bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–05–04
forty-one papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Fungus from the human gut slows liver disease in mice.
  2. Treg cells control female nociception.
  3. Nuclear receptor signaling regulates compartmentalized phosphatidylcholine remodeling to facilitate thermosensitive lipid droplet fusion.
  4. Cytokines target distinct brain areas to modulate behavioural responses.
  5. Star ecologist 'blurred boundaries' in lab - but colleagues criticize investigation.
  6. Short-range immunity.
  7. Direct microglia replacement reveals pathologic and therapeutic contributions of brain macrophages to a monogenic neurological disease.
  8. Skin-gut crosstalk.
  9. Acetylcholine-secreting B cells constrain macrophage responses to influenza virus.
  10. Unravelling the GIPR agonist versus antagonist paradox.
  11. Microglia in the periphery.
  12. Altering metabolism programs cell identity via NAD+-dependent deacetylation.
  13. How to fix a gut microbiome ravaged by antibiotics.
  14. DNA damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophages.
  15. T cell toxicity induced by tigecycline binding to the mitochondrial ribosome.
  16. Discovery research in physiologically maintained deceased.
  17. IgA clears gut viruses.
  18. scMultiMap: Cell-type-specific mapping of enhancers and target genes from single-cell multimodal data.
  19. Targeting blood pressure to protect the brain.
  20. Blood of man who's had 200 snake bites helps make a potent antivenom.
  21. GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice.
  22. Huge reproducibility project fails to validate dozens of biomedical studies.
  23. Starvation induces metabolic hepatocyte reprogramming.
  24. Mutant macrophages CHIP in to help solid tumors.
  25. Selective requirement of glycosphingolipid synthesis for natural killer and cytotoxic T cells.
  26. Precision neuroscience.
  27. Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases.
  28. NextGen Voices: Pursuing Science Abroad.
  29. Cell classification should be based on more than just DNA.
  30. Selective inhibition of stromal mechanosensing suppresses cardiac fibrosis.
  31. Interleukin-34-dependent perivascular macrophages promote vascular function in the brain.
  32. X inactivation shows frail ends when mice age.
  33. Advances in single-cell DNA sequencing enable insights into human somatic mosaicism.
  34. Gut T cell plasticity generates pathogenic TFH cells that promote systemic autoimmunity.
  35. Did a tardigrade get the world's tiniest tattoo? April's best science images.
  36. Divergent actions of physiological and pathological amyloid-β on synapses in live human brain slice cultures.
  37. Nitro-oleic acid enhances mitochondrial metabolism and ameliorates heart failure with preserved ejection fraction in mice.
  38. Non-human primate seasonal transcriptome atlas reveals seasonal changes in physiology and diseases.
  39. GIPR-Ab/GLP-1 peptide-antibody conjugate requires brain GIPR and GLP-1R for additive weight loss in obese mice.
  40. Cerebrospinal fluid biomarker predicts dementia onset and progression in Alzheimer's disease.
  41. A good side of STING.
  1. Nature. 2025 May 02.
    Fungus from the human gut slows liver disease in mice.
    Rita Aksenfeld.
      
    Keywords:  Metabolism; Microbiome
    DOI:  https://doi.org/10.1038/d41586-025-01360-0
  2. Nat Immunol. 2025 May;26(5): 639
    Treg cells control female nociception.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-025-02160-4
  3. Nat Commun. 2025 Apr 27. 16(1): 3955
    Nuclear receptor signaling regulates compartmentalized phosphatidylcholine remodeling to facilitate thermosensitive lipid droplet fusion.
    Qi Li, Xiaofang Zhou, Xiaocong Zhang, Chuqi Zhang, Shaobing O Zhang.
      Lipid droplet (LD) fusion plays a key role in cellular fat storage. How the phospholipid monolayer membrane of LD functions in fusion, however, is poorly understood. In Caenorhabditis elegans, loss of cytochrome P450 protein CYP-37A1 causes de-repression of nuclear receptor DAF-12, promoting thermosensitive LD fusion. Here, we report that in cyp-37A1 mutants, DAF-12 up-regulates the transcription and LD localization of seven fatty acid desaturases (FAT-1 to FAT-7) and a lysophosphatidylcholine acyltransferase 3 (LPCAT3) homolog MBOA-6. LD-targeting of these enzymes increases phosphatidylcholine (PC) containing ω-3 C20 polyunsaturated fatty acids, which are essential for thermosensitive fusion. ω-3 C20-PC increase LD membrane fluidity, as does high ambient temperature. Lowering LD membrane fluidity by a chemical membrane rigidifier attenuates thermosensitive fusion; ectopic targeting of ω3 desaturase FAT-1 or MBOA-6 to LDs increases fusion kinetics and thermosensitivity. Furthermore, human LPCAT3 localizes to LDs, positively regulates LD size in human cells and facilitates thermosensitive fusion in C. elegans. These results demonstrate that DAF-12 signaling regulates compartmentalized membrane remodeling and fluidization to facilitate conserved thermosensitive LD fusion.
    DOI:  https://doi.org/10.1038/s41467-025-59256-6
  4. Nat Rev Immunol. 2025 Apr 29.
    Cytokines target distinct brain areas to modulate behavioural responses.
    Yvonne Bordon.
      
    DOI:  https://doi.org/10.1038/s41577-025-01179-w
  5. Nature. 2025 May 02.
    Star ecologist 'blurred boundaries' in lab - but colleagues criticize investigation.
    Holly Else.
      
    Keywords:  Lab life
    DOI:  https://doi.org/10.1038/d41586-025-01363-x
  6. Nat Immunol. 2025 May;26(5): 639
    Short-range immunity.
    Ioana Staicu.
      
    DOI:  https://doi.org/10.1038/s41590-025-02157-z
  7. Immunity. 2025 Apr 21. pii: S1074-7613(25)00138-4. [Epub ahead of print]
    Direct microglia replacement reveals pathologic and therapeutic contributions of brain macrophages to a monogenic neurological disease.
    William H Aisenberg, Carleigh A O'Brien, Madison Sangster, Fazeela Yaqoob, Yuanchao Zhang, Brian Temsamrit, Searlait Thom, Luca Gosse, Sai Chaluvadi, Bilal Elfayomi, Gavin Lee, Vidhur Polam, Eli M Levitt, Gary Liu, Sonia I Lombroso, Kelsey M Nemec, Gavin Clowry, Cassaundra Nieves, Priyanka Rawat, Emily Church, Daniel Martinez, Clarissa Shoffler, Daliya Kancheva, Christopher Petucci, Deanne Taylor, Julia Kofler, Daniel Erskine, Kiavash Movahedi, Mariko L Bennett, F Chris Bennett.
      Krabbe disease, also named globoid cell (GC) leukodystrophy (GLD) for its distinct lipid-laden macrophages, is a severe leukodystrophy caused by galactosylceramidase (GALC) mutations. Hematopoietic stem cell transplant (HSCT) ameliorates disease and is associated with central nervous system (CNS) engraftment of GALC+ donor macrophages. Yet, the role of macrophages in GLD pathophysiology and HSCT remains unclear. Using single-cell sequencing, we revealed early interferon response signatures that preceded progressively severe macrophage dyshomeostasis and identified a molecular signature of GCs, which we validated in human brain specimens. Genetic depletion and direct microglia replacement by CNS monocyte injection rapidly replaced >80% of endogenous microglia with healthy macrophages in the twitcher (GalcW355∗) mouse model of GLD. Perinatal microglia replacement completely normalized transcriptional signatures, rescued histopathology, and doubled average survival. Overall, we uncovered distinct forms of microglial dysfunction and evidence that direct, CNS-limited microglia replacement improves a monogenic neurodegenerative disease, identifying a promising therapeutic target.
    Keywords:  Krabbe disease; disease-associated macrophage; globoid cell; globoid cell leukodystrophy; hematopoietic stem cell transplant; microglia; microglia replacement
    DOI:  https://doi.org/10.1016/j.immuni.2025.03.019
  8. Nat Immunol. 2025 May;26(5): 639
    Skin-gut crosstalk.
    Nicholas J Bernard.
      
    DOI:  https://doi.org/10.1038/s41590-025-02158-y
  9. Nat Immunol. 2025 May;26(5): 659-660
    Acetylcholine-secreting B cells constrain macrophage responses to influenza virus.
      
    DOI:  https://doi.org/10.1038/s41590-025-02148-0
  10. Nat Metab. 2025 Apr 29.
    Unravelling the GIPR agonist versus antagonist paradox.
    Alice E Adriaenssens.
      
    DOI:  https://doi.org/10.1038/s42255-025-01299-6
  11. Nat Rev Immunol. 2025 Apr 28.
    Microglia in the periphery.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-025-01180-3
  12. EMBO J. 2025 Apr 25.
    Altering metabolism programs cell identity via NAD+-dependent deacetylation.
    Robert A Bone, Molly P Lowndes, Silvia Raineri, Alba R Riveiro, Sarah L Lundregan, Morten Dall, Karolina Sulek, Jose A H Romero, Luna Malzard, Sandra Koigi, Indra J Heckenbach, Victor Solis-Mezarino, Moritz Völker-Albert, Catherine G Vasilopoulou, Florian Meier, Ala Trusina, Matthias Mann, Michael L Nielsen, Jonas T Treebak, Joshua M Brickman.
      Cells change their metabolic profiles in response to underlying gene regulatory networks, but how can alterations in metabolism encode specific transcriptional instructions? Here, we show that forcing a metabolic change in embryonic stem cells (ESCs) promotes a developmental identity that better approximates the inner cell mass (ICM) of the early mammalian blastocyst in cultures. This shift in cellular identity depends on the inhibition of glycolysis and stimulation of oxidative phosphorylation (OXPHOS) triggered by the replacement of D-glucose by D-galactose in ESC media. Enhanced OXPHOS in turn activates NAD + -dependent deacetylases of the Sirtuin family, resulting in the deacetylation of histones and key transcription factors to focus enhancer activity while reducing transcriptional noise, which results in a robustly enhanced ESC phenotype. This exploitation of a NAD + /NADH coenzyme coupled to OXPHOS as a means of programming lineage-specific transcription suggests new paradigms for how cells respond to alterations in their environment, and implies cellular rejuvenation exploits enzymatic activities for simultaneous activation of a discrete enhancer set alongside silencing genome-wide transcriptional noise.
    Keywords:  Aging; Enhancers; Metabolism; Pluripotency; Sirtuins
    DOI:  https://doi.org/10.1038/s44318-025-00417-0
  13. Nature. 2025 Apr 23.
    How to fix a gut microbiome ravaged by antibiotics.
    Heidi Ledford.
      
    Keywords:  Antibiotics; Microbiology; Microbiome
    DOI:  https://doi.org/10.1038/d41586-025-01313-7
  14. Nat Commun. 2025 Apr 28. 16(1): 3958
    DNA damage in proximal tubules triggers systemic metabolic dysfunction through epigenetically altered macrophages.
    Erina Sugita Nishimura, Akihito Hishikawa, Ran Nakamichi, Riki Akashio, Shunsuke Chikuma, Akinori Hashiguchi, Norifumi Yoshimoto, Eriko Yoshida Hama, Tomomi Maruki, Wataru Itoh, Shintaro Yamaguchi, Jun Yoshino, Hiroshi Itoh, Kaori Hayashi.
      DNA damage repair is a critical physiological process closely linked to aging. The accumulation of DNA damage in renal proximal tubular epithelial cells (PTEC) is related to a decline in kidney function. Here, we report that DNA double-strand breaks in PTECs lead to systemic metabolic dysfunction, including weight loss, reduced fat mass, impaired glucose tolerance with mitochondrial dysfunction, and increased inflammation in adipose tissues and the liver. Single-cell RNA sequencing analysis reveals expansion of CD11c+ Ccr2+ macrophages in the kidney cortex, liver, and adipose tissues and Ly6Chi monocytes in peripheral blood. DNA damage in PTECs is associated with hypomethylation of macrophage activation genes, including Gasdermin D, in peripheral blood cells, which is linked to reduced DNA methylation at KLF9-binding motifs. Macrophage depletion ameliorates metabolic abnormalities. These findings highlight the impact of kidney DNA damage on systemic metabolic homeostasis, revealing a kidney-blood-metabolism axis mediated by epigenetic changes in macrophages.
    DOI:  https://doi.org/10.1038/s41467-025-59297-x
  15. Nat Commun. 2025 May 01. 16(1): 4080
    T cell toxicity induced by tigecycline binding to the mitochondrial ribosome.
    Qiuya Shao, Anas Khawaja, Minh Duc Nguyen, Vivek Singh, Jingdian Zhang, Yong Liu, Joel Nordin, Monika Adori, C Axel Innis, Xaquin Castro Dopico, Joanna Rorbach.
      Tetracyclines are essential bacterial protein synthesis inhibitors under continual development to combat antibiotic resistance yet suffer from unwanted side effects. Mitoribosomes - responsible for generating oxidative phosphorylation (OXPHOS) subunits - share structural similarities with bacterial machinery and may suffer from cross-reactivity. Since lymphocytes rely upon OXPHOS upregulation to establish immunity, we set out to assess the impact of ribosome-targeting antibiotics on human T cells. We find tigecycline, a third-generation tetracycline, to be the most cytotoxic compound tested. In vitro, 5-10 μM tigecycline inhibits mitochondrial but not cytosolic translation, mitochondrial complex I, III and IV expression, and curtails the activation and expansion of unique T cell subsets. By cryo-EM, we find tigecycline to occupy three sites on T cell mitoribosomes. In addition to the conserved A-site found in bacteria, tigecycline also attaches to the peptidyl transferase center of the large subunit. Furthermore, a third, distinct binding site on the large subunit, aligns with helices analogous to those in bacteria, albeit lacking methylation in humans. The data provide a mechanism to explain part of the anti-inflammatory effects of these drugs and inform antibiotic design.
    DOI:  https://doi.org/10.1038/s41467-025-59388-9
  16. Science. 2025 May;388(6746): 473-476
    Discovery research in physiologically maintained deceased.
    Douglas B Pet, Brendan Parent, Neel S Singhal, Claire D Clelland.
      Expanded research opportunities in deceased humans require ongoing ethical inquiry.
    DOI:  https://doi.org/10.1126/science.adt3527
  17. Nat Immunol. 2025 May;26(5): 639
    IgA clears gut viruses.
    Paula Jauregui.
      
    DOI:  https://doi.org/10.1038/s41590-025-02159-x
  18. Nat Commun. 2025 Apr 26. 16(1): 3941
    scMultiMap: Cell-type-specific mapping of enhancers and target genes from single-cell multimodal data.
    Chang Su, Dongsoo Lee, Peng Jin, Jingfei Zhang.
      Mapping enhancers and target genes in disease-related cell types provides critical insights into the functional mechanisms of genome-wide association studies (GWAS) variants. Single-cell multimodal data, which measure gene expression and chromatin accessibility in the same cells, enable the cell-type-specific inference of enhancer-gene pairs. However, this task is challenged by high data sparsity, sequencing depth variation, and the computational burden of analyzing a large number of pairs. We introduce scMultiMap, a statistical method that infers enhancer-gene association from sparse multimodal counts using a joint latent-variable model. It adjusts for technical confounding, permits fast moment-based estimation and provides analytically derived p-values. In blood and brain data, scMultiMap shows appropriate type I error control, high statistical power, and computational efficiency (1% of existing methods). When applied to Alzheimer's disease (AD) data, scMultiMap gives the highest heritability enrichment in microglia and reveals insights into the regulatory mechanisms of AD GWAS variants.
    DOI:  https://doi.org/10.1038/s41467-025-59306-z
  19. Nat Med. 2025 May 02.
    Targeting blood pressure to protect the brain.
    Josef Coresh, Salim S Virani, Rebecca F Gottesman.
      
    DOI:  https://doi.org/10.1038/s41591-025-03694-8
  20. Nature. 2025 May 02.
    Blood of man who's had 200 snake bites helps make a potent antivenom.
    Katherine Bourzac.
      
    Keywords:  Drug discovery; Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-025-01325-3
  21. Nat Metab. 2025 Apr 29.
    GIPR agonism and antagonism decrease body weight and food intake via different mechanisms in male mice.
    Robert M Gutgesell, Ahmed Khalil, Arkadiusz Liskiewicz, Gandhari Maity-Kumar, Aaron Novikoff, Gerald Grandl, Daniela Liskiewicz, Callum Coupland, Ezgi Karaoglu, Seun Akindehin, Russell Castelino, Fabiola Curion, Xue Liu, Cristina Garcia-Caceres, Alberto Cebrian-Serrano, Jonathan D Douros, Patrick J Knerr, Brian Finan, Richard D DiMarchi, Kyle W Sloop, Ricardo J Samms, Fabian J Theis, Matthias H Tschöp, Timo D Müller.
      Agonists and antagonists of the glucose-dependent insulinotropic polypeptide receptor (GIPR) enhance body weight loss induced by glucagon-like peptide-1 receptor (GLP-1R) agonism. However, while GIPR agonism decreases body weight and food intake in a GLP-1R-independent manner via GABAergic GIPR+ neurons, it remains unclear whether GIPR antagonism affects energy metabolism via a similar mechanism. Here we show that the body weight and food intake effects of GIPR antagonism are eliminated in mice with global loss of either Gipr or Glp-1r but are preserved in mice with loss of Gipr in either GABAergic neurons of the central nervous system or peripherin-expressing neurons of the peripheral nervous system. Single-nucleus RNA-sequencing shows opposing effects of GIPR agonism and antagonism in the dorsal vagal complex, with antagonism, but not agonism, closely resembling GLP-1R signalling. Additionally, GIPR antagonism and GLP-1R agonism both regulate genes implicated in synaptic plasticity. Collectively, we show that GIPR agonism and antagonism decrease body weight via different mechanisms, with GIPR antagonism, unlike agonism, depending on functional GLP-1R signalling.
    DOI:  https://doi.org/10.1038/s42255-025-01294-x
  22. Nature. 2025 Apr 25.
    Huge reproducibility project fails to validate dozens of biomedical studies.
    Rodrigo de Oliveira Andrade.
      
    Keywords:  Medical research; Publishing; Research management; Scientific community
    DOI:  https://doi.org/10.1038/d41586-025-01266-x
  23. Nat Metab. 2025 Apr 25.
    Starvation induces metabolic hepatocyte reprogramming.
    Coenraad F Slabber, Jan S Tchorz.
      
    DOI:  https://doi.org/10.1038/s42255-025-01286-x
  24. Cell. 2025 May 01. pii: S0092-8674(25)00401-5. [Epub ahead of print]188(9): 2309-2311
    Mutant macrophages CHIP in to help solid tumors.
    Isak W Tengesdal, Siddhartha Jaiswal.
      Clonal hematopoiesis of indeterminate potential (CHIP) promotes adverse outcomes in age-related diseases. However, the impact of CHIP on solid tumors has yet to be elucidated in large-scale cancer-focused cohorts. In a recently published article in the New England Journal of Medicine, Pich et al. provide evidence for a tumor-promoting role of CHIP in solid malignancies.
    DOI:  https://doi.org/10.1016/j.cell.2025.03.049
  25. Cell. 2025 Apr 25. pii: S0092-8674(25)00409-X. [Epub ahead of print]
    Selective requirement of glycosphingolipid synthesis for natural killer and cytotoxic T cells.
    Tasha A Morrison, Jaelyn Vigee, Kevin A Tovar, Taylor A Talley, Adriana M Mujal, Mari Kono, Rachael Philips, Hiroyuki Nagashima, Stephen R Brooks, Hannah Dada, Isaiah Rozich, Kelly Hudspeth, Colleen M Lau, Chen Yao, Giuseppe Sciumè, Hong-Wei Sun, Juan S Bonifacino, Yuka Kanno, Michael L Dustin, Davide Randazzo, Richard L Proia, Joseph C Sun, Han-Yu Shih, John J O'Shea.
      Cell identity genes that exhibit complex regulation are marked by super-enhancer (SE) architecture. Assessment of SEs in natural killer (NK) cells identified Ugcg, encoding the enzyme responsible for glycosphingolipid (GSL) synthesis. Conditional deletion of Ugcg in early hematopoiesis abrogated NK cell generation while sparing other lineages. Pharmacological inhibition of UGCG disrupted cytotoxic granules and cytotoxicity, reduced expansion after viral infection, and promoted apoptosis. B4galt5 transcribes an enzyme downstream of UGCG and possesses SE structure. Addition of its product, lactosylceramide (LacCer), reversed apoptosis due to UGCG inhibition. By contrast, complex GSLs, such as asialo-GM1, were not required for NK cell viability and granule integrity. Ugcg and B4galt5 were upregulated in CD8+ T cells during viral infection, correlating with the acquisition of cytotoxic machinery. Antigen-specific CD8+ T cells lacking Ugcg failed to expand during infection. Our study reveals a selective and essential role of GSL metabolism in NK and CD8+ T cell biology.
    Keywords:  B4galt5; CD8(+) T cells; Ugcg; cytotoxic granules; glycosphingolipids; immunometabolism; lactosylceramide; lymphocytes; natural killer cells; super-enhancers
    DOI:  https://doi.org/10.1016/j.cell.2025.04.007
  26. Nat Biotechnol. 2025 Apr 28.
    Precision neuroscience.
    Melanie Senior.
      
    DOI:  https://doi.org/10.1038/s41587-025-02673-1
  27. Nat Commun. 2025 Apr 28. 16(1): 3765
    Dissecting cross-population polygenic heterogeneity across respiratory and cardiometabolic diseases.
    BioBank Japan Project
      Biological mechanisms underlying multimorbidity remain elusive. To dissect the polygenic heterogeneity of multimorbidity in twelve complex traits across populations, we leveraged biobank resources of genome-wide association studies (GWAS) for 232,987 East Asian individuals (the 1st and 2nd cohorts of BioBank Japan) and 751,051 European individuals (UK Biobank and FinnGen). Cross-trait analyses of respiratory and cardiometabolic diseases, rheumatoid arthritis, and smoking identified negative genetic correlations between respiratory and cardiometabolic diseases in East Asian individuals, opposite from the positive associations in European individuals. Associating genome-wide polygenic risk scores (PRS) with 325 blood metabolome and 2917 proteome biomarkers supported the negative cross-trait genetic correlations in East Asian individuals. Bayesian pathway PRS analysis revealed a negative association between asthma and dyslipidemia in a gene set of peroxisome proliferator-activated receptors. The pathway suggested heterogeneity of cell type specificity in the enrichment analysis of the lung single-cell RNA-sequencing dataset. Our study highlights the heterogeneous pleiotropy of immunometabolic dysfunction in multimorbidity.
    DOI:  https://doi.org/10.1038/s41467-025-58149-y
  28. Science. 2025 May;388(6746): 481
    NextGen Voices: Pursuing Science Abroad.
      
    DOI:  https://doi.org/10.1126/science.ady6155
  29. Nature. 2025 May;641(8061): 39
    Cell classification should be based on more than just DNA.
    Howard Lopes Ribeiro Junior.
      
    Keywords:  Cell biology; Genomics
    DOI:  https://doi.org/10.1038/d41586-025-01329-z
  30. Nature. 2025 Apr 30.
    Selective inhibition of stromal mechanosensing suppresses cardiac fibrosis.
    Sangkyun Cho, Siyeon Rhee, Christopher M Madl, Arianne Caudal, Dilip Thomas, Hyeonyu Kim, Ana Kojic, Hye Sook Shin, Abhay Mahajan, James W Jahng, Xi Wang, Phung N Thai, David T Paik, Mingqiang Wang, McKay Mullen, Natalie M Baker, Jeremy Leitz, Souhrid Mukherjee, Virginia D Winn, Y Joseph Woo, Helen M Blau, Joseph C Wu.
      Matrix-derived biophysical cues are known to regulate the activation of fibroblasts and their subsequent transdifferentiation into myofibroblasts1-6, but whether modulation of these signals can suppress fibrosis in intact tissues remains unclear, particularly in the cardiovascular system7-10. Here we demonstrate across multiple scales that inhibition of matrix mechanosensing in persistently activated cardiac fibroblasts potentiates-in concert with soluble regulators of the TGFβ pathway-a robust transcriptomic, morphological and metabolic shift towards quiescence. By conducting a meta-analysis of public human and mouse single-cell sequencing datasets, we identify the focal-adhesion-associated tyrosine kinase SRC as a fibroblast-enriched mechanosensor that can be targeted selectively in stromal cells to mimic the effects of matrix softening in vivo. Pharmacological inhibition of SRC by saracatinib, coupled with TGFβ suppression, induces synergistic repression of key profibrotic gene programs in fibroblasts, characterized by a marked inhibition of the MRTF-SRF pathway, which is not seen after treatment with either drug alone. Importantly, the dual treatment alleviates contractile dysfunction in fibrotic engineered heart tissues and in a mouse model of heart failure. Our findings point to joint inhibition of SRC-mediated stromal mechanosensing and TGFβ signalling as a potential mechanotherapeutic strategy for treating cardiovascular fibrosis.
    DOI:  https://doi.org/10.1038/s41586-025-08945-9
  31. Immunity. 2025 Apr 26. pii: S1074-7613(25)00166-9. [Epub ahead of print]
    Interleukin-34-dependent perivascular macrophages promote vascular function in the brain.
    Hannah Van Hove, Chaim Glück, Wiebke Mildenberger, Ekaterina Petrova, Upasana Maheshwari, Philipp Häne, Victor Kreiner, Mitchell Bijnen, Caroline Mussak, Sebastian G Utz, Jeanne Droux, Florian Ingelfinger, Christian Ashworth, Sebastian A Stifter, Elsa Roussel, Iva Lelios, Marijne Vermeer, Sheng-Fu Huang, Quanyu Zhou, Zhenyue Chen, Charlotte Calvet, Soline Bourgeois, Johanna Schaffenrath, Daniel Razansky, Jean X Juang, Kenichi Asano, Pawel Pelczar, Sarah Mundt, Bruno Weber, Susanne Wegener, Sonia Tugues, Christian Stockmann, Burkhard Becher, Annika Keller, Mohamad El Amki, Melanie Greter.
      The development of most macrophages depends on the colony-stimulating factor 1 (CSF-1) receptor, which has two ligands: CSF-1 and interleukin-34 (IL-34). While IL-34 is required for the homeostasis of microglia, the parenchymal macrophages in the central nervous system (CNS), it is unclear whether brain border-associated macrophages (BAMs) also depend on this cytokine. Here, we demonstrated that the embryonic development of murine BAMs in the choroid plexus, leptomeninges, and perivascular spaces required CSF-1, while IL-34 was critical for their maintenance in adulthood. In the brain, Il34 was expressed by mural cells and perivascular fibroblasts, and its transgenic deletion in these cells interrupted BAM maintenance. Il34 deficiency coincided with transcriptional changes in vascular cells, leading to increased flow velocity and vasomotion in pial and penetrating arterioles. Similarly, Mrc1CreCsf1rfl/fl mice lacking CD206+ perivascular BAMs exhibited increased hemodynamics in arterial networks. These findings reveal a crosstalk between vascular cells and CNS macrophages regulating cerebrovascular function.
    Keywords:  BAM; CSF-1R; IL-34; blood flow; brain macrophage; microglia; perivascular macrophages; vasomotion
    DOI:  https://doi.org/10.1016/j.immuni.2025.04.003
  32. Nat Aging. 2025 May 01.
    X inactivation shows frail ends when mice age.
    Anton Wutz.
      
    DOI:  https://doi.org/10.1038/s43587-025-00874-6
  33. Nat Rev Genet. 2025 Apr 25.
    Advances in single-cell DNA sequencing enable insights into human somatic mosaicism.
    Diane D Shao, Andrea J Kriz, Daniel A Snellings, Zinan Zhou, Yifan Zhao, Liz Enyenihi, Christopher Walsh.
      DNA sequencing from bulk or clonal human tissues has shown that genetic mosaicism is common and contributes to both cancer and non-cancerous disorders. However, single-cell resolution is required to understand the full genetic heterogeneity that exists within a tissue and the mechanisms that lead to somatic mosaicism. Single-cell DNA-sequencing technologies have traditionally trailed behind those of single-cell transcriptomics and epigenomics, largely because most applications require whole-genome amplification before costly whole-genome sequencing. Now, recent technological and computational advances are enabling the use of single-cell DNA sequencing to tackle previously intractable problems, such as delineating the genetic landscape of tissues with complex clonal patterns, of samples where cellular material is scarce and of non-cycling, postmitotic cells. Single-cell genomes are also revealing the mutational patterns that arise from biological processes or disease states, and have made it possible to track cell lineage in human tissues. These advances in our understanding of tissue biology and our ability to identify disease mechanisms will ultimately transform how disease is diagnosed and monitored.
    DOI:  https://doi.org/10.1038/s41576-025-00832-3
  34. Nat Immunol. 2025 May;26(5): 657-658
    Gut T cell plasticity generates pathogenic TFH cells that promote systemic autoimmunity.
      
    DOI:  https://doi.org/10.1038/s41590-025-02147-1
  35. Nature. 2025 Apr 30.
    Did a tardigrade get the world's tiniest tattoo? April's best science images.
    Emma Stoye.
      
    Keywords:  Media
    DOI:  https://doi.org/10.1038/d41586-025-01320-8
  36. Nat Commun. 2025 Apr 30. 16(1): 3753
    Divergent actions of physiological and pathological amyloid-β on synapses in live human brain slice cultures.
    Robert I McGeachan, Soraya Meftah, Lewis W Taylor, James H Catterson, Danilo Negro, Calum Bonthron, Kristján Holt, Jane Tulloch, Jamie L Rose, Francesco Gobbo, Ya Yin Chang, Jamie Elliott, Lauren McLay, Declan King, Imran Liaquat, Tara L Spires-Jones, Sam A Booker, Paul M Brennan, Claire S Durrant.
      In Alzheimer's disease, amyloid beta (Aβ) and tau pathology are thought to drive synapse loss. However, there is limited information on how endogenous levels of tau, Aβ and other biomarkers relate to patient characteristics, or how manipulating physiological levels of Aβ impacts synapses in living adult human brain. Using live human brain slice cultures, we report that Aβ1-40 and tau release levels vary with donor age and brain region, respectively. Release of other biomarkers such as KLK-6, NCAM-1, and Neurogranin vary between brain region, while TDP-43 and NCAM-1 release is impacted by sex. Pharmacological manipulation of Aβ in either direction results in a loss of synaptophysin puncta, with increased physiological Aβ triggering potentially compensatory synaptic transcript changes. In contrast, treatment with Aβ-containing Alzheimer's disease brain extract results in post-synaptic Aβ uptake and pre-synaptic puncta loss without affecting synaptic transcripts. These data reveal distinct effects of physiological and pathological Aβ on synapses in human brain tissue.
    DOI:  https://doi.org/10.1038/s41467-025-58879-z
  37. Nat Commun. 2025 Apr 26. 16(1): 3933
    Nitro-oleic acid enhances mitochondrial metabolism and ameliorates heart failure with preserved ejection fraction in mice.
    Marion Müller, Torben Schubert, Cornelius Welke, Tibor Maske, Thomas Patschkowski, Elfi Donhauser, Jacqueline Heinen-Weiler, Felix-Levin Hormann, Sven Heiles, Tina Johanna Schulz, Luisa Andrea Lengenfelder, Lucia Landwehrjohann, Elisa Theres Vogt, Bernd Stratmann, Jurek Hense, Simon Lüdtke, Martina Düfer, Elena Tolstik, Johann Dierks, Kristina Lorenz, Tamino Huxohl, Jan-Christian Reil, Vasco Sequeira, Francisco Jose Schopfer, Bruce A Freeman, Volker Rudolph, Uwe Schlomann, Anna Klinke.
      The prevalence of heart failure with preserved ejection fraction (HFpEF) is increasing, while treatment options are inadequate. Hypertension and obesity-related metabolic dysfunction contribute to HFpEF. Nitro-oleic acid (NO2-OA) impacts metabolic syndromes by improving glucose tolerance and adipocyte function. Here we show that treatment with NO2-OA ameliorates diastolic dysfunction and heart failure symptoms in a HFpEF mouse model induced by high-fat diet and inhibition of the endothelial nitric oxide synthase. Proteomic analysis of left ventricular tissue reveals that one-third of identified proteins, predominantly mitochondrial, are upregulated in hearts of NO2-OA-treated HFpEF mice compared to naïve and vehicle-treated HFpEF mice. Increased mitochondrial mass and numbers, and enhanced mitochondrial respiration are linked with this response, as assessed by transmission electron microscopy and high-resolution respirometry. Activation of the 5'-adenosine-monophosphate-activated-protein-kinase (AMPK) signaling pathway mediates the enhancement of mitochondrial dynamics in hearts of NO2-OA-treated HFpEF mice. These findings suggest that targeting mitochondrial function with NO2-OA may represent a promising therapeutic strategy for HFpEF.
    DOI:  https://doi.org/10.1038/s41467-025-59192-5
  38. Nat Commun. 2025 Apr 28. 16(1): 3906
    Non-human primate seasonal transcriptome atlas reveals seasonal changes in physiology and diseases.
    Junfeng Chen, Kousuke Okimura, Liang Ren, Yusuke Nakane, Tomoya Nakayama, Yang Chen, Kai Fukawa, Soutarou Sugiyama, Takayoshi Natsume, Naoko Suda-Hashimoto, Mayumi Morimoto, Takako Miyabe-Nishiwaki, Takao Oishi, Yuma Katada, Manhui Zhang, Kohei Kobayashi, Shoko Matsumoto, Taiki Yamaguchi, Ying-Jey Guh, Issey Takahashi, Taeko Nishiwaki-Ohkawa, Daiki X Sato, Yoshiharu Murata, Kenta Sumiyama, Atsushi J Nagano, Hiroo Imai, Takashi Yoshimura.
      The metabolic, immune, and endocrine systems show profound seasonal changes in animals, including humans. In addition, morbidity from cardiovascular and psychiatric diseases is more severe and mortality rate is higher in winter. However, their molecular mechanisms remain unknown. Here we report the seasonal transcriptome of 80 tissues collected over 1 year from male and female rhesus macaques kept in a semi-natural outdoor environment. We find seasonal changes in plasma metabolites and hormones. Transcriptome analysis identifies sex differences in seasonally oscillating genes (SOGs) in all tissues studied, and we generate the web database 'Non-Human Primate Seasonal Transcriptome Atlas (NHPSTA).' Transcriptional regulatory network analysis, siRNA knockdown, and mutant mouse analyses reveal regulation of SOGs by GA-binding protein (GABP). We also demonstrate seasonal oscillations in the expression of disease risk factor genes and drug interacting genes. NHPSTA provides a molecular resource for seasonally regulated physiology and targets for therapeutic interventions for seasonally regulated diseases.
    DOI:  https://doi.org/10.1038/s41467-025-57994-1
  39. Nat Metab. 2025 Apr 29.
    GIPR-Ab/GLP-1 peptide-antibody conjugate requires brain GIPR and GLP-1R for additive weight loss in obese mice.
    Clarissa M Liu, Elizabeth A Killion, Rola Hammoud, Shu-Chen Lu, Renee Komorowski, Tongyu Liu, Matt Kanke, Veena A Thomas, Kevin Cook, Glenn N Sivits, Aerielle B Ben, Larissa I Atangan, Rajaa Hussien, Amy Tang, Artem Shkumatov, Chi-Ming Li, Daniel J Drucker, Murielle M Véniant.
      Glucose-dependent insulinotropic polypeptide receptor (GIPR) and glucagon-like peptide 1 receptor (GLP-1R) are expressed in the central nervous system (CNS) and regulate food intake. Here, we demonstrate that a peptide-antibody conjugate that blocks GIPR while simultaneously activating GLP-1R (GIPR-Ab/GLP-1) requires both CNS GIPR and CNS GLP-1R for maximal weight loss in obese, primarily male, mice. Moreover, dulaglutide produces greater weight loss in CNS GIPR knockout (KO) mice, and the weight loss achieved with dulaglutide + GIPR-Ab is attenuated in CNS GIPR KO mice. Wild-type mice treated with GIPR-Ab/GLP-1 and CNS GIPR KO mice exhibit similar changes in gene expression related to tissue remodelling, lipid metabolism and inflammation in white adipose tissue and liver. Moreover, GIPR-Ab/GLP-1 is detected in circumventricular organs in the brain and activates c-FOS in downstream neural substrates involved in appetite regulation. Hence, both CNS GIPR and GLP-1R signalling are required for the full weight loss effect of a GIPR-Ab/GLP-1 peptide-antibody conjugate.
    DOI:  https://doi.org/10.1038/s42255-025-01295-w
  40. Nat Med. 2025 Apr 28.
    Cerebrospinal fluid biomarker predicts dementia onset and progression in Alzheimer's disease.
      
    DOI:  https://doi.org/10.1038/s41591-025-03700-z
  41. Sci Signal. 2025 Apr 29. 18(884): eady4818
    A good side of STING.
    Leslie K Ferrarelli.
      The innate immunity mediator STING senses and repairs lysosomal dysfunction.
    DOI:  https://doi.org/10.1126/scisignal.ady4818
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