < 5 × 10-9), with enrichment in bone remodeling, metabolism, and hematopoiesis pathway. Furthermore, genetic correlation highlighted a significant association between BMFF and skeletal disease. In about 300,000 individuals, polygenic risk scores derived from three proximal femur BMFF were significantly associated with increased osteoporosis risk. Notably, Mendelian randomization analyses revealed a causal link between proximal femur BMFF and osteoporosis. Here, we show critical insights into the genetic determinants of BMFF and offer perspectives on the biological mechanisms driving osteoporosis development.
    DOI:  https://doi.org/10.1038/s41467-025-62826-3
  4. Nat Immunol. 2025 Aug 12.
    TNF and type I interferon crosstalk controls the fate and function of plasmacytoid dendritic cells.
    Rebeca Arroyo Hornero, Raul A Maqueda-Alfaro, Miguel A Solís-Barbosa, Rebecca A Leylek, Olin Medina Chavez, Olivia M Martinez, Andres Gottfried-Blackmore, Juliana Idoyaga.
      Plasmacytoid dendritic cells (pDCs) are major producers of type I interferon (IFN-I), an important antiviral cytokine, and activity of these cells must be tightly controlled to prevent harmful inflammation and autoimmunity. Evidence exists that one regulatory mechanism is a fate-switching process from an IFN-I-secreting pDC to a professional antigen-presenting conventional dendritic cell (cDC) that lacks IFN-I-secreting capacity. However, this differentiation process is controversial owing to limitations in tracking the fate of individual cells over time. Here we use single-cell omics and functional experiments to show that activated human pDCs can lose their identity as IFN-I-secreting cells and acquire the transcriptional, epigenetic and functional features of cDCs. This pDC fate-switching process is promoted by tumor necrosis factor but blocked by IFN-I. Importantly, it occurs in vivo during human skin inflammatory diseases and injury, and physiologically in elderly people. This work identifies the pDC-to-cDC reprogramming trajectory and unveils a mechanistic framework for harnessing it therapeutically.
    DOI:  https://doi.org/10.1038/s41590-025-02234-3
  5. Science. 2025 Aug 14. 389(6761): eadp3971
    Platelets sequester extracellular DNA, capturing tumor-derived and free fetal DNA.
    Lauren Murphy, Jeanne Inchauspé, Giampiero Valenzano, Pamela Holland, Nikolaos Sousos, Hayley L Belnoue-Davis, Rong Li, Natalie J Jooss, Camelia Benlabiod, Eleanor Murphy, Zohar Etzioni, Emelie Shepherd, Lucy Denly, Sujata Biswas, Lin Chen, Jennifer O'Sullivan, Michael P Rimmer, Abdullah O Khan, Christina Simoglou Karali, Nadia Nasreddin, Ian S Hitchcock, Milka Koupenova, Skirmantas Kriaucionis, Jim R Hughes, Eric O'Neill, Manu Vatish, Paul Rees, Simon Leedham, Michael Desborough, Adam J Mead, Benjamin Schuster-Böckler, Christopher D Gregory, Bethan Psaila.
      Platelets are anucleate blood cells vital for hemostasis and immunity. During cell death and aberrant mitosis, nucleated cells release DNA, resulting in "cell-free" DNA in plasma (cfDNA). An excess of cfDNA is deleterious. Given their ability to internalize pathogen-derived nucleic acids, we hypothesized that platelets may also clear endogenous cfDNA. We found that, despite lacking a nucleus, platelets contained a repertoire of DNA fragments mapping across the nuclear genome. We detected fetal DNA in maternal platelets and cancer-derived DNA in platelets from patients with premalignant and cancerous lesions. As current liquid biopsy approaches utilize platelet-depleted plasma, important genetic information contained within platelets is being missed. This study establishes a physiological role for platelets that has not previously been highlighted, with broad translational relevance.
    DOI:  https://doi.org/10.1126/science.adp3971
  6. Nat Cell Biol. 2025 Aug;27(8): 1208-1209
    The liver metabolizes dietary galactose to fuel antitumour T cell immunity.
      
    DOI:  https://doi.org/10.1038/s41556-025-01717-7
  7. Nat Commun. 2025 Aug 14. 16(1): 7570
    Dysregulation of GTPase-activating protein-binding protein1 in the pathogenesis of metabolic dysfunction-associated steatotic liver disease.
    Qinqin Ouyang, Jiaqi Su, Yixuan Li, Haiping Liao, Haiying Guo, Yanan Sun, Xiaoyu Wang, Juan Chen, Josephine Thinwa, Wen-Xing Ding, Herbert Tilg, Fazheng Ren, Hao Zhang, Rong Liu.
      Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are two common liver disorders characterized by abnormal lipid accumulation. Our study found reduced levels of GTPase-activating protein-binding protein1 (G3BP1) in patients with MASLD and MASH, suggesting its involvement in these liver disorders. Hepatocyte-specific G3BP1 knockout (G3BP1 HKO) male mice had more severe MASLD and MASH than their corresponding controls. Intriguingly, the G3BP1 HKO MASLD model male mice exhibit dysregulated autophagy, and biochemical analyses demonstrated that G3BP1 promotes autophagosome-lysosome fusion through direct interactions with the SNARE proteins STX17 and VAMP8. We also show that hepatic knockout of G3BP1 promotes de novo lipogenesis, and ultimately found that G3BP1 is required for the nuclear translocation of the well-known liver-lipid-regulating transcription factor TFE3. Taken together, our results suggest that G3BP1 should be investigated as a potential target for developing medical interventions to treat MASLD and MASH.
    DOI:  https://doi.org/10.1038/s41467-025-63022-z
  8. Nat Commun. 2025 Aug 12. 16(1): 7455
    Dual-targeted siRubicon delivery strategy triggers hepatocellular lipophagy for mitigating liver steatosis.
    Tingting Lan, Qiushi Li, Mingxing Yu, Xu Duan, Tao Ming, Shuo Li, Chunjiong Wang, Yi Zhu, Zhongyang Shen, Deling Kong, Yang Liu.
      Metabolic dysfunction-associated steatotic liver disease is marked by fat accumulation and inflammation, partly due to impaired lipophagy-a cellular process in which lipid droplets are broken down through autophagy. Rubicon, a protein that inhibits this process, worsens the condition by blocking fat breakdown. Small interfering RNA molecules targeting Rubicon show therapeutic potential but face challenges such as instability and off-target effects. Here we show a dual-targeted nanoparticle system designed for efficient delivery of Rubicon-targeting small interfering RNA to liver cells. This system has a core-shell structure that ensures stability in the bloodstream and responsiveness to oxidative stress, commonly found in metabolic dysfunction-associated steatotic liver disease. Once inside the liver cells, the nanoparticles release the RNA molecules, which reduce Rubicon levels, restore lipophagy, and alleviate fatty liver buildup. This strategy offers a flexible platform for targeted gene silencing therapy in liver diseases.
    DOI:  https://doi.org/10.1038/s41467-025-61965-x
  9. Nature. 2025 Aug 12.
    How Paris dealt with lightning in the Age of Enlightenment.
      
    Keywords:  Cell biology; Engineering; History
    DOI:  https://doi.org/10.1038/d41586-025-02429-6
  10. Nat Neurosci. 2025 Aug 11.
    Cross-species analysis of adult hippocampal neurogenesis reveals human-specific gene expression but convergent biological processes.
    Yi Zhou, Yijing Su, Qian Yang, Jiaqi Li, Yan Hong, Taosha Gao, Yanqing Zhong, Xueting Ma, Mengmeng Jin, Xinglan Liu, Nini Yuan, Benjamin C Kennedy, Lizhou Wang, Longying Yan, Angela N Viaene, Ingo Helbig, Sudha K Kessler, Joel E Kleinman, Thomas M Hyde, David W Nauen, Cirong Liu, Zhen Liu, Zhiming Shen, Chao Li, Shengjin Xu, Jie He, Daniel R Weinberger, Guo-Li Ming, Hongjun Song.
      Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity, learning and memory, but their evolutionary changes across species and specialized features in humans remain poorly understood. Here we performed machine-learning-augmented analysis of published single-nucleus RNA-sequencing datasets and identified macaque imGCs with transcriptome-wide immature neuronal characteristics. Our cross-species comparisons among humans, monkeys, pigs and mice showed few shared (such as DPYSL5), but mostly species-specific gene expression in imGCs that converged onto common biological processes regulating neuronal development. We further identified human-specific transcriptomic features of imGCs and demonstrated the functional roles of human imGC-enriched expression of a family of proton-transporting vacuolar-type ATPase subtypes in the development of imGCs derived from human pluripotent stem cells. Our study reveals divergent gene expression patterns but convergent biological processes in the molecular characteristics of imGCs across species, highlighting the importance of conducting independent molecular and functional analyses for adult neurogenesis in different species.
    DOI:  https://doi.org/10.1038/s41593-025-02027-9
  11. Nat Immunol. 2025 Aug 11.
    T cells fast-track gut signals to the brain.
    Emanuela Pasciuto, Adrian Liston.
      
    DOI:  https://doi.org/10.1038/s41590-025-02237-0
  12. Nat Commun. 2025 Aug 09. 16(1): 7367
    Mitochondrial damage triggers the concerted degradation of negative regulators of neuronal autophagy.
    Bishal Basak, Erika L F Holzbaur.
      Mutations that disrupt the clearance of damaged mitochondria via mitophagy are causative for neurological disorders including Parkinson's. Here, we identify a Mitophagic Stress Response (MitoSR) activated by mitochondrial damage in neurons and operating in parallel to canonical Pink1/Parkin-dependent mitophagy. Increasing levels of mitochondrial stress trigger a graded response that induces the concerted degradation of negative regulators of autophagy including Myotubularin-related phosphatase (MTMR)5, MTMR2 and Rubicon via the ubiquitin-proteasome pathway and selective proteolysis. MTMR5/MTMR2 inhibit autophagosome biogenesis; consistent with this, mitochondrial engulfment by autophagosomes is enhanced upon MTMR2 depletion. Rubicon inhibits lysosomal function, blocking later steps of neuronal autophagy; Rubicon depletion relieves this inhibition. Targeted depletion of both MTMR2 and Rubicon is sufficient to enhance mitophagy, promoting autophagosome biogenesis and facilitating mitophagosome-lysosome fusion. Together, these findings suggest that therapeutic activation of MitoSR to induce the selective degradation of negative regulators of autophagy may enhance mitochondrial quality control in stressed neurons.
    DOI:  https://doi.org/10.1038/s41467-025-62379-5
  13. Immunity. 2025 Aug 12. pii: S1074-7613(25)00328-0. [Epub ahead of print]58(8): 1880-1882
    No STINGs attached: How APOE-Christchurch dampens Alzheimer's pathology.
    Leyla Anne Akay, Li-Huei Tsai.
      The "Christchurch" protective variant in the APOE gene has recently been identified, but its mechanisms of action remain unknown. In this issue of Immunity, Naguib and Lopez-Lee et al. provide evidence for the APOE-Christchurch variant suppressing microglial cGAS-STING responses and increasing clearance of pathological tau aggregates in mouse models of Alzheimer's disease.
    DOI:  https://doi.org/10.1016/j.immuni.2025.07.019
  14. Nat Immunol. 2025 Aug 13.
    Clock genes tune plasticity of group 3 innate lymphoid cells.
    Siu Ling Tai, Louis Ngai, Arthur Mortha.
      
    DOI:  https://doi.org/10.1038/s41590-025-02245-0
  15. Cell Metab. 2025 Aug 08. pii: S1550-4131(25)00355-9. [Epub ahead of print]
    Glucose-dependent insulinotropic polypeptide receptor signaling in oligodendrocytes increases the weight-loss action of GLP-1R agonism.
    Robert Hansford, Sophie Buller, Anthony H Tsang, Simon Benoit, Anna G Roberts, Emmy Erskine, Thomas Brown, Valentina Pirro, Frank Reimann, Norio Harada, Nobuya Inagaki, Ricardo J Samms, Johannes Broichhagen, David J Hodson, Alice Adriaenssens, Soyoung Park, Clemence Blouet.
      The next generation of obesity medicines harness the activity of the glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 receptors (GIPR and GLP-1R), but their mechanism of action remains unclear. Here, we report that the GIPR is enriched in oligodendrocytes and GIPR signaling bidirectionally regulates oligodendrogenesis. In mice with adult-onset deletion of GIPR in oligodendrocytes, GIPR agonism fails to enhance the weight-loss effects of GLP-1R agonism. Mechanistically, GIPR agonism increases brain access of GLP-1R agonists, and GIPR signaling in oligodendrocytes is required for this effect. In addition, we show that vasopressin neurons of the paraventricular hypothalamus are necessary for the weight-loss response to GLP-1R activation, targeted by peripherally administered GLP-1R agonists via their axonal compartment, and this access is increased by activation of the GIPR in oligodendrocytes. Collectively, our findings identify a novel mechanism by which incretin therapies may function to promote synergistic weight loss in the management of excess adiposity.
    Keywords:  blood-brain barrier; glucose-dependent insulinotropic peptide; hypothalamus; incretin; median eminence; obesity; oligodendrocytes; weight loss
    DOI:  https://doi.org/10.1016/j.cmet.2025.07.009
  16. Nat Commun. 2025 Aug 15. 16(1): 7595
    MacroD1 sustains mitochondrial integrity and oxidative metabolism.
    Ann-Katrin Hopp, Lorenza P Ferretti, Lisa Schlicker, Amalia Ruiz-Serrano, Udo Hetzel, Francesco Prisco, Anja Kipar, Lukas Muskalla, Elena Ferrari, Carsten C Scholz, Karsten Hiller, Francisco Verdeguer, Deena M Leslie Pedrioli, Michael O Hottiger.
      The mono-ADP-ribosylhydrolase MacroD1 has been recently reported to localize to mitochondria exclusively. However, the extent and means by which MacroD1 regulates metabolic homeostasis remains unclear. Here we show that the absence of MacroD1 in mice decreased mitochondrial load and negatively impacted muscle function, reducing maximal exercise capacity. Knockdown of MacroD1 in C2C12 myoblast cells amplified the production of reactive oxygen species which ultimately resulted in increased mitochondrial fission. Proteomic and metabolomic profiling showed that loss of MacroD1 re-routed metabolite flux from glucose to the pentose-phosphate cycle instead of the tricarboxylic acid cycle to support the production of antioxidants, including glutathione and NADPH. This resulted in increased glucose uptake and dependency both in vitro and in vivo. Hence, our research establishes MacroD1 as a regulator of metabolic homeostasis, which ensures the coordination of cellular carbohydrate flux and optimal mitochondrial function.
    DOI:  https://doi.org/10.1038/s41467-025-62410-9
  17. Nat Aging. 2025 Aug;5(8): 1425-1440
    Metabolic regulation of immunological aging.
    Hee-Hoon Kim, Vishwa Deep Dixit.
      All biological activities require energy through the intake and generation of metabolites. After reproductive age, altered metabolism, together with cellular and molecular perturbations in the immune system, are linked to organismal functional decline. Unresolved chronic inflammation originating from innate immune cells and loss of naive T cells with restriction of T cell receptor repertoire diversity emanating from age-related thymic involution are some of the mechanisms that limit healthspan and even lifespan. Here, we provide an overview of the hallmarks of immunological aging and synthesize how the immune system, coupled to cellular and organismal metabolism, controls disease susceptibility. Furthermore, we highlight the potential unifying immunometabolic mechanisms of various genetic, pharmacological and dietary interventions that may underlie lifespan-healthspan extension. Given that immune and metabolic systems are modifiable and targetable, understanding the role of myriads of organ-resident immune cells and the underlying metabolic mechanisms that cause dysfunction can have transformational potential for the health of older adults.
    DOI:  https://doi.org/10.1038/s43587-025-00921-2
  18. Nat Commun. 2025 Aug 13. 16(1): 7523
    Fbxo42 promotes the degradation of Ataxin-2 granules to trigger terminal Xbp1 signaling.
    Cristiana C Santos, Nadine Schweizer, Fátima Cairrão, Juanma Ramirez, Nerea Osinalde, Ming Yang, Catarina J Gaspar, Vanya I Rasheva, Miguel L Trigo, Zach Hensel, Colin Adrain, Tiago N Cordeiro, Franka Voigt, Paulo A Gameiro, Ugo Mayor, Pedro M Domingos.
      The Unfolded Protein Response (UPR) is activated by the accumulation of misfolded proteins in the Endoplasmic Reticulum (ER), a condition known as ER stress. Prolonged ER stress and UPR activation cause cell death, by mechanisms that remain poorly understood. Here, we report that regulation of Ataxin-2 by Fbxo42 is a crucial step during UPR-induced cell death. From a genetic screen in Drosophila, we identify loss of function mutations in Fbxo42 that suppress cell death and retinal degeneration induced by the overexpression of Xbp1spliced, an important mediator of the UPR. We identify the RNA binding protein Ataxin-2 as a substrate of Fbxo42, which, as part of a Skp-A/Cullin-1 complex, promotes the ubiquitylation and degradation of Ataxin-2. Upon ER-stress, the mRNA of Xbp1 is sequestered and stabilized in Ataxin-2 granules, where it remains untranslated. Fbxo42 recruitment to these granules promotes the degradation of Ataxin-2, allowing for the translation of Xbp1 mRNA and triggering cell death during the terminal stages of UPR activation.
    DOI:  https://doi.org/10.1038/s41467-025-62417-2
  19. Nat Commun. 2025 Aug 14. 16(1): 7546
    A reconceptualized framework for human microbiome transmission in early life.
    Seth Rakoff-Nahoum, Justine Debelius, Mireia Valles-Colomer, Hanna Theodora Noordzij, Maria Esteban-Torres, Alexandra Zhernakova, Nele Brusselaers, Veronika Kuchařová Pettersen.
      Human development and physiology are fundamentally linked with the microbiome. This is particularly true during early life, a critical period for microbiome assembly and its impact on the host. Understanding microbial acquisition in early life is thus central to both our basic understanding of the human microbiome and strategies for disease prevention and treatment. Here, we review the historical approaches to categorize microbial transmission originating from the fields of infectious disease epidemiology and evolutionary biology and discuss how this lexicon has influenced our approach to studying the early-life microbiome, often leading to confusion and misinterpretation. We then present a conceptual framework to capture the multifaceted nature of human microbiome acquisition based on four key components: what, where, who, and when. We present ways these parameters may be assigned, with a particular focus on the 'transmitted strain' through metagenomics to capture these elements. We end with a discussion of approaches for implementing this framework toward defining each component of microbiome acquisition.
    DOI:  https://doi.org/10.1038/s41467-025-61998-2
  20. Nat Commun. 2025 Aug 11. 16(1): 7412
    European and African ancestry-specific plasma protein-QTL and metabolite-QTL analyses identify ancestry-specific T2D effector proteins and metabolites.
    Chengran Yang, Priyanka Gorijala, Jigyasha Timsina, Lihua Wang, Menghan Liu, Ciyang Wang, William Brock, Yueyao Wang, Fumihiko Urano, Yun Ju Sung, Carlos Cruchaga.
      In this study, we generated and integrated plasma proteomics and metabolomics with the genotype datasets of over 2300 European (EUR) and 400 African (AFR) ancestries to identify ancestry-specific multi-omics quantitative trait loci (QTLs). In total, we mapped 954 AFR pQTLs, 2848 EUR pQTLs, 65 AFR mQTLs, and 490 EUR mQTLs. We further applied these QTLs to ancestry-stratified type-2 diabetes (T2D) risk to pinpoint key proteins and metabolites underlying the disease-associated genetic loci. Using INTACT that combined trait-imputation and colocalization results, we nominated 270 proteins and 72 metabolites from the EUR set; seven proteins and one metabolite from the AFR set as molecular effectors of T2D risk in an ancestry-stratified manner. Here, we show that the integration of genetic and omic studies of different ancestries can be used to identify distinct effector molecular traits underlying the same disease across diverse ancestral groups.
    DOI:  https://doi.org/10.1038/s41467-025-62463-w
  21. Nat Commun. 2025 Aug 11. 16(1): 7199
    A continuously oxygenated macroencapsulation system enables high-density packing and delivery of insulin-secreting cells.
    Tung T Pham, Phuong L Tran, Linda A Tempelman, Simon G Stone, Christopher Piccirillo, Alan Li, James A Flanders, Minglin Ma.
      The encapsulation of insulin-secreting cells offers a promising strategy for curative treatment of type 1 diabetes without immunosuppression. However, insufficient oxygen within encapsulation systems remains a major challenge, restricting cell survival, function, and scalability. Here, we report an encapsulation platform combining a miniaturized implantable electrochemical oxygen generator (iEOG) with a scalable, linear cell pouch designed for minimally invasive implantation and retrieval. This system enables continuous oxygen supply via electrolysis of tissue moisture, supporting high-density cell encapsulation (60,000 IEQ/mL). Oxygen generated by our system was stable, controllable, and sufficient to maintain cell viability and function under hypoxic (1% O₂) conditions in vitro. In an allogeneic rat model, the oxygenated system implanted subcutaneously reversed diabetes for up to three months without immunosuppression, while non-oxygenated controls remained hyperglycemic. These findings demonstrate the feasibility of sustained oxygenation to enable functional, high-density islet encapsulation in subcutaneous sites, advancing the development of clinically translatable cell-based therapies.
    DOI:  https://doi.org/10.1038/s41467-025-62271-2
  22. Cell Discov. 2025 Aug 12. 11(1): 68
    Breast cancer induces CD62L+ Kupffer cells via DMBT1 to promote neutrophil extracellular trap formation and liver metastasis.
    Pu Tian, Qiuyao Wu, Dasa He, Wenjing Zhao, Lichao Luo, Zhenchang Jia, Wenqian Luo, Xianzhe Lv, Yanan Liu, Yuan Wang, Qian Wang, Peiyuan Zhang, Yajun Liang, Qifeng Yang, Guohong Hu.
      The liver is a major target organ for breast cancer metastasis, while the regulatory mechanism of liver colonization by breast cancer remains largely unclear. Neutrophils are known to play important roles in metastatic colonization of cancer cells by the formation of neutrophil extracellular traps (NETs). Here we show the role and mechanism of a subpopulation of Kupffer cells (KCs), the liver resident macrophages, in mediating tumoral induction of NETs and liver metastasis. NETs are activated more abundantly in liver metastases of breast cancer, as compared to metastases to other organs and primary tumors. Liver-tropic tumor cells induce CD62L-expressing KCs by a secretory protein DMBT1, and CD62L+ KCs activate neutrophils for NETosis via the chemokine CCL8. Inhibition of CCL8 or its receptor on neutrophils, CCR1, impairs NETosis and metastasis. In addition, we identified a KC membrane protein MUC1 that binds to DMBT1 and subsequently activates NF-κB signaling in KCs, leading to CCL8 and CD62L expression. KCs with MUC1 inhibition effectively suppress liver metastasis. Furthermore, a DMBT1 neutralizing antibody was developed with the promise to inhibit tumor-KC interaction and treat metastatic cancer. In conclusion, our work reveals a KC subset that accounts for the liver tropism of breast cancer cells and NETs, and provides potential strategies in metastasis treatment.
    DOI:  https://doi.org/10.1038/s41421-025-00819-8
  23. Nat Commun. 2025 Aug 14. 16(1): 7551
    Astrocyte priming enhances microglial Aβ clearance and is compromised by APOE4.
    Se-In Lee, Jichang Yu, Hyein Lee, Buyun Kim, Min Jun Jang, Hyeonbin Jo, Na Yeon Kim, Malk Eun Pak, Jae Kwang Kim, Sukhee Cho, Hong-Hee Won, Min Soo Kim, Fan Gao, Younghoon Go, Jinsoo Seo.
      The innate immune system can develop a form of memory called priming, where prior exposure to a stimulus enhances subsequent responses. While well-characterized in peripheral immunity, its function in brain-resident cells such as astrocytes under non-disease conditions remains unclear. Here we show that human astrocytes derived from the induced pluripotent stem cells of healthy female donors, but not microglia, acquire a primed state following transient immune stimulations. Upon subsequent exposure to amyloid-β (Aβ), these astrocytes secrete elevated levels of cytokines and promote microglial Aβ uptake. In contrast, astrocytes carrying the Alzheimer's disease (AD) risk allele APOE4 exhibit reduced priming and fail to support microglial phagocytosis. These findings are validated in astrocyte-microglial co-cultures, cerebral organoids, and male mice, where astrocyte priming enhances Aβ clearance in an APOE4-sensitive manner. Our findings identify astrocytic immune memory as a modulator of microglial function and Aβ pathology, providing insights into how early protective responses in AD may be disrupted by genetic risk factors.
    DOI:  https://doi.org/10.1038/s41467-025-62995-1
  24. Nat Immunol. 2025 Aug 13.
    Multimodal profiling reveals tissue-directed signatures of human immune cells altered with age.
    Steven B Wells, Daniel B Rainbow, Michal Mark, Peter A Szabo, Can Ergen, Daniel P Caron, Ana Raquel Maceiras, Elior Rahmani, Eli Benuck, Valeh Valiollah Pour Amiri, David Chen, Allon Wagner, Sarah K Howlett, Lorna B Jarvis, Karen L Ellis, Masaru Kubota, Rei Matsumoto, Krishnaa Mahbubani, Kouresh Saeb-Parsy, Cecilia Dominguez Conde, Laura Richardson, Chuan Xu, Shuang Li, Lira Mamanova, Liam Bolt, Alicja Wilk, Sarah A Teichmann, Donna L Farber, Peter A Sims, Joanne L Jones, Nir Yosef.
      The immune system comprises multiple cell lineages and subsets maintained in tissues throughout the lifespan, with unknown effects of tissue and age on immune cell function. Here we comprehensively profiled RNA and surface protein expression of over 1.25 million immune cells from blood and lymphoid and mucosal tissues from 24 organ donors aged 20-75 years. We annotated major lineages (T cells, B cells, innate lymphoid cells and myeloid cells) and corresponding subsets using a multimodal classifier and probabilistic modeling for comparison across tissue sites and age. We identified dominant site-specific effects on immune cell composition and function across lineages; age-associated effects were manifested by site and lineage for macrophages in mucosal sites, B cells in lymphoid organs, and circulating T cells and natural killer cells across blood and tissues. Our results reveal tissue-specific signatures of immune homeostasis throughout the body, from which to define immune pathologies across the human lifespan.
    DOI:  https://doi.org/10.1038/s41590-025-02241-4
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