bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–10–05
twenty-six papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Forcing cell fate.
  2. Genetic perturbations link autoimmune risk variants to T cell function.
  3. MTCH2 modulates CPT1 activity to regulate lipid metabolism of adipocytes.
  4. Macrophages drive fat cell differentiation.
  5. Power and profit drive what we eat: here's why the food system needs a revolution.
  6. Effector-memory ILC2s.
  7. Evading tumor evasion.
  8. Prenatal exposure to Zika virus shapes offspring neutrophil function in a sex-specific manner.
  9. ER shaping closes the gap in wound healing.
  10. Efferocytic remodelling of pancreatic islet macrophages by limited β-cell death.
  11. Regulators of CD8+ T cell exhaustion.
  12. Proteotoxic stress response drives T cell exhaustion and immune evasion.
  13. A genetic map of human metabolism across the allele frequency spectrum.
  14. Phase separation meets energy generation to boost longevity.
  15. CTLA-4 blockade shifts the B cell repertoire towards autoimmunity.
  16. Creative hobbies could slow brain ageing at the molecular level.
  17. Motion impact score for detecting spurious brain-behavior associations.
  18. Macrophage WDFY3 mitigates autoimmunity by enhancing efferocytosis and suppressing T cell activation in mice.
  19. Age is an intrinsic driver of inflammatory responses to malaria.
  20. The power of the few: RORγt+ dendritic cells promote food-specific peripheral regulatory T cells.
  21. The inner nuclear membrane protein LEMD3 organizes the 3D chromatin architecture to maintain vascular smooth muscle cell identity.
  22. Age-Associated Transcriptomic and Epigenetic Alterations in Mouse Hippocampus.
  23. Genetic determinants of monocyte splicing are enriched for disease susceptibility loci.
  24. Acetyl-CoA carboxylase-1 inhibition increases regulatory T-Cell metabolism and graft-vs-host disease treatment efficacy via mitochondrial fusion.
  25. Endothelial gateways for brain lipid uptake and metabolism.
  26. Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1.
  1. Nat Cell Biol. 2025 Sep 29.
    Forcing cell fate.
    Roberto Mayor.
      
    DOI:  https://doi.org/10.1038/s41556-025-01775-x
  2. Nat Genet. 2025 Sep 29.
    Genetic perturbations link autoimmune risk variants to T cell function.
      
    DOI:  https://doi.org/10.1038/s41588-025-02302-2
  3. Nat Commun. 2025 Oct 03. 16(1): 8831
    MTCH2 modulates CPT1 activity to regulate lipid metabolism of adipocytes.
    Chunyan Wu, Tongtong Wang, Adhideb Ghosh, Fen Long, Anand Kumar Sharma, Tina Dahlby, Falko Noé, Ilenia Severi, Georgia Colleluori, Saverio Cinti, Antonio Giordano, Lianggong Ding, Radhika Khandelwal, Sarantos Kostidis, Martin Giera, Lucia Balazova, Vincent Gardeux, Laith Abu-Nawwas, Bart Deplancke, Sabita Chourasia, Sandra Kleiner, Bradford S Hamilton, Juan Manuel Alcántara Alcántara, Jonatan R Ruiz, Matthias Blüher, Anton Pekcec, Miroslav Balaz, Atan Gross, Heike Neubauer, Christian Wolfrum.
      Metabolic disorders, including obesity and metabolic-associated steatohepatitis, arise from a chronic energy surplus. Thus, enhancing energy dissipation through increased respiration holds significant therapeutic potential for metabolic disorders. Through a comprehensive analysis of human and murine adipose tissues, along with a functional screen, we identify mitochondrial carrier homolog 2, a mitochondrial outer membrane protein, as a pivotal regulator of mitochondrial metabolism. Intriguingly, its expression in adipose tissue is a strong determinant of obesity in humans. Adipocyte-specific ablation of mitochondrial carrier homolog 2 improves mitochondrial function and whole-body energy expenditure, independent of uncoupling protein 1. Furthermore, mitochondrial carrier homolog 2 regulates mitochondrial influx of free fatty acids by modulating the sensitivity of carnitine palmitoyltransferase 1 to malonyl-CoA through direct physical interaction, leading to enhanced energy expenditure in adipocytes/adipose tissue. Here we show mitochondrial carrier homolog 2 functions as a negative regulator of energy metabolism in adipocytes and represents a potential target for treating obesity and related metabolic disorders.
    DOI:  https://doi.org/10.1038/s41467-025-63880-7
  4. Nat Immunol. 2025 Oct;26(10): 1627
    Macrophages drive fat cell differentiation.
    Stephanie Houston.
      
    DOI:  https://doi.org/10.1038/s41590-025-02305-5
  5. Nature. 2025 Oct;646(8083): 29-30
    Power and profit drive what we eat: here's why the food system needs a revolution.
    Laura Kelly.
      
    Keywords:  Agriculture; Industry; Nutrition; Obesity
    DOI:  https://doi.org/10.1038/d41586-025-03150-0
  6. Nat Immunol. 2025 Oct;26(10): 1627
    Effector-memory ILC2s.
    Paula Jauregui.
      
    DOI:  https://doi.org/10.1038/s41590-025-02304-6
  7. Nat Immunol. 2025 Oct;26(10): 1627
    Evading tumor evasion.
    Laurie A Dempsey.
      
    DOI:  https://doi.org/10.1038/s41590-025-02303-7
  8. Nat Commun. 2025 Oct 03. 16(1): 8839
    Prenatal exposure to Zika virus shapes offspring neutrophil function in a sex-specific manner.
    Jiahui Ding, Anna Hu, Annie Thy Nguyen, Grace M Swanson, Aditi Singh, Nicholas Adzibolosu, Diana Manchorova, Elizabeth Findeis, Anthony Maxwell, Yuan He, Marta Rodriguez Garcia, Gil Mor.
      Maternal viral infection during pregnancy can have lasting consequences on offspring immune development. Zika virus (ZIKV) is known to trigger maternal immune activation (MIA), yet its impact on fetal and postnatal innate immunity remains poorly understood. Here, we investigate how prenatal exposure to ZIKV influences offspring neutrophil function using a murine model of maternal infection. We identify a sex-dimorphic placental response to ZIKV and observed hyperinflammation in ZIKV-exposed male offspring following LPS challenge. Functional assays reveal impaired reactive oxygen species production and defective neutrophil extracellular trap formation in neutrophils from ZIKV-exposed offspring. Furthermore, we identify A20 as a key sex-dimorphic regulator of neutrophil activation and survival. Here, we show that maternal viral infection during pregnancy programs long-term offspring immunity in a sex-specific manner, providing insights into the developmental origins of differential susceptibility to infections and inflammatory diseases later in life.
    DOI:  https://doi.org/10.1038/s41467-025-63941-x
  9. Nat Cell Biol. 2025 Sep 30.
    ER shaping closes the gap in wound healing.
    Craig Blackstone.
      
    DOI:  https://doi.org/10.1038/s41556-025-01779-7
  10. Nature. 2025 Oct 01.
    Efferocytic remodelling of pancreatic islet macrophages by limited β-cell death.
    Pavel N Zakharov, Chanchal S Chowdhury, Orion J Peterson, Brady Barron, Anthony N Vomund, Laurent Gorvel, Emil R Unanue, Eynav Klechevsky, Xiaoxiao Wan, Kodi S Ravichandran.
      The primary driver of type I diabetes is the autoimmune T cells that destroy insulin-producing β-cells within the islets of Langerhans in the pancreas1. Pancreatic islet macrophages have also been variably linked to disease onset and progression. As macrophage-mediated removal of dying cells through efferocytosis regulates tissue homeostasis and immune responses2, here we investigated how efferocytosis by intra-islet macrophages influences the immune environment of pancreatic islets. Using a series of complementary omics-based and functional approaches, we identify a subset of anti-inflammatory intra-islet efferocytic macrophages (e-Mac) within the pancreas of mice and humans. When limited β-cell apoptosis is induced in vivo in wild-type C57BL/6 mice and diabetic-prone NOD mice, islet macrophages adopt this e-Mac phenotype without an apparent increase in the total numbers of intra-islet macrophages. Such limited β-cell apoptosis and increase in e-Mac numbers led to long-term suppression of autoimmune diabetes in NOD mice. This e-Mac phenotype could also be recapitulated ex vivo by co-culturing macrophages with apoptotic β-cells. Mechanistically, the e-Mac-enriched populations imparted an anergic-like state on CD4+ T cells ex vivo and promoted accumulation of such anergic-like CD4+ T cells in vivo within the islets. Analysing macrophage-T cell interactions within pancreatic islets using NicheNet and targeted experimental validation, we identify the IGF-1-IGF1R axis as a contributor to the anergic-like T cell phenotype in the islets. Collectively, these data advance a concept that efferocytosis-associated reprogramming of the islet macrophages and the subsequent influence on the adaptive immune response could be beneficial in modulating diabetic autoimmunity.
    DOI:  https://doi.org/10.1038/s41586-025-09560-4
  11. Nat Rev Immunol. 2025 Oct 01.
    Regulators of CD8+ T cell exhaustion.
    Qinli Sun, Chen Dong.
      T cell exhaustion is an adaptive and distinct cell fate that emerges in response to persistent antigen stimulation, primarily in chronic infections and cancer. It is characterized by a progressive loss of effector functions and sustained expression of multiple inhibitory receptors. Progression to T cell exhaustion is driven by persistent antigen stimulation through the T cell receptor and is modulated by signals from co-stimulatory and inhibitory molecules as well as by microenvironmental factors such as cytokines, metabolites and neuronal factors. These extrinsic cellular factors reshape the T cell transcriptome, epigenome and metabolism towards a state of exhaustion through critical intrinsic cell regulators. In this Review, we summarize our current understanding of the regulators involved in T cell exhaustion, highlighting their roles in directing the fates and functionalities of distinct exhausted T cell subsets and how they may be harnessed for the development of improved immunotherapies against cancer and chronic infections.
    DOI:  https://doi.org/10.1038/s41577-025-01221-x
  12. Nature. 2025 Oct 01.
    Proteotoxic stress response drives T cell exhaustion and immune evasion.
    Yi Wang, Anjun Ma, No-Joon Song, Ariana E Shannon, Yaa S Amankwah, Xingyu Chen, Weidong Wu, Ziyu Wang, Abbey A Saadey, Amir Yousif, Gautam Ghosh, Jay K Mandula, Maria Velegraki, Tong Xiao, Haitao Wen, Stanley Ching-Cheng Huang, Ruoning Wang, Christian M Beusch, Abdelhameed S Dawood, David E Gordon, Mohamed S Abdel-Hakeem, Hazem E Ghoneim, Gang Xin, Brian C Searle, Zihai Li.
      Chronic infections and cancer cause T cell dysfunction known as exhaustion. This cell state is caused by persistent antigen exposure, suboptimal co-stimulation and a plethora of hostile factors that dampen protective immunity and limit the efficacy of immunotherapies1-4. The mechanisms that underlie T cell exhaustion remain poorly understood. Here we analyse the proteome of CD8+ exhausted T (Tex) cells across multiple states of exhaustion in the context of both chronic viral infections and cancer. We show that there is a non-stochastic pathway-specific discordance between mRNA and protein dynamics between T effector (Teff) and Tex cells. We identify a distinct proteotoxic stress response (PSR) in Tex cells, which we term Tex-PSR. Contrary to canonical stress responses that induce a reduction in protein synthesis5,6, Tex-PSR involves an increase in global translation activity and an upregulation of specialized chaperone proteins. Tex-PSR is further characterized by the accumulation of protein aggregates and stress granules and an increase in autophagy-dominant protein catabolism. We establish that disruption of proteostasis alone can convert Teff cells to Tex cells, and we link Tex-PSR mechanistically to persistent AKT signalling. Finally, disruption of Tex-PSR-associated chaperones in CD8+ T cells improves cancer immunotherapy in preclinical models. Moreover, a high Tex-PSR in T cells from patients with cancer confers poor responses to clinical immunotherapy. Collectively, our findings indicate that Tex-PSR is a hallmark and a mechanistic driver of T cell exhaustion, which raises the possibility of targeting proteostasis pathways as an approach for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-025-09539-1
  13. Nat Genet. 2025 Oct 03.
    A genetic map of human metabolism across the allele frequency spectrum.
    Martijn Zoodsma, Carl Beuchel, Summaira Yasmeen, Leonhard Kohleick, Aakash Nepal, Mine Koprulu, Florian Kronenberg, Manuel Mayr, Alice Williamson, Maik Pietzner, Claudia Langenberg.
      Genetic studies of human metabolism have been limited in scale and allelic breadth. Here we provide a data-driven map of the genetic regulation of circulating small molecules and lipoprotein characteristics (249 traits) measured using proton nuclear magnetic resonance spectroscopy across the allele frequency spectrum in ~450,000 individuals. Trans-ancestral meta-analyses identify 29,824 locus-metabolite associations mapping to 753 regions with effects largely consistent between men and women and large ancestral groups represented in UK Biobank. We observe and classify extreme genetic pleiotropy, identify regulators of lipid metabolism, and assign effector genes at >100 loci through rare-to-common allelic series. We propose roles for genes less established in metabolic control (for example, SIDT2), genes characterized by phenotypic heterogeneity (for example, APOA1) and genes with specific disease relevance (for example, VEGFA). Our study demonstrates the value of broad, large-scale metabolomic phenotyping to identify and characterize regulators of human metabolism.
    DOI:  https://doi.org/10.1038/s41588-025-02355-3
  14. Nat Aging. 2025 Oct 03.
    Phase separation meets energy generation to boost longevity.
    Nektarios Tavernarakis.
      
    DOI:  https://doi.org/10.1038/s43587-025-00989-w
  15. J Clin Invest. 2025 Sep 30. pii: e189074. [Epub ahead of print]
    CTLA-4 blockade shifts the B cell repertoire towards autoimmunity.
    Elif Çakan, Meng Wang, Yile Dai, Adrien Mirouse, Clarence Rachel Villanueva-Pachas, Delphine Bouis, Joshua M Boeckers, Ruchi Gera, Sally Yraita, Leslie Clapp, Ana Luisa Perdigoto, Fabien R Delmotte, Christopher Massad, Antonietta Bacchiocchi, Aaron M Ring, Yuval Kluger, Harriet M Kluger, Kevan C Herold, Eric Meffre.
      Checkpoint inhibitors targeting CTLA-4 and PD-1 revolutionized the treatment of cancer patients, but their use is limited by the emergence of immune-related adverse events (irAE). We assessed autoreactive B cell frequencies in the blood of cancer patients before and after treatment with checkpoint inhibitors by testing the reactivity of recombinant antibodies cloned from single B cells. We found that anti-PD-1 and anti-CTLA-4 combination therapy induced the emergence of autoreactive mature naïve B cells, whereas central B-cell tolerance remained functional. In contrast, anti-PD-1 alone did not alter autoreactive B cell counterselection. Anti-CTLA-4 injections in humanized mice also resulted in the production of autoreactive B cells, whereas anti-PD-1 did not. We conclude that CTLA-4 but not PD-1 is required for the removal of developing autoreactive mature naïve B cells and that CTLA-4 blockade broadens the peripheral B cell repertoire which likely contains clones that promote not only irAEs but also anti-tumor responses.
    Keywords:  Autoimmunity; Cancer immunotherapy; Diabetes; Immunology; Tolerance
    DOI:  https://doi.org/10.1172/JCI189074
  16. Nature. 2025 Oct 03.
    Creative hobbies could slow brain ageing at the molecular level.
    Gemma Conroy.
      
    Keywords:  Ageing; Brain; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-03197-z
  17. Nat Commun. 2025 Sep 29. 16(1): 8614
    Motion impact score for detecting spurious brain-behavior associations.
    Benjamin P Kay, David F Montez, Scott Marek, Brenden Tervo-Clemmens, Joshua S Siegel, Babatunde Adeyemo, Timothy O Laumann, Athanasia Metoki, Roselyne J Chauvin, Andrew N Van, Vahdeta Suljic, Samuel R Krimmel, Ryland L Miller, Dillan J Newbold, Annie Zheng, Nicole A Seider, Kristen M Scheidter, Julia S Monk, Eric Feczko, Anita Randolph, Óscar Miranda-Domínguez, Lucille A Moore, Anders J Perrone, Gregory M Conan, Eric A Earl, Stephen M Malone, Michaela Cordova, Olivia Doyle, Benjamin J Lynch, James C Wilgenbusch, Thomas Pengo, Alice M Graham, Jarod L Roland, Evan M Gordon, Abraham Z Snyder, Deanna M Barch, Damien A Fair, Nico U F Dosenbach.
      In-scanner head motion introduces systematic bias to resting-state fMRI functional connectivity (FC) not completely removed by denoising algorithms. Researchers studying traits associated with motion (e.g. psychiatric disorders) need to know if their trait-FC relationships are impacted by residual motion to avoid reporting false positive results. We devised Split Half Analysis of Motion Associated Networks (SHAMAN) to assign a motion impact score to specific trait-FC relationships. SHAMAN distinguishes between motion causing overestimation or underestimation of trait-FC effects. We assessed 45 traits from n = 7270 participants in the Adolescent Brain Cognitive Development (ABCD) Study. After standard denoising with ABCD-BIDS and without motion censoring, 42% (19/45) of traits had significant (p < 0.05) motion overestimation scores and 38% (17/45) had significant underestimation scores. Censoring at framewise displacement (FD) < 0.2 mm reduced significant overestimation to 2% (1/45) of traits but did not decrease the number of traits with significant motion underestimation scores.
    DOI:  https://doi.org/10.1038/s41467-025-63661-2
  18. Nat Commun. 2025 Sep 30. 16(1): 8694
    Macrophage WDFY3 mitigates autoimmunity by enhancing efferocytosis and suppressing T cell activation in mice.
    Xun Wu, Ziyi Wang, Katherine R Croce, Fang Li, Jian Cui, Vivette D D'Agati, Rajesh K Soni, Ira Tabas, Ai Yamamoto, Hanrui Zhang.
      Efficient efferocytosis is crucial for immune homeostasis. Conversely, excessive apoptotic cell (AC) death and impaired macrophage efferocytosis lead to autoantigen release, autoantibody production, and immune activation. It is unclear whether immunogenic autoantigens from impaired clearance are the sole cause of autoimmunity or if AC efferocytosis directly alters macrophage function, affecting T cell activation and amplifying autoimmunity. Our prior work identified WDFY3 as essential for macrophage efferocytosis. Here, we demonstrate that myeloid Wdfy3 knockout exacerbates autoimmunity in young mice receiving systemic AC injections and middle-aged mice developing autoreactivity. Mechanistically, myeloid Wdfy3 deletion impairs efferocytosis, increasing autoantigen availability, and augments MHC-II-mediated antigen presentation and cytokine dysregulation, thereby promoting CD4+ T cell activation. In contrast, WDFY3 overexpression enhances efferocytosis, suppresses macrophage-mediated CD4+ T cell activation, and mitigates autoimmunity. Thus, macrophage WDFY3 functions as a protective factor against autoimmunity. Enhancing macrophage efferocytosis and reprogramming macrophage responses to ACs may represent promising strategies to limit autoimmune disorders and age-associated autoimmunity.
    DOI:  https://doi.org/10.1038/s41467-025-63741-3
  19. Nat Commun. 2025 Sep 30. 16(1): 8665
    Age is an intrinsic driver of inflammatory responses to malaria.
    Jessica R Loughland, Nicholas L Dooley, Zuleima Pava, Arya SheelaNair, Dean W Andrew, Peta Tipping, Peter Bourke, Christian R Engwerda, J Alejandro Lopez, Kim A Piera, Timothy William, Bridget E Barber, Matthew J Grigg, Nicholas M Anstey, Gabriela Minigo, Michelle J Boyle.
      Age is a critical factor in immune responses to infection. In malaria, severe disease risk increases with age in non-immune individuals. Malaria severity is in part driven by inflammation, but mechanisms contributing to age-dependent disease risk are incompletely understood. We assessed inflammatory cytokines during malaria in non-immune children and adults, and innate cell responses in vitro to malaria parasites in naive children and adults. We show during malaria age is associated with increased inflammatory chemokines CCL2, CCL3, CXCL8, CXCL9, along with CRP, and IDO, which associate with symptoms. In naive individuals, classical monocyte and Vδ2+ γδ T cells from adults have higher inflammatory cytokine production, and transcriptional activation following stimulation with parasites. Classical monocyte responses in adults are dominated by CCL2, while in children increased IL10 and enrichment of IL10 signaling pathways is detected. Findings identify age-dependent cellular mechanisms that play crucial roles in driving inflammatory responses in malaria.
    DOI:  https://doi.org/10.1038/s41467-025-63638-1
  20. Sci Immunol. 2025 Oct 03. 10(112): eaec5741
    The power of the few: RORγt+ dendritic cells promote food-specific peripheral regulatory T cells.
    Elise G Liu, Adam Williams.
      Food antigen-specific peripheral regulatory T cell induction in the gut is driven by RORγt+ dendritic cells.
    DOI:  https://doi.org/10.1126/sciimmunol.aec5741
  21. Nat Commun. 2025 Oct 03. 16(1): 8826
    The inner nuclear membrane protein LEMD3 organizes the 3D chromatin architecture to maintain vascular smooth muscle cell identity.
    Wenqiang Li, Yunxi Liao, Zhujiang Liu, Longjian Niu, Jiaqi Huang, Yiting Jia, Ran Xu, Sudun Guan, Zhenhui Liang, Yiran Li, Hao Wu, Shirong Zhu, Liao Tan, Fang Yu, Zhihua Wang, Luyang Sun, Dongyu Zhao, Wei Kong, Yi Fu.
      Maintaining the contractile phenotype of vascular smooth muscle cells (VSMCs) is critical for vascular homeostasis. However, the role of the 3D chromatin architecture in regulating VSMC identity remains elusive. A genome-scale CRISPR screen identifies LEMD3 as a potential regulator to maintain VSMC identity. Lemd3 deficiency in VSMCs results in the loss of the contractile phenotype and exacerbates intimal hyperplasia in mice. Protein interactome analysis reveals that LEMD3 interacts with CBX3, a principal reader of H3K9me2/3, subsequently anchoring heterochromatin at the nuclear periphery. Employing the DNA polymer model based on Hi-C data, whole-chromosome simulations demonstrate that Lemd3 depletion disturbs the chromatin structure. Multi-omics analysis further reveals that Lemd3 depletion alters the genome conformation as the increase of inter-TAD (topologically associated domain) interactions at the boundaries of A and B compartments, which correlates with decreased chromatin accessibility and repressed expression of VSMC contractile genes. This study reveals that LEMD3 organizes the 3D chromatin architecture by anchoring heterochromatin at the nuclear periphery to maintain the VSMC contractile identity.
    DOI:  https://doi.org/10.1038/s41467-025-63876-3
  22. Aging Cell. 2025 Sep 28. e70233
    Age-Associated Transcriptomic and Epigenetic Alterations in Mouse Hippocampus.
    Merve Bilgic, Rinka Obata, Vlada-Iuliana Panfil, Ziying Zhu, Mai Saeki, Yukiko Gotoh, Yusuke Kishi.
      Aging represents a major risk for human neurodegenerative disorders, such as dementia and Alzheimer's disease, and is associated with a functional decline in neurons and impaired synaptic plasticity, leading to a gradual decline in memory. Previous research has identified molecular and functional changes associated with aging through transcriptomic studies and neuronal excitability measurements, while the role of chromatin-level regulation in vulnerability to aging-related diseases is not well understood. Moreover, the causal relationship between molecular alterations and aging-associated decline in functions of different cell types remains poorly understood. Here, we systematically characterized gene regulatory networks in a cell type-specific manner in the aging mouse hippocampus, a central brain region involved in learning and memory formation, by simultaneously profiling gene expression and chromatin accessibility at a single-nucleus level. The analysis of multiome (RNA and ATAC) sequencing recapitulated the diversity of glial and neuronal cell types in the hippocampus and revealed transcriptomic and chromatin accessibility level changes in different cell types, among which oligodendrocytes and dentate gyrus (DG) neurons exhibited the most drastic changes. We found pronounced aging-dependent chromatin-level changes among neurons, especially for genes related to synaptic plasticity. Our data suggest that BACH2, a candidate transcription factor implicated in aging-mediated functional decline of DG neurons, potentially regulates genes associated with synaptic plasticity, cell death, and inflammation during aging. Taken together, our single-nucleus multiome analysis reveals potential cell type-specific regulators involved in the aging of neurons and glial cells.
    Keywords:  BACH2; aging; chromatin accessibility; glia; hippocampus; neuron; single‐nucleus multiome; transcriptome
    DOI:  https://doi.org/10.1111/acel.70233
  23. Nat Commun. 2025 Sep 29. 16(1): 8616
    Genetic determinants of monocyte splicing are enriched for disease susceptibility loci.
    Isar Nassiri, James J Gilchrist, Orion Tong, Evelyn Lau, Sara Danielli, Hussein Al Mossawi, Matthew J Neville, Julian C Knight, Benjamin P Fairfax.
      Insights into variation in monocyte context-specific splicing and transcript usage are limited. Here, we perform paired gene and transcript QTL mapping across distinct immune states using RNA sequencing data of monocytes isolated from a cohort of 185 healthy Europeans incubated alone or in the presence of interferon gamma (IFN-γ) or lipopolysaccharide (LPS). We identify regulatory variants for 5749 genes and 8727 transcripts, with 291 context-specific transcript QTL colocalizing with GWAS loci. Notable disease relevant associations include IFN-γ specific transcript QTL at COVID-19 severity locus rs10735079, where allelic variation modulates context-specific splicing of OAS1, and at rs4072037, a risk allele for gastro-esophageal cancer, which associates with context-specific splicing of MUC1. We use DNA methylation data from the same cells to demonstrate overlap between methylation QTL and causal context-specific expression QTL, permitting inference of the direction of effect. Finally, we identify a subset of expression QTL that uncouple genes from proximally acting regulatory networks, creating 'co-expression QTL' with different allele-specific correlation networks. Our findings highlight the interplay between context and genetics in the regulation of the monocyte gene expression and splicing, revealing putative mechanisms of diverse disease risk alleles including for COVID-19 and cancer.
    DOI:  https://doi.org/10.1038/s41467-025-63624-7
  24. J Clin Invest. 2025 Sep 30. pii: e182480. [Epub ahead of print]
    Acetyl-CoA carboxylase-1 inhibition increases regulatory T-Cell metabolism and graft-vs-host disease treatment efficacy via mitochondrial fusion.
    Cameron McDonald-Hyman, Ethan G Aguilar, Ewoud B Compeer, Michael C Zaiken, Stephanie Y Rhee, Fathima A Mohamed, Jemma H Larson, Michael L Loschi, Christopher Lees, Govindarajan Thangavelu, Margaret L Sleeth, Kyle D Smith, Jennifer S Whangbo, Jerome Ritz, Tim D Sparwasser, Roddy S O'Connor, Peter A Crawford, Jeffrey C Rathmell, Leslie S Kean, Robert Zeiser, Keli L Hippen, Michael L Dustin, Bruce R Blazar.
      Regulatory T-cells (Treg) are critical for maintaining immune homeostasis, and their adoptive transfer can treat murine inflammatory disorders. In patients, Treg therapies have been variably efficacious. Therefore, new strategies to enhance Treg therapeutic efficacy are needed. Treg predominantly depend upon oxidative phosphorylation (OXPHOS) for energy and suppressive function. Fatty acid oxidation (FAO) contributes to Treg OXPHOS and can be important for Treg "effector" differentiation, but FAO activity is inhibited by coordinated activity of isoenzymes acetyl-CoA Carboxylase-1 and -2 (ACC1/2). Here, we show that small molecule inhibition or Treg-specific genetic deletion of ACC1 significantly increases Treg suppressive function in vitro and in mice with established chronic GVHD. ACC1 inhibition skewed Treg towards an "effector" phenotype and enhanced FAO-mediated OXPHOS, mitochondrial function, and mitochondrial fusion. Inhibiting mitochondrial fusion diminished the effect of ACC1 inhibition. Reciprocally, promoting mitochondrial fusion, even in the absence of ACC1 modulation, resulted in a Treg functional and metabolic phenotype similar to ACC1 inhibition, indicating a key role for mitochondrial fusion in Treg suppressive potency. Ex vivo expanded, ACC1 inhibitor treated human Treg similarly augmented suppressor function as observed with murine Treg. Together, these data suggest that ACC1 manipulation may be exploited to modulate Treg function in patients.
    Keywords:  Bone marrow transplantation; Immunology; Metabolism; Mitochondria; T cells
    DOI:  https://doi.org/10.1172/JCI182480
  25. J Clin Invest. 2025 Oct 01. pii: e198352. [Epub ahead of print]135(19):
    Endothelial gateways for brain lipid uptake and metabolism.
    A Dushani Ranasinghe, Timothy Hla.
      Lipids, which constitute half of the brain's solid matter, are essential for forming specialized membranes of neural cells, providing energy sources, and facilitating cell-to-cell communication. Although the blood-brain barrier restricts lipid movement between peripheral circulation and the brain, multiple mechanisms supply the building blocks necessary to synthesize the diverse lipid species present in the central nervous system (CNS). In this issue of the JCI, Song et al. characterize specialized microvascular niches that metabolize circulating triglyceride-rich lipoproteins (TRLs) to deliver fatty acids into the brain. They located GPIHBP1, an essential chaperone for lipoprotein lipase (LPL) in the fenestrated endothelial cells of the choroid plexus (ChP) and circumventricular organs (CVOs), demonstrating lipolytic processing of peripheral TRLs and brain uptake of fatty acids. This advance implicates the GPIHBP1/LPL lipid metabolic hub in supporting the roles of the ChP and CVO in cerebrospinal fluid composition, immunity, satiety, thirst, and metabolic homeostasis.
    DOI:  https://doi.org/10.1172/JCI198352
  26. Nat Commun. 2025 Sep 30. 16(1): 8685
    Cardiolipin dynamics promote membrane remodeling by mitochondrial OPA1.
    Sirikrishna Thatavarthy, Luciano A Abriata, Fernando Teixeira Pinto Meireles, Kelly E Zuccaro, Akhil Gargey Iragavarapu, Gabriela May Sullivan, Frank R Moss, Adam Frost, Matteo Dal Peraro, Halil Aydin.
      Cardiolipin is a mitochondria-specific phospholipid that forms heterotypic interactions with membrane-shaping proteins and regulates the dynamic remodeling and function of mitochondria. However, the precise mechanisms through which cardiolipin influences mitochondrial morphology are not well understood. In this study, employing molecular dynamics simulations, we determined that cardiolipin molecules extensively engage with the paddle domain of mitochondrial fusion protein OPA1, which controls membrane-shaping mechanisms. Structure-function analysis confirmed the interactions between cardiolipin and two conserved motifs of OPA1 at the membrane-binding sites. We further developed a bromine-labeled cardiolipin probe to enhance cryoEM contrast and characterized the structure of OPA1 assemblies bound to the cardiolipin brominated lipid bilayers. Our images provide direct evidence of cardiolipin enrichment within the OPA1-binding leaflet. Last, we observed a decrease in membrane remodeling activity for OPA1 in lipid compositions with increasing concentrations of monolyso-cardiolipin. This suggests that the partial replacement of cardiolipin by monolyso-cardiolipin, as observed in Barth syndrome, alters the malleability of the membrane and compromises proper remodeling. Together, these data provide insights into how biological membranes regulate the mechanisms governing mitochondrial homeostasis.
    DOI:  https://doi.org/10.1038/s41467-025-63813-4
This page is being maintained by Thomas Krichel. It was last updated on 2025‒10‒05 at 5:50.