bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–06–22
28 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging.
  2. Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH differentiation.
  3. Is there a link between gut microbes and ageing?
  4. FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression.
  5. Daily briefing: The most-energetic molecule ever made.
  6. How your brain controls ageing - and why zombie cells could be key.
  7. Grow up, beta cells.
  8. Organoids.
  9. Mice with human cells developed using 'game-changing' technique.
  10. Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells.
  11. Why science recruiters struggle to find high-calibre candidates.
  12. Myelin-axon interface vulnerability in Alzheimer's disease revealed by subcellular proteomics and imaging of human and mouse brain.
  13. Surveilling ribosome biogenesis.
  14. pDCs drive immunopathology by sensing oxidized mitochondrial DNA.
  15. Kupffer cell programming by maternal obesity triggers fatty liver disease.
  16. TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation.
  17. Dynamic Ca2+-Dependent Transcription Links Metabolic Stress to Impaired β-Cell Identity.
  18. Hemodynamic forces prevent myxomatous valve disease in mice through KLF2/4 signaling.
  19. A conserved immune dysregulation signature is associated with infection severity, risk factors prior to infection, and treatment response.
  20. Cryo-EM structure of a natural RNA nanocage.
  21. Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations.
  22. Activation of STING pathway by mitochondrial fission negatively regulates adipogenic differentiation of 3 T3-L1 cells.
  23. Toll-like receptors in B cells and obesity.
  24. Loss of effector Treg signature in APOB-reactive CD4+ T cells in patients with coronary artery disease.
  25. A brief guide to statistical analysis of grouped data in preclinical research.
  26. Organelle conversations drive ferroptosis.
  27. Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis.
  28. The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis.
  1. Mol Cell. 2025 Jun 19. pii: S1097-2765(25)00464-2. [Epub ahead of print]85(12): 2390-2408.e6
    SIRT7 regulates NUCKS1 chromatin binding to elicit metabolic and inflammatory gene expression in senescence and liver aging.
    Khoa A Tran, Michael Gilbert, Berta N Vazquez, Alessandro Ianni, Benjamin A Garcia, Alejandro Vaquero, Shelley L Berger.
      Sirtuin enzymes are deeply associated with senescence and aging. Sirtuin proteins are tightly regulated, but how their levels are governed during aging and how they elicit tissue-specific cellular changes are unclear. Here, we demonstrate that SIRT7 undergoes proteasomal degradation during senescence via targeting by the E3 ligase TRIP12. We identified the transcription factor nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) as an interactor of SIRT7 and found NUCKS1 recruitment onto chromatin during senescence mediated by SIRT7 loss, correlating with increased NUCKS1 acetylation. NUCKS1 depletion delayed senescence, leading to reduced inflammatory gene expression associated with transcription factors RELA and CEBPβ. In Sirt7 knockout and aged mouse livers, NUCKS1 was bound at the promoters and enhancers of age-related genes, and these regulatory regions gained accessibility during aging. Overall, our results uncover NUCKS1 as an interactor of SIRT7 and indicate that proteasomal loss of SIRT7 during senescence and liver aging promotes NUCKS1 acetylation and chromatin binding to induce metabolic and inflammatory genes.
    Keywords:  NUCKS1; SIRT7; acetylation; aging; post-translation modification; protein regulation; senescence; sirtuins
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.025
  2. Nat Immunol. 2025 Jun 17.
    Mitochondrial DNA oxidation propagates autoimmunity by enabling plasmacytoid dendritic cells to induce TFH differentiation.
    Hongxu Xian, Kosuke Watari, Masafumi Ohira, Jonathan S Brito, Peng He, Janset Onyuru, Elina I Zuniga, Hal M Hoffman, Michael Karin.
      Stress-induced oxidized mitochondrial DNA (Ox-mtDNA) fragments enter the cytoplasm, activating the NLRP3 inflammasome and caspase-1 and enabling gasdermin-D-mediated circulatory release of mtDNA. Elevated amounts of circulating mtDNA, presumably oxidized, have been detected in older individuals and patients with metabolic or autoimmune disorders. Here we show that sustained Ox-mtDNA release, triggered by a prototypical NLRP3 inflammasome activator, induces autoantibody production and glomerulonephritis in mice. Similar autoimmune responses, dependent on plasmacytoid dendritic cells (pDCs) and follicular helper T (TFH) cells, are elicited by in vitro-generated Ox-mtDNA, but not by non-oxidized mtDNA. Although both mtDNA forms are internalized by pDCs and induce interferon-α, only Ox-mtDNA stimulates autocrine interleukin (IL)-1β signaling that induces co-stimulatory molecules and IL-21, which enable mouse and human pDCs to induce functional TFH differentiation, supportive of autoantibody production. These findings underscore the role of pDC-generated IL-1β in autoantibody production and highlight Ox-mtDNA as an important autoimmune trigger, suggesting potential therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s41590-025-02179-7
  3. Nature. 2025 Jun;642(8068): 572
    Is there a link between gut microbes and ageing?
    Christina T Kozycki, Ruchi Sharma, Kapil Bharti, Richard W J Lee.
      
    Keywords:  Ageing; Microbiome
    DOI:  https://doi.org/10.1038/d41586-025-01905-3
  4. Cell Metab. 2025 Jun 12. pii: S1550-4131(25)00267-0. [Epub ahead of print]
    FGF21 promotes longevity in diet-induced obesity through metabolic benefits independent of growth suppression.
    Christy M Gliniak, Ruth Gordillo, Yun-Hee Youm, Qian Lin, Clair Crewe, Zhuzhen Zhang, Bianca C Field, Teppei Fujikawa, Megan Virostek, Shangang Zhao, Yi Zhu, Clifford J Rosen, Tamas L Horvath, Vishwa Deep Dixit, Philipp E Scherer.
      Approximately 35% of US adults over 65 are obese, highlighting the need for therapies targeting age-related metabolic issues. Fibroblast growth factor 21 (FGF21), a hormone mainly produced by the liver, improves metabolism and extends lifespan. To explore its effects without developmental confounders, we generated mice with adipocyte-specific FGF21 overexpression beginning in adulthood. When fed a high-fat diet, these mice lived up to 3.3 years, resisted weight gain, improved insulin sensitivity, and showed reduced liver steatosis. Aged transgenic mice also displayed lower levels of inflammatory immune cells and lipotoxic ceramides in visceral adipose tissue, benefits that occurred even in the absence of adiponectin, a hormone known to regulate ceramide breakdown. These results suggest that fat tissue is a central site for FGF21's beneficial effects and point to its potential for treating metabolic syndrome and age-related diseases by promoting a healthier metabolic profile under dietary stress and extending healthspan and lifespan.
    Keywords:  FGF21; adipocytes; adiponectin; adipose tissue; aging; ceramides; inflammation; insulin sensitivity; longevity; obesity
    DOI:  https://doi.org/10.1016/j.cmet.2025.05.011
  5. Nature. 2025 Jun 18.
    Daily briefing: The most-energetic molecule ever made.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-025-01948-6
  6. Nature. 2025 Jun;642(8068): 563-565
    How your brain controls ageing - and why zombie cells could be key.
    Diana Kwon.
      
    Keywords:  Ageing; Brain
    DOI:  https://doi.org/10.1038/d41586-025-01886-3
  7. Nat Cell Biol. 2025 Jun;27(6): 878
    Grow up, beta cells.
    Angela R Parrish.
      
    DOI:  https://doi.org/10.1038/s41556-025-01705-x
  8. Nat Biotechnol. 2025 Jun;43(6): 863
    Organoids.
      
    DOI:  https://doi.org/10.1038/s41587-025-02698-6
  9. Nature. 2025 Jun 16.
    Mice with human cells developed using 'game-changing' technique.
    Smriti Mallapaty.
      
    Keywords:  Brain; Cell biology; Stem cells
    DOI:  https://doi.org/10.1038/d41586-025-01898-z
  10. Nat Commun. 2025 Jun 20. 16(1): 5355
    Iron deficiency causes aspartate-sensitive dysfunction in CD8+ T cells.
    Megan R Teh, Nancy Gudgeon, Joe N Frost, Linda V Sinclair, Alastair L Smith, Christopher L Millington, Barbara Kronsteiner, Jennie Roberts, Bryan P Marzullo, Hannah Murray, Alexandra E Preston, Victoria Stavrou, Jan Rehwinkel, Thomas A Milne, Daniel A Tennant, Susanna J Dunachie, Andrew E Armitage, Sarah Dimeloe, Hal Drakesmith.
      Iron is an irreplaceable co-factor for metabolism. Iron deficiency affects >1 billion people and decreased iron availability impairs immunity. Nevertheless, how iron deprivation impacts immune cell function remains poorly characterised. We interrogate how physiologically low iron availability affects CD8+ T cell metabolism and function, using multi-omic and metabolic labelling approaches. Iron limitation does not substantially alter initial post-activation increases in cell size and CD25 upregulation. However, low iron profoundly stalls proliferation (without influencing cell viability), alters histone methylation status, gene expression, and disrupts mitochondrial membrane potential. Glucose and glutamine metabolism in the TCA cycle is limited and partially reverses to a reductive trajectory. Previous studies identified mitochondria-derived aspartate as crucial for proliferation of transformed cells. Despite aberrant TCA cycling, aspartate is increased in stalled iron deficient CD8+ T cells but is not utilised for nucleotide synthesis, likely due to trapping within depolarised mitochondria. Exogenous aspartate markedly rescues expansion and some functions of severely iron-deficient CD8+ T cells. Overall, iron scarcity creates a mitochondrial-located metabolic bottleneck, which is bypassed by supplying inhibited biochemical processes with aspartate. These findings reveal molecular consequences of iron deficiency for CD8+ T cell function, providing mechanistic insight into the basis for immune impairment during iron deficiency.
    DOI:  https://doi.org/10.1038/s41467-025-60204-7
  11. Nature. 2025 Jun 13.
    Why science recruiters struggle to find high-calibre candidates.
    Julie Gould.
      
    Keywords:  Careers; Industry; Lab life
    DOI:  https://doi.org/10.1038/d41586-025-01851-0
  12. Nat Neurosci. 2025 Jun 13.
    Myelin-axon interface vulnerability in Alzheimer's disease revealed by subcellular proteomics and imaging of human and mouse brain.
    Yifei Cai, Iguaracy Pinheiro-de-Sousa, Mykhaylo Slobodyanyuk, Fuyi Chen, Tram Huynh, Jean Kanyo, Peiyang Tang, Lukas A Fuentes, Amber Braker, Rachel Welch, Anita Huttner, Lei Tong, Peng Yuan, TuKiet T Lam, Evangelia Petsalaki, Jüri Reimand, Angus C Nairn, Jaime Grutzendler.
      Myelin ensheathment is essential for rapid axonal conduction, metabolic support and neuronal plasticity. In Alzheimer's disease (AD), disruptions in myelin and axonal structures occur, although the underlying mechanisms remain unclear. We implemented proximity labeling subcellular proteomics of the myelin-axon interface in postmortem human brains from AD donors and 15-month-old male and female 5XFAD mice. We uncovered multiple dysregulated signaling pathways and ligand-receptor interactions, including those linked to amyloid-β processing, axonal outgrowth and lipid metabolism. Expansion microscopy confirmed the subcellular localization of top proteomic hits and revealed amyloid-β aggregation within the internodal periaxonal space and paranodal/juxtaparanodal channels. Although overall myelin coverage is preserved, we found reduced paranode density, aberrant myelination and altered paranode positioning around amyloid-plaque-associated dystrophic axons. These findings suggest that the myelin-axon interface is a critical site of protein aggregation and disrupted neuro-glial signaling in AD.
    DOI:  https://doi.org/10.1038/s41593-025-01973-8
  13. Nat Cell Biol. 2025 Jun;27(6): 878
    Surveilling ribosome biogenesis.
    Daryl J V David.
      
    DOI:  https://doi.org/10.1038/s41556-025-01700-2
  14. Nat Immunol. 2025 Jun 17.
    pDCs drive immunopathology by sensing oxidized mitochondrial DNA.
    Moshe Arditi, Timothy R Crother.
      
    DOI:  https://doi.org/10.1038/s41590-025-02193-9
  15. Nature. 2025 Jun 18.
    Kupffer cell programming by maternal obesity triggers fatty liver disease.
    Hao Huang, Nora R Balzer, Lea Seep, Iva Splichalova, Nelli Blank-Stein, Maria Francesca Viola, Eliana Franco Taveras, Kerim Acil, Diana Fink, Franzisca Petrovic, Nikola Makdissi, Seyhmus Bayar, Katharina Mauel, Carolin Radwaniak, Jelena Zurkovic, Amir H Kayvanjoo, Klaus Wunderling, Malin Jessen, Mohamed H Yaghmour, Lukas Kenner, Thomas Ulas, Stephan Grein, Joachim L Schultze, Charlotte L Scott, Martin Guilliams, Zhaoyuan Liu, Florent Ginhoux, Marc D Beyer, Christoph Thiele, Felix Meissner, Jan Hasenauer, Dagmar Wachten, Elvira Mass.
      Kupffer cells (KCs) are tissue-resident macrophages that colonize the liver early during embryogenesis1. Upon liver colonization, KCs rapidly acquire a tissue-specific transcriptional signature, mature alongside the developing liver and adapt to its functions1-3. Throughout development and adulthood, KCs perform distinct core functions that are essential for liver and organismal homeostasis, including supporting fetal erythropoiesis, postnatal erythrocyte recycling and liver metabolism4. However, whether perturbations of macrophage core functions during development contribute to or cause disease at postnatal stages is poorly understood. Here, we utilize a mouse model of maternal obesity to perturb KC functions during gestation. We show that offspring exposed to maternal obesity develop fatty liver disease, driven by aberrant developmental programming of KCs that persists into adulthood. Programmed KCs promote lipid uptake by hepatocytes through apolipoprotein secretion. KC depletion in neonate mice born to obese mothers, followed by replenishment with naive monocytes, rescues fatty liver disease. Furthermore, genetic ablation of the gene encoding hypoxia-inducible factor-α (HIF1α) in macrophages during gestation prevents the metabolic programming of KCs from oxidative phosphorylation to glycolysis, thereby averting the development of fatty liver disease. These results establish developmental perturbation of KC functions as a causal factor in fatty liver disease in adulthood and position fetal-derived macrophages as critical intergenerational messengers within the concept of developmental origins of health and diseases5.
    DOI:  https://doi.org/10.1038/s41586-025-09190-w
  16. Nat Commun. 2025 Jun 19. 16(1): 5344
    TGFα controls checkpoints in CNS resident and infiltrating immune cells to promote resolution of inflammation.
    Lena Lößlein, Mathias Linnerbauer, Finnja Zuber, Thanos Tsaktanis, Oliver Vandrey, Anne Peter, Franziska Panier, Julia Zissler, Vivienne Riekher, Tobias Bäuerle, Jannis Hanspach, Frederik B Laun, Lisa Nagel, Lisa Mészáros, Friederike Zunke, Jürgen Winkler, Ulrike J Naumann, Nora Schwingen, Emely Neumaier, Arthur Liesz, Francisco Quintana, Veit Rothhammer.
      After acute lesions in the central nervous system (CNS), the interaction of microglia, astrocytes, and infiltrating immune cells decides over their resolution or chronification. However, this CNS-intrinsic cross-talk is poorly characterized. Analyzing cerebrospinal fluid (CSF) samples of Multiple Sclerosis (MS) patients as well as CNS samples of female mice with experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we identify microglia-derived TGFα as key factor driving recovery. Through mechanistic in vitro studies, in vivo treatment paradigms, scRNA sequencing, CRISPR-Cas9 genetic perturbation models and MRI in the EAE model, we show that together with other glial and non-glial cells, microglia secrete TGFα in a highly regulated temporospatial manner in EAE. Here, TGFα contributes to recovery by decreasing infiltrating T cells, pro-inflammatory myeloid cells, oligodendrocyte loss, demyelination, axonal damage and neuron loss even at late disease stages. In a therapeutic approach in EAE, blood-brain barrier penetrating intranasal application of TGFα attenuates pro-inflammatory signaling in astrocytes and CNS infiltrating immune cells while promoting neuronal survival and lesion resolution. Together, microglia-derived TGFα is an important mediator of glial-immune crosstalk, highlighting its therapeutic potential in resolving acute CNS inflammation.
    DOI:  https://doi.org/10.1038/s41467-025-60363-7
  17. Diabetes. 2025 Jun 17. pii: db241141. [Epub ahead of print]
    Dynamic Ca2+-Dependent Transcription Links Metabolic Stress to Impaired β-Cell Identity.
    Anna B Osipovich, Matthew T Dickerson, Jean-Philippe Cartailler, Shristi Shrestha, Nicole M Wright, David A Jacobson, Mark A Magnuson.
       ARTICLE HIGHLIGHTS: This study was undertaken to establish a temporal link between an increase in intracellular Ca2+ concentration and the loss of pancreatic β-cell identity. We profiled the alterations in Ca2+ dynamics and gene transcription that occur in freshly isolated islets following membrane depolarization. We show that initially adaptive Ca2+-dependent transcription changes, mediated largely by CREB and CREB-dependent transcription factors, rapidly become maladaptive, causing the loss of β-cell identity and function. We also show that many effector genes linked to nearby human type 2 diabetes susceptibility loci are regulated by Ca2+-dependent mechanisms.
    DOI:  https://doi.org/10.2337/db24-1141
  18. J Clin Invest. 2025 Jun 16. pii: e186593. [Epub ahead of print]135(12):
    Hemodynamic forces prevent myxomatous valve disease in mice through KLF2/4 signaling.
    Jesse A Pace, Lauren M Goddard, Courtney C Hong, Liqing Wang, Jisheng Yang, Mei Chen, Yitian Xu, Martin H Dominguez, Siqi Gao, Xiaowen Chen, Patricia Mericko-Ishizuka, Can Tan, Tsutomu Kume, Wenbao Yu, Kai Tan, Wayne W Hancock, Giovanni Ferrari, Mark L Kahn.
      Myxomatous valve disease (MVD) is the most common form of cardiac valve disease in the developed world. A small fraction of MVD is syndromic and arises in association with matrix protein defects such as those in Marfan syndrome, but most MVD is acquired later in life through an undefined pathogenesis. The KLF2/4 transcription factors mediate endothelial fluid shear responses, including those required to create cardiac valves during embryonic development. Here we test the role of hemodynamic shear forces and downstream endothelial KLF2/4 in mature cardiac valves. We find that loss of hemodynamic forces in heterotopically transplanted hearts or genetic deletion of KLF2/4 in cardiac valve endothelium confers valve cell proliferation and matrix deposition associated with valve thickening, findings also observed in mice expressing the mutant fibrillin-1 protein known to cause human MVD. Transcriptomic and histologic analysis reveals increased monocyte recruitment and TGF-β signaling in both fibrillin-1-mutant valves and valves lacking hemodynamic forces or endothelial KLF2/4 function, but only loss of TGF-β/SMAD signaling rescued myxomatous changes. We observed reduced KLF2/4 expression and augmented SMAD signaling in human MVD. These studies identify hemodynamic activation of endothelial KLF2/4 as an environmental homeostatic regulator of cardiac valves and suggest that non-syndromic MVD may arise in association with disturbed blood flow across the aging valve.
    Keywords:  Cardiology; Cardiovascular disease; Endothelial cells; Vascular biology
    DOI:  https://doi.org/10.1172/JCI186593
  19. Immunity. 2025 Jun 11. pii: S1074-7613(25)00241-9. [Epub ahead of print]
    A conserved immune dysregulation signature is associated with infection severity, risk factors prior to infection, and treatment response.
    Ananthakrishnan Ganesan, Andrew R Moore, Hong Zheng, Jiaying Toh, Michael Freedman, Andrew T Magis, James R Heath, Purvesh Khatri.
      Older age, being male, obesity, smoking, and comorbidities (e.g., diabetes, asthma) are associated with an increased risk for severe infections. We hypothesized that there is a conserved common immune dysregulation across these risk factors. We integrated single-cell and bulk transcriptomic data and proteomic data from 12,026 blood samples across 68 cohorts to test this hypothesis. We found that our previously described 42-gene Severe-or-Mild (SoM) signature was associated with each of these risk factors prior to infection. Furthermore, this conserved immune signature was modifiable using immunomodulatory drugs and lifestyle changes. The SoM score predicted the individuals with sepsis who would be harmed by hydrocortisone treatment and individuals with asthma who would not respond to monoclonal antibody treatment. Finally, the SoM score was associated with all-cause mortality. The SoM signature has the potential to redefine the immunologic framing of the baseline immune state and response to chronic, subacute, and acute illnesses.
    Keywords:  all-cause mortality; conserved immune dysregulation; impact of lifestyle changes; multi-cohort analysis; multi-omics; risk factors for severe infections; sepsis; treatment response prediction
    DOI:  https://doi.org/10.1016/j.immuni.2025.05.020
  20. Nature. 2025 Jun 16.
    Cryo-EM structure of a natural RNA nanocage.
    Xiaobin Ling, Dmitrij Golovenko, Jianhua Gan, Jinbiao Ma, Andrei A Korostelev, Wenwen Fang.
      Long (>200 nucleotides) non-coding RNAs (lncRNAs) play important roles in diverse aspects of life. Over 20 classes of lncRNAs have been identified in bacteria and bacteriophages through comparative genomics analyses, but their biological functions remain largely unexplored1-3. Due to the large sizes, the structural determinants of most lncRNAs also remain uncharacterized. Here we report the structures of two natural RNA nanocages formed by the lncRNA ROOL (rumen-originating, ornate, large) found in bacterial and phage genomes. ~2.9 Å cryo-electron microscopy (cryo-EM) structures reveal that ROOL RNAs form an octameric nanocage with a 28-nm diameter and 20-nm axial length, whose hollow inside features poorly ordered regions. The octamer is stabilized by numerous tertiary and quaternary interactions, including triple-strand A-minors that we propose to name "A-minor staples". The structure of an isolated ROOL monomer at ~3.2-Å resolution indicates that nanocage assembly involves a strand-swapping mechanism resulting in quaternary kissing loops. Finally, we show that ROOL RNA fused to an RNA aptamer, tRNA, or microRNA retains its structure forming a nanocage with radially displayed cargos. Our findings therefore may enable the engineering of novel RNA nanocages as delivery vehicles for research and therapeutic applications.
    DOI:  https://doi.org/10.1038/s41586-025-09262-x
  21. Nat Genet. 2025 Jun 18.
    Transferability of European-derived Alzheimer's disease polygenic risk scores across multiancestry populations.
    EADB
      A polygenic score (PGS) for Alzheimer's disease (AD) was derived recently from data on genome-wide significant loci in European ancestry populations. We applied this PGS to populations in 17 European countries and observed a consistent association with the AD risk, age at onset and cerebrospinal fluid levels of AD biomarkers, independently of apolipoprotein E locus (APOE). This PGS was also associated with the AD risk in many other populations of diverse ancestries. A cross-ancestry polygenic risk score improved the association with the AD risk in most of the multiancestry populations tested when the APOE region was included. Finally, we found that the PGS/polygenic risk score captured AD-specific information because the association weakened as the diagnosis was broadened. In conclusion, a simple PGS captures the AD-specific genetic information that is common to populations of different ancestries, although studies of more diverse populations are still needed to better characterize the genetics of AD.
    DOI:  https://doi.org/10.1038/s41588-025-02227-w
  22. Cell Signal. 2025 Jun 16. pii: S0898-6568(25)00363-8. [Epub ahead of print] 111948
    Activation of STING pathway by mitochondrial fission negatively regulates adipogenic differentiation of 3 T3-L1 cells.
    Kai Ma, Haoxuan Sun, Xiaoyun Wu, Jinping Quan, Rong Tang, Weiwei Liu, Toshihiko Hayashi, Kazunori Mizuno, Shunji Hattori, Hitomi Fujisaki, Takashi Ikejima.
      Adipocyte hyperplasia refers to the increase in the number of adipocytes, whereas adipocyte hypertrophy pertains to the enlargement of individual adipocytes resulting from the accumulation of lipid droplets. In this study, we found that activation of the STING signalling pathway occurs during adipogenic differentiation of 3 T3-L1 preadipocytes. Interestingly, inhibiting the STING pathway by using STING antagonist H151 or siRNA targeting STING promotes adipocyte differentiation and increases adipocyte numbers, while activation of STING inhibits adipogenic differentiation. Silencing the STING canonical downstream IRF3, or inhibiting the proton channel activity of STING enhances adipogenic differentiation, confirming the negative modulation of adipogenic differentiation by STING. In vivo, intraperitoneal injection of H151 into mice with a high-fat diet further enhances the adipocyte hyperplasia, as shown by the increased volume of adipose tissues, but consistent sizes of adipocytes. During the adipogenic differentiation of 3 T3-L1 cells, DRP1-mediated mitochondrial fission is enhanced, and causes mitochondrial DNA leakage, which in turn activates the STING pathway. However, inhibition of mitochondrial fission represses adipogenic differentiation of 3 T3-L1 cells in spite of the down-regulation of STING pathway. Therefore, our results indicate that adipogenic differentiation is associated with DRP1-induced mitochondrial fission. However, the leakage of mitochondrial DNA caused by DRP1-induced mitochondrial fission activates the STING signalling pathway, which negatively regulates adipogenic differentiation. Tissue specific reduction of DRP1-associated mitochondrial fission or STING enhancement might be new strategies for the therapy of obesity-associated diseases.
    Keywords:  3 T3-L1 cells; Adipocyte differentiation; DRP1; Mitochondria; STING
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111948
  23. Trends Mol Med. 2025 Jun 16. pii: S1471-4914(25)00116-9. [Epub ahead of print]
    Toll-like receptors in B cells and obesity.
    Pai Wang, Can Hou, F Susan Wong, Li Wen.
      Toll-like receptors (TLRs) play a pivotal role in both innate and adaptive immunity, primarily by detecting pathogen-associated molecular patterns (PAMPs) and orchestrating immune responses. Although TLR-driven activation of dendritic cells (DCs) and subsequent T cell differentiation are well characterized, the function of TLRs in B cells remains underexplored. In the context of obesity, excessive adipose tissue accumulation triggers chronic inflammation driven in part by activation of TLR signaling. This review explores the expression, function, and signaling mechanisms of TLRs in B cells, and emphasizes their role in modulating immune responses associated with obesity. Furthermore, we discuss how TLR-mediated inflammatory activity in B cells may contribute to metabolic dysregulation, and offer insights into the crosstalk between immune function and metabolic disease in obesity.
    Keywords:  B cell; Toll-like receptors; adaptive immunity; innate immunity; obesity
    DOI:  https://doi.org/10.1016/j.molmed.2025.05.005
  24. Nat Cardiovasc Res. 2025 Jun 18.
    Loss of effector Treg signature in APOB-reactive CD4+ T cells in patients with coronary artery disease.
    Payel Roy, Anusha Bellapu, Sujit Silas Armstrong Suthahar, Mohammad Oliaeimotlagh, Qingkang Lyu, Smriti Parashar, Jeffrey Makings, Runpei Wu, Sunil Kumar, Megh Mehta, Austin W T Chiang, Alessandro Sette, Coleen A McNamara, Klaus Ley.
      Atherosclerosis underlies most coronary artery disease (CAD). It involves a significant autoimmune component against apolipoprotein B (APOB). In this study, we used short activation-induced marker (AIM) assays to characterize APOB-reactive CD4+ T cells in patients with angiographically verified CAD. APOB-reactive CD4+ T cells expressing CD25 and 4-1BB markers were the most abundant. Their frequency correlated positively with CAD severity. Transcriptomic analysis revealed that these cells were clonally expanded and significantly enriched in genes expressed in tissue-homing effector regulatory T (eTreg) cells. They shared signatures with CD4+ T cells in mouse and human plaques, including expression of the plaque-homing chemokine receptor CXCR6. With increasing disease severity, the Treg signature was progressively and significantly lost. Conversely, APOB-specific Treg cells from patients with severe CAD gained glycolytic and interferon response signatures. We conclude that mild CAD is associated with a regulatory program in APOB-reactive CD4+ T cells, which is replaced by a pro-inflammatory program in patients with severe CAD.
    DOI:  https://doi.org/10.1038/s44161-025-00671-9
  25. Nat Metab. 2025 Jun 20.
    A brief guide to statistical analysis of grouped data in preclinical research.
    Colby J Vorland, Lilian Golzarri-Arroyo, David B Allison.
      
    DOI:  https://doi.org/10.1038/s42255-025-01323-9
  26. Nat Cell Biol. 2025 Jun 19.
    Organelle conversations drive ferroptosis.
    Ancély Ferreira Dos Santos, José Pedro Friedmann Angeli.
      
    DOI:  https://doi.org/10.1038/s41556-025-01694-x
  27. J Clin Invest. 2025 Jun 19. pii: e181034. [Epub ahead of print]
    Blood immunophenotyping identifies distinct kidney histopathology and outcomes in patients with lupus nephritis.
    Alice Horisberger, Alec Griffith, Joshua Keegan, Arnon Arazi, John Pulford, Ekaterina Murzin, Kaitlyn Howard, Brandon Hancock, Andrea Fava, Takanori Sasaki, Tusharkanti Ghosh, Jun Inamo, Rebecca Beuschel, Ye Cao, Katie Preisinger, Maria Gutierrez-Arcelus, Thomas M Eisenhaure, Joel Guthridge, Paul J Hoover, Maria Dall'Era, David Wofsy, Diane L Kamen, Kenneth C Kalunian, Richard Furie, Michael Belmont, Peter Izmirly, Robert Clancy, David Hildeman, E Steve Woodle, William Apruzzese, Maureen A McMahon, Jennifer Grossman, Jennifer L Barnas, Fernanda Payan-Schober, Mariko Ishimori, Michael Weisman, Matthias Kretzler, Celine C Berthier, Jeffrey B Hodgin, Dawit S Demeke, Chaim Putterman, Michael B Brenner, Jennifer H Anolik, Soumya Raychaudhuri, Nir Hacohen, Judith A James, Anne Davidson, Michelle A Petri, Jill P Buyon, Betty Diamond, Fan Zhang, James A Lederer, Deepak A Rao.
      Lupus nephritis (LN) is a frequent manifestation of systemic lupus erythematosus, and fewer than half of patients achieve complete renal response with standard immunosuppressants. Identifying non-invasive, blood-based immune alterations associated with renal injury could aid therapeutic decisions. Here, we used mass cytometry immunophenotyping of peripheral blood mononuclear cells in 145 patients with biopsy-proven LN and 40 healthy controls to evaluate the heterogeneity of immune activation and identify correlates of renal parameters. Unbiased analysis identified three immunologically distinct groups of patients that were associated with different patterns of histopathology, renal cell infiltrates, urine proteomic profiles, and treatment response at one year. Patients with enriched circulating granzyme B+ T cells showed more active disease and increased numbers of activated CD8 T cells in the kidney, yet they had the highest likelihood of treatment response. A second group characterized by a high type I interferon signature had a lower likelihood of response to therapy, while a third group appeared immunologically inactive but with chronic renal injuries. The major immunologic axes of variation could be distilled down to five simple cytometric parameters that recapitulate several clinical associations, highlighting the potential for blood immunoprofiling to translate to clinically useful non-invasive metrics to assess immune-mediated disease in LN.
    Keywords:  Autoimmunity; Biomarkers; Immunology; Lupus
    DOI:  https://doi.org/10.1172/JCI181034
  28. Cell. 2025 Jun 13. pii: S0092-8674(25)00616-6. [Epub ahead of print]
    The immunoproteasome disturbs neuronal metabolism and drives neurodegeneration in multiple sclerosis.
    Marcel S Woo, Johannes Brand, Lukas C Bal, Manuela Moritz, Mark Walkenhorst, Vanessa Vieira, Inbal Ipenberg, Nicola Rothammer, Man Wang, Batuhan Dogan, Desirée Loreth, Christina Mayer, Darwin Nagel, Ingrid Wagner, Lena Kristina Pfeffer, Peter Landgraf, Marco van Ham, Kuno M-J Mattern, Ingo Winschel, Noah Frantz, Jana K Sonner, Henrike K Grosshans, Albert Miguela, Simone Bauer, Nina Meurs, Anke Müller, Lars Binkle-Ladisch, Gabriela Salinas, Lothar Jänsch, Daniela C Dieterich, Maria Riedner, Elke Krüger, Frank L Heppner, Markus Glatzel, Victor G Puelles, Jan Broder Engler, Jens Randel Nyengaard, Thomas Misgeld, Martin Kerschensteiner, Doron Merkler, Catherine Meyer-Schwesinger, Manuel A Friese.
      Inflammation, aberrant proteostasis, and energy depletion are hallmarks of neurodegenerative diseases such as multiple sclerosis (MS). However, the interplay between inflammation, proteasomal dysfunction in neurons, and its consequences for neuronal integrity remains unclear. Using transcriptional, proteomic, and functional analyses of proteasomal subunits in inflamed neurons, we found that interferon-γ-mediated induction of the immunoproteasome subunit, proteasome 20S beta 8 (PSMB8) impairs the proteasomal balance, resulting in reduced proteasome activity. This reduction causes the accumulation of phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a key metabolic regulator, leading to enhanced neuronal glycolysis, reduced pentose phosphate pathway activity, oxidative injury, and ferroptosis. Neuron-specific genetic and systemic pharmacological targeting of PSMB8 or PFKFB3 protected neurons in vitro and in a mouse model of MS. Our findings provide a unifying explanation for proteasomal dysfunction in MS and possibly other neurodegenerative diseases, linking inflammation to metabolic disruption, and presenting an opportunity for targeted neuroprotective therapies.
    Keywords:  excitotoxicity; ferroptosis; glycolysis; immunoproteasome; interferon-γ; metabolism; multiple sclerosis; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.1016/j.cell.2025.05.029
This page is being maintained by Thomas Krichel. It was last updated on 2025‒06‒24 at 15:43.