bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–12–14
27 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function.
  2. Huge genetic study reveals hidden links between psychiatric conditions.
  3. Tolerance to ferroptosis facilitates lipid metabolism and pathogenic type 2 immunity in allergic airway inflammation.
  4. AGPAT2 acts at the crossroads of lipid biosynthesis and DRP1-mediated ER morphogenesis.
  5. Pancreatic cancer is evasive. Is the nervous system the reason why?
  6. Multimodal mass spectrometry imaging for plaque- and region-specific neurolipidomics in Alzheimer's disease mouse models.
  7. Erythropoietin receptor on cDC1s dictates immune tolerance.
  8. 3D imaging of human pancreas suggests islet size and endocrine composition influence their loss in type 1 diabetes.
  9. Neutrophils preserve energy storage in sympathetically activated adipocytes.
  10. NK cells limit antibody breadth.
  11. Limitations in PPARα-dependent mitochondrial programming restrain the differentiation of human stem cell-derived β cells.
  12. Plasma metabolomic signature of breastfeeding and risk of cardiometabolic diseases.
  13. Hepatic metabolic reprogramming in male mice during short-term caloric restriction involves enhanced glucocorticoid rhythms.
  14. Diet-induced RKIP downregulation disrupts PC/PE-ER homeostasis to drive MASLD.
  15. Is addiction the next frontier for GLP-1 receptor agonists?
  16. Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment.
  17. The gift that shaped my career in science.
  18. Dynamic changes in mitochondria support phenotypic flexibility of microglia.
  19. A circadian checkpoint relocates neutrophils to minimize injury.
  20. Structural insights into GM4951 as a lipid droplet GTPase regulating hepatic lipid metabolism.
  21. Dietary restriction reprograms CD8+ T cell fate to enhance anti-tumour immunity and immunotherapy responses.
  22. Notable advances 2025.
  23. Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control.
  24. Nationwide implementation of a diabetes self-management and network system improves outcomes in type 1 diabetes: real-world evidence from Thailand.
  25. Imbalance of stem-like and effector T cell states in children with early type 1 diabetes across conventional and regulatory subsets.
  26. The experiment I didn't plan.
  27. Nef stabilizes actin to prevent HIV-1 sensing by RIG-I-like receptors.
  1. Nat Commun. 2025 Dec 10. 16(1): 11010
    GLP-1R associates with VAPB and SPHKAP at ERMCSs to regulate β-cell mitochondrial remodelling and function.
    Gregory Austin, Affiong I Oqua, Liliane El Eid, Mingli Zhu, Yusman Manchanda, Priyanka Peres, Helena Coyle, Yelyzaveta Poliakova, Zhanna Balkhiyarova, Karim Bouzakri, Alex Montoya, Dominic J Withers, Michele Solimena, Ben Jones, Steven J Millership, Steffen Burgold, David C A Gaboriau, Endre Majorovits, Evelyn Garlick, Maria Augusta do R B F Lima, Inga Prokopenko, Jonathon Nixon-Abell, Andreas Müller, Alejandra Tomas.
      Glucagon-like peptide-1 receptor (GLP-1R) agonists (GLP-1RAs) ameliorate mitochondrial health by increasing mitochondrial turnover in metabolically relevant tissues. Mitochondrial adaptation to metabolic stress is crucial to maintain pancreatic β-cell function and prevent type 2 diabetes (T2D) progression. While the GLP-1R is well-known to stimulate cAMP production leading to Protein Kinase A (PKA) and Exchange Protein Activated by cyclic AMP 2 (Epac2) activation, there is a lack of understanding of the molecular mechanisms linking GLP-1R signalling with mitochondrial and β-cell functional adaptation. Here, we present a comprehensive study in β-cell lines and primary islets that demonstrates that, following GLP-1RA stimulation, GLP-1R-positive endosomes associate with the endoplasmic reticulum (ER) membrane contact site (MCS) tether VAPB at ER-mitochondria MCSs (ERMCSs), where active GLP-1R engages with SPHKAP, an A-kinase anchoring protein (AKAP) previously linked to T2D and adiposity risk in genome-wide association studies (GWAS). The inter-organelle complex formed by endosomal GLP-1R, ER VAPB and SPHKAP triggers a pool of ERMCS-localised cAMP/PKA signalling via the formation of a PKA-RIα biomolecular condensate which leads to changes in mitochondrial contact site and cristae organising system (MICOS) complex phosphorylation, mitochondrial remodelling, and β-cell functional adaptation, with important consequences for the regulation of β-cell insulin secretion and survival to stress.
    DOI:  https://doi.org/10.1038/s41467-025-66115-x
  2. Nature. 2025 Dec 10.
    Huge genetic study reveals hidden links between psychiatric conditions.
    Max Kozlov.
      
    Keywords:  Brain; Genetics; Neuroscience; Psychiatric disorders
    DOI:  https://doi.org/10.1038/d41586-025-04037-w
  3. Immunity. 2025 Dec 10. pii: S1074-7613(25)00520-5. [Epub ahead of print]
    Tolerance to ferroptosis facilitates lipid metabolism and pathogenic type 2 immunity in allergic airway inflammation.
    Chantal Wientjens, Maria Doverman, Jelena Zurkovic, Tushar More, Jayagopi Surendar, Svetozar Nesic, Carola Sarici, Timon D Utecht, Johanna Pohl, Jonathan Pollock, David Voehringer, Karsten Hiller, Christoph Thiele, Christoph Wilhelm.
      Type 2 innate lymphoid cells (ILC2s) are essential for maintaining and protecting barrier tissues, but they also drive chronic inflammation, a process associated with altered metabolic activity. Identifying and targeting the metabolic pathways driving ILC2-mediated inflammation could restore tissue homeostasis. Here, we find that in allergic airway inflammation, pathogenic ILC2s rely on cystine for enhanced metabolic flexibility and survival. Cystine acquisition fuels glutathione (GSH) synthesis, which, together with increased expression of glutathione peroxidase 4 (GPX4) and thioredoxin reductase 1 (TXNRD1), confers resistance to ferroptosis by counteracting lipid peroxidation and reactive oxygen species (ROS). This adaptation enables accelerated lipid acquisition and metabolism, fostering ILC2 and T helper type 2 (Th2) cell expansion. Conversely, ablation of GPX4 and TXNRD1 in ILC2s or pharmacological inhibition of TXNRD1 constrains lipid metabolism and prevents ILC2 accumulation in allergen-induced airway inflammation. This demonstrates that increased reliance on antioxidant systems represents a metabolic vulnerability that can be exploited therapeutically to treat asthma.
    Keywords:  GPX4; ILC2; ROS; asthma; cysteine; fatty acids; ferroptosis; innate lymphoid cells; lipid metabolism; thioredoxin
    DOI:  https://doi.org/10.1016/j.immuni.2025.11.018
  4. Nat Commun. 2025 Dec 12.
    AGPAT2 acts at the crossroads of lipid biosynthesis and DRP1-mediated ER morphogenesis.
    Yoshihiro Adachi, Mauricio Torres, Allen H Hunter, Woo Jung Cho, Meixia Pan, Xianlin Han, Guangwei Du, Ling Qi, Miho Iijima, Hiromi Sesaki.
      The morphology of the endoplasmic reticulum (ER), characterized by central sheets and peripheral tubules, is controlled by membrane-shaping proteins. However, the role of lipids in ER morphogenesis remains elusive, despite the ER being the major site for lipid synthesis. Here, by examining the role of eighteen phosphatidic acid (PA)-generating enzymes in ER morphology, we identify lysophosphatidic acid acyltransferase 2 (AGPAT2) as a critical factor in mouse and human cells. AGPAT2 produces PA in the glycerophospholipid/triacylglycerol biosynthesis pathway, and its mutations cause congenital generalized lipodystrophy. We find that AGPAT2-generated PA drives ER tubulation through gene knockout, 3D structural analysis by FIB-SEM, super-resolution microscopy, lipidomics, AlphaFold, and in vitro reconstitutions of ER tubulation and AGPAT2 activity. AGPAT2 interacts with and supplies PA to the PA-binding, dynamin-related GTPase, DRP1, which subsequently tubulates the ER in a manner independent of GTP hydrolysis and oligomerization, distinct from its function in mitochondrial division. Consistently, the reduction of PA levels by ectopic expression of a PA phosphatase, LIPIN1, transforms ER tubules into sheets. Our results reveal an unforeseen interplay between lipid biosynthesis and membrane organization in the ER.
    DOI:  https://doi.org/10.1038/s41467-025-66474-5
  5. Nature. 2025 Dec;648(8093): S49-S50
    Pancreatic cancer is evasive. Is the nervous system the reason why?
    Laura Dattaro.
      
    Keywords:  Cancer; Drug discovery; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-03943-3
  6. Nat Commun. 2025 Dec 09. 16(1): 10969
    Multimodal mass spectrometry imaging for plaque- and region-specific neurolipidomics in Alzheimer's disease mouse models.
    Timothy J Trinklein, Stanislav S Rubakhin, Samuel Okyem, Seth W Croslow, Marisa Asadian, K R Sabitha, Orly Lazarov, Fan Lam, Jonathan V Sweedler.
      The progressive accumulation of amyloid beta (Aβ) plaques is a hallmark of Alzheimer's disease (AD). However, the biochemical mechanisms of their formation and the consequences associated with plaque formation remain elusive. In female 5xFAD and APPNL-G-F mice, we map region-specific, plaque-associated lipids with large molecular coverage including isomers. We describe a multimodal framework that integrates matrix assisted laser desorption/ionization with laser-induced postionization (MALDI-2) mass spectrometry imaging, trapped ion mobility spectrometry, and fluorescence microscopy. Our approach improves detectability and spatial-chemical resolution. We couple these measurements with a computational pipeline for multimodal image coregistration and discovery of plaque-altered lipids. Here, we show the lipids in and around Aβ plaques are highly heterogeneous. Integration of our data with existing spatial transcriptomics data suggests that region-specific accumulation of simple gangliosides is likely driven by lysosomal degradation of complex species. Together, this work provides a generalizable framework to understand lipid alterations within the Aβ plaque microenvironment.
    DOI:  https://doi.org/10.1038/s41467-025-65956-w
  7. Nature. 2025 Dec 10.
    Erythropoietin receptor on cDC1s dictates immune tolerance.
    Xiangyue Zhang, Christopher S McGinnis, Guotao Yu, Sijie Chen, Pingping Zheng, Christian M Schürch, Kamir J Hiam-Galvez, Nathan E Reticker-Flynn, Wenhui Guo, Winnie Yao, Jingtao Qiu, Alexander Muselman, Ian L Linde, John W Hickey, Hao Yan, Victoria M Tran, Wenli Qiu, Delphine Brichart-Vernos, Toshihito Hirai, Bo Yu, Xiuli An, Yanling Xiao, Helena Paidassi, Tiffany C Scharschmidt, Michael Angelo, Dean Sheppard, Hongbo Chi, Ansuman T Satpathy, Sing Sing Way, Bernard Malissen, Samuel Strober, Edgar G Engleman.
      Type 1 conventional dendritic cells (cDC1s) are unique in their efferocytosis1 and cross-presenting abilities2, resulting in antigen-specific T cell immunity3 or tolerance4-8. However, the mechanisms that underlie cDC1 tolerogenic function remain largely unknown. Here we show that the erythropoietin receptor (EPOR) acts as a critical switch that determines the tolerogenic function of cDC1s and the threshold of antigen-specific T cell responses. In total lymphoid irradiation-induced allograft tolerance9,10, cDC1s upregulate EPOR expression, and conditional knockout of EPOR in cDC1s diminishes antigen-specific induction and expansion of FOXP3+ regulatory T (Treg) cells, resulting in allograft rejection. Mechanistically, EPOR promotes efferocytosis-induced tolerogenic maturation7,11 of splenic cDC1s towards late-stage CCR7+ cDC1s characterized by increased expression of the integrin β8 gene12 (Itgb8), and conditional knockout of Itgb8 in cDC1s impairs tolerance induced by total lymphoid irradiation plus anti-thymocyte serum. Migratory cDC1s in peripheral lymph nodes preferentially express EPOR, and their FOXP3+ Treg cell-inducing capacity is enhanced by erythropoietin. Reciprocally, loss of EPOR enables immunogenic maturation of peripheral lymph node migratory and splenic CCR7+ cDC1s by upregulating genes involved in MHC class II- and class I-mediated antigen presentation, cross-presentation and costimulation. EPOR deficiency in cDC1s reduces tumour growth by enhancing anti-tumour T cell immunity, particularly increasing the generation of precursor exhausted tumour antigen-specific CD8+ T cells13 in tumour-draining lymph nodes and supporting their maintenance within tumours, while concurrently reducing intratumoural Treg cells. Targeting EPOR on cDC1s to induce or inhibit T cell immune tolerance could have potential for treating a variety of diseases.
    DOI:  https://doi.org/10.1038/s41586-025-09824-z
  8. Nat Commun. 2025 Dec 11.
    3D imaging of human pancreas suggests islet size and endocrine composition influence their loss in type 1 diabetes.
    Alexandra Rippa, Amanda L Posgai, Seth Currlin, Maigan Brusko, MacKenzie D Williams, John S Kaddis, Irina Kusmartseva, Clive H Wasserfall, Martha Campbell-Thompson, Mark A Atkinson.
      A high-definition description of pancreatic islets would prove beneficial for understanding the pathophysiology of type 1 diabetes (T1D), yet significant knowledge gaps exist in terms of their size, endocrine cell composition, and number in both health and disease. Here, 3-dimensional (3D) analyses of pancreata from control persons without diabetes (ND) demonstrate approximately 50% of islets are insulin-positive (INS + ) glucagon-negative (GCG-). Non-diabetic individuals positive for a single Glutamic acid decarboxylase autoantibody (GADA + ) yet at increased risk for disease consistently demonstrate endocrine features, including islet volume and cell composition, closely resembling the age-matched ND controls. In contrast, pancreata from individuals with short-duration T1D demonstrate significantly reduced islet density and a dramatic loss of INS + GCG- islets with preservation of large INS + GCG+ islets. The size and cellular composition of pancreatic islets may, therefore, represent influential factors that impact β-cell loss during T1D disease progression.
    DOI:  https://doi.org/10.1038/s41467-025-66198-6
  9. Nature. 2025 Dec 10.
    Neutrophils preserve energy storage in sympathetically activated adipocytes.
    Seunghwan Son, Cindy Xu, Haipeng Fu, Churaibhon Wisessaowapak, Joseph M Valentine, Garam An, Janice Jang, Maddox Dinh, Yang Dai, Weiwei Fan, Ruth T Yu, Michael Downes, Wei Ying, Yuliya Skorobogatko, Ronald M Evans, Alan R Saltiel.
      Adipose tissue maintains energy homeostasis by storing lipids during nutrient surplus and releasing them through lipolysis in times of energy demand1,2. While lipolysis is essential for short-term metabolic adaptation, prolonged metabolic stress requires adaptive changes that preserve energy reserves2,3. Here we report that β3-adrenergic activation of adipocytes induces a transient and depot-specific infiltration of neutrophils into white adipose tissue (WAT), particularly in lipid-rich visceral WAT. Neutrophil recruitment requires the stimulation of both lipolysis and p38 MAPK in adipocytes, and is mediated by the secretion of leukotriene B4. Recruited neutrophils undergo activation in situ, and locally secrete IL-1β, which suppresses lipolysis and limits excessive energy loss. Neutrophil depletion or blockade of IL-1β production increases lipolysis, leading to reduced WAT mass after repeated β3-adrenergic stimulation. Together, these findings reveal a role of neutrophil-derived IL-1β in preserving lipid stores during metabolic stress, highlighting a physiological function of innate immune cells in limiting lipid loss and maintaining energy homeostasis.
    DOI:  https://doi.org/10.1038/s41586-025-09839-6
  10. Nat Rev Immunol. 2025 Dec 09.
    NK cells limit antibody breadth.
    Lucy Bird.
      
    DOI:  https://doi.org/10.1038/s41577-025-01260-4
  11. Nat Commun. 2025 Dec 10. 16(1): 11037
    Limitations in PPARα-dependent mitochondrial programming restrain the differentiation of human stem cell-derived β cells.
    Anne C Lietzke, Emily M Walker, Elizabeth Bealer, Kelly Crumley, Jessica King, Ava M Stendahl, Jie Zhu, Gemma L Pearson, Elena Levi-D'Ancona, Belle Henry-Kanarek, Rebecca K Davidson, Jin Li, Emma C Reck, Yifei Wu, Manikanta Arnipalli, John-Paul Pham, Lakshmi Mundada, Vaibhav Sidarala, Todd J Herron, Maria M Coronel, Subramaniam Pennathur, Jesper G S Madsen, Lonnie D Shea, Scott A Soleimanpour.
      Pluripotent stem cell (SC)-derived islets offer hope as a renewable source for β cell replacement for type 1 diabetes (T1D), yet functional and metabolic immaturity may limit their long-term therapeutic potential. Here, we show that limitations in mitochondrial transcriptional programming impede the formation of SC-derived β (SC-β) cells. Utilizing transcriptomic profiling, assessments of chromatin accessibility, mitochondrial phenotyping, and lipidomics analyses, we observe that SC-β cells exhibit reduced oxidative and mitochondrial fatty acid metabolism compared to primary human islets that are related to limitations in key mitochondrial transcriptional networks. Surprisingly, we find that reductions in glucose-stimulated mitochondrial respiration in SC-islets were not associated with alterations in mitochondrial mass, structure, or genome integrity. In contrast, SC-islets show limited expression of targets of PPARα, which regulate mitochondrial programming, yet whose functions in β cell differentiation are unknown. Importantly, treatment with WY14643, a potent PPARα agonist, induces expression of mitochondrial targets, improves insulin secretion, and increases the formation of SC-β cells both in vitro and following transplantation. Thus, PPARα-dependent mitochondrial programming promotes the differentiation of SC-β cells and may be a promising target to improve β cell replacement efforts for T1D.
    DOI:  https://doi.org/10.1038/s41467-025-66022-1
  12. Nat Commun. 2025 Dec 08.
    Plasma metabolomic signature of breastfeeding and risk of cardiometabolic diseases.
    Anna Birukov, Nan Lin, Jennifer Mongiovi, Cristina Razquin, Fenglei Wang, Zhila Semnani-Azad, Anne-Julie Tessier, Marta Guasch-Ferré, Sylvia H Ley, JoAnn E Manson, Rachel G Sinkey, Bernhard Haring, Aladdin H Shadyab, Raji Balasubramanian, Miguel A Martínez-González, Kathryn M Rexrode, Frank B Hu, Cuilin Zhang, Oana A Zeleznik, Naoko Sasamoto.
      Breastfeeding is inversely associated with cardiometabolic disease incidence in prospective studies; however, the metabolic pathways underlying these associations remain largely unknown. Here, we derive a plasma metabolomic score of lifetime total duration of breastfeeding using elastic net regularized regression in Nurses' Health Studies (n = 4349) and replicate in the Women's Health Initiative (n = 2088). Data include 181 untargeted plasma metabolites profiled by liquid chromatography mass spectrometry using blood samples collected in mid-life, and self-reported lifetime total duration of breastfeeding. We then examine the associations between the metabolite-based breastfeeding score and risk of T2D and CVD using multivariable Cox regression models and replicated in two external cohorts. The metabolite-based breastfeeding score comprised of 5 metabolites (i.e., C54:2 triglyceride, C56:2 triglyceride, C56:3 triglyceride, cotinine, indole-3-propionate), which show a modest but statistically significant correlation with lifetime total duration of breastfeeding. The metabolite-based breastfeeding score significantly inversely associate with T2D incidence (HR = 0.76, 95%CI = 0.71-0.82) and with CVD incidence (HR = 0.88, 95%CI = 0.84-0.93) independent of T2D and CVD risk factors. We identify plasma metabolite profiles in mid-life associated with breastfeeding duration, which is also linked to CVD and T2D risk.
    DOI:  https://doi.org/10.1038/s41467-025-65977-5
  13. Nat Commun. 2025 Dec 11. 16(1): 11106
    Hepatic metabolic reprogramming in male mice during short-term caloric restriction involves enhanced glucocorticoid rhythms.
    Konstantinos Makris, Vlera Fonda, Fania Feby Ramadhani, Lina Fadel, Morgane Davezac, Bertrand Payet, Ioannis K Deligiannis, Liwei Zhang, Teresa Horn, Laura Heimerl, Céline Jouffe, Marjolein Heddes, Celia P Martinez-Jimenez, Fabiana Quagliarini, N Henriette Uhlenhaut.
      Caloric restriction prolongs lifespan and preserves health across species, with feeding times synchronized to day-night cycles further maximizing benefits. However, the mechanisms linking diet, diurnal rhythms, and lifespan remain unclear. In mice, the time point most strongly tied to dietary effects on lifespan coincides with the peak of glucocorticoid secretion (ZT12, lights-off). Caloric restriction raises circulating glucocorticoid hormone levels, implicating these signals as candidate mediators for its benefits. Here we show that in the liver, the glucocorticoid receptor (GR) is required for the metabolic response to caloric restriction. Hepatocyte-specific GR mutant males fail to mount this response, indicating that increased glucocorticoid amplitude is necessary for the adaptation. Using multiomics, we find that nutrient deprivation elicits a nuclear switch from active STAT signaling to increased FOXO1 activity, enabling GR to activate diet-specific gene expression programs. Our results suggest that glucocorticoid rhythms are crucial for caloric restriction-induced metabolic reprogramming.
    DOI:  https://doi.org/10.1038/s41467-025-67228-z
  14. Nat Commun. 2025 Dec 12. 16(1): 11092
    Diet-induced RKIP downregulation disrupts PC/PE-ER homeostasis to drive MASLD.
    Mengjie Li, Qian Ou, Qiang Qin, Jiaxi Chen, Sen Yang, Jie Zhao, Hua Meng, Xu Li, Pinglong Xu, Cunqi Ye, Xiaojian Wang.
      High-fat diet (HFD) is a risk factor for metabolic dysfunction-associated steatotic liver disease (MASLD), yet the molecular pathways that connect dietary fats to liver dysfunction remain unclear. Here, we discover that hepatic downregulation of Raf kinase inhibitory protein (RKIP) in MASLD patients and male mice is linked to fatty acid uptake, which causes endoplasmic reticulum (ER)-associated degradation of RKIP by inhibiting its S-palmitoylation. Via facilitating the m6A-modified RNA binding of YTHDF1, RKIP is required for the efficient translation of PEMT, an essential enzyme in maintaining phosphatidylcholine (PC) / phosphatidylethanolamine (PE) ratio and ER homeostasis. Hepatocyte-specific RKIP depletion in male mice exacerbates the PC/PE imbalance and ER stress, resulting in lipid droplets accumulation and MASLD progression. Notably, RKIP correlates positively with PEMT protein but inversely with MASLD development. These findings uncover a cellular mechanism of HFD-RKIP-PEMT that underlies diet-induced liver metabolic disease and propose RKIP as a target for MASLD prevention.
    DOI:  https://doi.org/10.1038/s41467-025-65982-8
  15. Nat Med. 2025 Dec 08.
    Is addiction the next frontier for GLP-1 receptor agonists?
    Natalie Healey.
      
    DOI:  https://doi.org/10.1038/d41591-025-00069-x
  16. Nat Commun. 2025 Dec 12. 16(1): 11104
    Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment.
    Alicia N Pietramale, Xhoela Bame, Megan E Doty, Kiera E Schwarz, Robert A Hill.
      Microglia continually surveil the brain allowing for rapid detection of tissue damage or infection. Microglial metabolism is linked to tissue homeostasis, yet how mitochondria are subcellularly partitioned in microglia and dynamically reorganize during surveillance, injury responses, and phagocytic engulfment in the intact brain are not known. Here, we performed intravital imaging and ultrastructural analyses of microglia mitochondria in mice and human tissue, revealing that microglial processes diverge in their mitochondrial content, with some containing multiple mitochondria while others are completely void. Microtubules and hexokinase 2 mirror this uneven mitochondrial distribution indicating that these cytoskeletal and metabolic components are linked to mitochondrial organization in microglia. Microglial processes that engage in minute-to-minute surveillance typically do not have mitochondria. Moreover, unlike process surveillance, mitochondrial motility does not change with animal anesthesia. Likewise, the processes that acutely chemoattract to a lesion site or initially engage with a neuron undergoing programmed cell death do not contain mitochondria. Rather, microglia mitochondria have a delayed arrival into the responding cell processes. Thus, there is subcellular heterogeneity of mitochondrial partitioning. Moreover, microglial processes that surveil and acutely respond to damage do not contain mitochondria.
    DOI:  https://doi.org/10.1038/s41467-025-66708-6
  17. Nature. 2025 Dec 11.
    The gift that shaped my career in science.
    Anne Marie Conlon.
      
    Keywords:  Careers; Lab life; Scientific community
    DOI:  https://doi.org/10.1038/d41586-025-03897-6
  18. Nat Commun. 2025 Dec 12. 16(1): 11103
    Dynamic changes in mitochondria support phenotypic flexibility of microglia.
    Katherine Espinoza, Ari W Schaler, Daniel T Gray, Arielle R Sass, Adrian Escobar, Kamilia Moore, Megan E Yu, Casandra G Chamorro, Lindsay M De Biase.
      Microglial capacity to adapt to tissue needs is a hallmark feature of these cells. New studies show that mitochondria critically regulate the phenotypic adaptability of macrophages. To determine whether these organelles play similar roles in shaping microglial phenotypes, we generated transgenic mouse crosses to accurately visualize and manipulate microglial mitochondria. We find that brain-region differences in microglial attributes and responses to aging are accompanied by regional differences in mitochondrial mass and aging-associated mitochondrial remodeling. Microglial mitochondria are also altered within hours of LPS injections and microglial expression of inflammation-, trophic-, and phagocytosis-relevant genes is strongly correlated with expression of mitochondria-relevant genes. Finally, direct genetic manipulation of microglial mitochondria alters microglial morphology and leads to brain-region specific effects on microglial gene expression. Overall, this study advances our understanding of microglial mitochondria and supports the idea that mitochondria influence basal microglial phenotypes and phenotypic remodeling that takes place over hours to months.
    DOI:  https://doi.org/10.1038/s41467-025-66709-5
  19. J Exp Med. 2026 Feb 02. pii: e20250240. [Epub ahead of print]223(2):
    A circadian checkpoint relocates neutrophils to minimize injury.
    Alejandra Aroca-Crevillén, Sandra Martín-Salamanca, Lidiane S Torres, Georgiana Crainiciuc, Jon Sicilia, Eduardo Peñaloza-Martínez, Nicolás Rosillo, Miguel Molina-Moreno, Jose M Adrover, Andrea Rubio-Ponce, Tommaso Vicanolo, Xiaosong Liu, Kanin Wichapong, Vanessa Núñez, Karl Balabanian, Françoise Bachelerie, David Sancho, María Casanova-Acebes, José T Ortiz-Pérez, María Ángeles Moro, Héctor Bueno, Gerry A F Nicolaes, Andrés Hidalgo.
      Inflammation-driven injury, a significant source of morbidity and mortality worldwide, is largely mediated by the cytotoxic activities of neutrophils, which extend the initial lesion and jeopardize organ function. Intriguingly, inflammatory injury naturally declines at specific times of day, suggesting that circadian mechanisms exist that mitigate the destructive activity of neutrophils and protect the host. Here, we show that the periods of diurnal protection coincide with peaks in plasma CXCL12, a chemokine that inhibits the neutrophil-intrinsic circadian clock by signaling through CXCR4. Genetic deletion of this clock, or a hyperactive form of CXCR4, prevented the diurnal spikes of injury, and treatment with a synthetic CXCR4 agonist conferred protection from myocardial and vascular injury. In tissues, this protection was mediated by repositioning neutrophils in the wound core, which spared neighboring host cells from apoptotic death. Thus, a circadian neutrophil checkpoint protects from exuberant inflammation and can be activated to protect the host.
    DOI:  https://doi.org/10.1084/jem.20250240
  20. Nat Commun. 2025 Dec 12.
    Structural insights into GM4951 as a lipid droplet GTPase regulating hepatic lipid metabolism.
    Rishi Raj, Yiao Jiang, Rahul Kumar Jha, Eva Marie Y Moresco, Himanshu Joshi, Zhao Zhang, Bruce Beutler.
      GM4951 is an immunity-related GTPase (IRG) that counteracts hepatic lipid accumulation in mice fed a high-fat diet. We determine full-length protein structures of GTPγS- and GDP-bound GM4951, and two missense mutants (N86K or D125G) associated with metabolic dysfunction-associated steatotic liver disease (MASLD) in mice. All four structures reveal a conserved GTPase domain fold and a helix bundle composed of the N- and C-terminal regions. Each mutation alters the dynamics of the switch-I and switch-II loops important for catalytic function and lipid droplet (LD) localization. GM4951 predominantly forms dimers in vitro. Cryo-electron microscopy reveals a dimer interface formed by the helical domains of two protomers (tail to tail), distinct from other IRGs. The N-terminal helices are necessary for LD localization, while a disulfide bond between helices in the GTPase domain and C-terminus is necessary for interaction with MASLD-associated HSD17B13. Distinct N- and C-terminal conformations set GM4951 apart from other IRGs structurally and functionally.
    DOI:  https://doi.org/10.1038/s41467-025-66253-2
  21. Nat Metab. 2025 Dec 09.
    Dietary restriction reprograms CD8+ T cell fate to enhance anti-tumour immunity and immunotherapy responses.
    Brandon M Oswald, Lisa M DeCamp, Joseph Longo, Michael S Dahabieh, Nicholas Bunda, Benjamin K Johnson, McLane J Watson, Shixin Ma, Samuel E J Preston, Ryan D Sheldon, Michael P Vincent, Abigail E Ellis, Molly T Soper-Hopper, Christine Isaguirre, Dahlya Kamarudin, Hui Shen, Kelsey S Williams, Peter A Crawford, Susan Kaech, H Josh Jang, Evan C Lien, Connie M Krawczyk, Russell G Jones.
      Reducing calorie intake through dietary restriction (DR) slows tumour growth in mammals, yet the underlying mechanisms are poorly defined. Here, we show that DR enhances anti-tumour immunity by optimizing CD8+ T cell function within the tumour microenvironment (TME). Using syngeneic xenograft tumour models, we found that DR induces a profound reprogramming of CD8+ T cell fate in the TME, favouring the expansion of effector T cell subsets with enhanced metabolic capacity and cytotoxic potential, while limiting the accumulation of terminally exhausted T cells. This metabolic reprogramming is driven by enhanced ketone body oxidation, particularly β-hydroxybutyrate (βOHB), which is elevated in both the circulation and tumour tissues of DR-fed mice. βOHB fuels T cell oxidative metabolism under DR, increasing mitochondrial membrane potential and tricarboxylic acid cycle-dependent pathways critical for T cell effector function, including acetyl-CoA production. By contrast, T cells deficient for ketone body oxidation exhibit reduced mitochondrial function, increased exhaustion and fail to control tumour growth under DR conditions. Importantly, DR synergizes with anti-PD1 immunotherapy, further augmenting anti-tumour T cell responses and limiting tumour progression. Our findings reveal that T cell metabolic reprogramming is central to the anti-tumour effects of DR, highlighting nutritional control of CD8+ T cell fate as a key driver of anti-tumour immunity.
    DOI:  https://doi.org/10.1038/s42255-025-01415-6
  22. Nat Med. 2025 Dec 12.
    Notable advances 2025.
    Karen O'Leary.
      
    DOI:  https://doi.org/10.1038/s41591-025-04098-4
  23. Nat Metab. 2025 Dec 08.
    Inhibition of IRAK4 by microbial trimethylamine blunts metabolic inflammation and ameliorates glycemic control.
    Julien Chilloux, Francois Brial, Amandine Everard, David Smyth, Petros Andrikopoulos, Liyong Zhang, Hubert Plovier, Antonis Myridakis, Lesley Hoyles, José Maria Moreno-Navarrete, Jèssica Latorre Luque, Viviana Casagrande, Rossella Menghini, Blerina Ahmetaj-Shala, Christine Blancher, Laura Martinez-Gili, Selin Gencer, Jane F Fearnside, Richard H Barton, Ana Luisa Neves, Alice R Rothwell, Christelle Gérard, Sophie Calderari, Mark J Williamson, Julian E Fuchs, Lata Govada, Claire L Boulangé, Saroor Patel, James Scott, Mark Thursz, Naomi Chayen, Robert C Glen, Nigel J Gooderham, Jeremy K Nicholson, Massimo Federici, José Manuel Fernández-Real, Dominique Gauguier, Peter P Liu, Patrice D Cani, Marc-Emmanuel Dumas.
      The global type 2 diabetes epidemic is a major health crisis. Although the microbiome has roles in the onset of insulin resistance (IR), low-grade inflammation and diabetes, the microbial compounds controlling these processes remain to be discovered. Here, we show that the microbial metabolite trimethylamine (TMA) decouples inflammation and IR from diet-induced obesity by inhibiting interleukin-1 receptor-associated kinase 4 (IRAK4), a central kinase in the Toll-like receptor pathway sensing danger signals. TMA blunts TLR4 signalling in primary human hepatocytes and peripheral blood monocytic cells and rescues mouse survival after lipopolysaccharide-induced septic shock. Genetic deletion and chemical inhibition of IRAK4 result in metabolic and immune improvements in high-fat diets. Remarkably, our results suggest that TMA-unlike its liver co-metabolite trimethylamine N-oxide, which is associated with cardiovascular disease-improves immune tone and glycemic control in diet-induced obesity. Altogether, this study supports the emerging role of the kinome in the microbial-mammalian chemical crosstalk.
    DOI:  https://doi.org/10.1038/s42255-025-01413-8
  24. BMC Endocr Disord. 2025 Dec 13.
    Nationwide implementation of a diabetes self-management and network system improves outcomes in type 1 diabetes: real-world evidence from Thailand.
    Thai-Type 1 Diabetes and Diabetes diagnosed Age before 30 years Registry, Care and Network (T1DDAR CN) committee and members
      
    Keywords:  Diabetes self-management program; Insulin-dependent diabetes mellitus; Network system; Type 1 diabetes
    DOI:  https://doi.org/10.1186/s12902-025-02123-8
  25. Nat Commun. 2025 Dec 11.
    Imbalance of stem-like and effector T cell states in children with early type 1 diabetes across conventional and regulatory subsets.
    Veronika Niederlova, Ales Neuwirth, Vit Neuman, Juraj Michalik, Bela Charvatova, Martin Modrak, Zdenek Sumnik, Ondrej Stepanek.
      Type 1 diabetes (T1D) is an autoimmune disease caused by the loss of self-tolerance toward insulin-producing pancreatic β-cells. Its etiology remains incompletely understood but involves dysregulated T cell responses. Here, we perform single-cell transcriptomic analysis of peripheral blood T cells from children newly diagnosed with T1D, the same children after one year, and healthy donors. We observe that children with diabetes show diminished effector and cytotoxic programs and enhanced stemness-associated gene signature across diverse T cell subsets, especially at diagnosis. In parallel, we detect signs of impaired regulatory capacity in regulatory T cells and regulatory TR3-56 cells. These findings are supported by flow cytometry analysis of the same cohort and reanalysis of publicly available datasets. Overall, our results suggest that T1D is associated with impaired T cell effector differentiation and regulatory T cell dysfunction, both of which may contribute to immune imbalance and loss of self-tolerance.
    DOI:  https://doi.org/10.1038/s41467-025-66459-4
  26. Science. 2025 Dec 11. 390(6778): 1182
    The experiment I didn't plan.
    Monika Gulia-Nuss.
      
    DOI:  https://doi.org/10.1126/science.aee5278
  27. Nat Commun. 2025 Dec 07. 16(1): 10945
    Nef stabilizes actin to prevent HIV-1 sensing by RIG-I-like receptors.
    Alexandre Laliberté, Caterina Prelli Bozzo, Dhiraj Acharya, Aurora De Luna, Maximilian Hirschenberger, Junji Zhu, Meta Volcic, Bettina Stolp, Cristina M Rodriguez-Quinteros, Oliver T Fackler, Michaela U Gack, Konstantin M J Sparrer, Frank Kirchhoff.
      Sensing of viral pathogens by RIG-I-like receptors (RLRs) requires their priming via dephosphorylation mediated by the protein phosphatase 1 regulatory subunit 12 C (R12C), which is activated upon virus-induced actin rearrangements. Here, we show that the HIV-1 accessory protein Nef prevents R12C-mediated RLR priming, thereby suppressing viral sensing. HIV-1 variants containing single point mutations in Nef (F/R191A) that ablate its ability to bind the actin-modulating kinase PAK2 trigger increased interferon (IFN) responses in primary CD4+ T cells, macrophages, and dendritic cells. Neutralization of IFN suppresses innate immune activation and enhances the replication of Nef-mutated HIV-1. We further demonstrate that HIV-1 encoding Nef F/R191A is sensed by MDA5 after proviral integration in an R12C-dependent manner. Mechanistically, PAK2 binding by Nef promotes actin repair and stabilization, thereby preventing re-localization of R12C to MDA5 and RIG-I and their subsequent dephosphorylation. Our data identify Nef as an antagonist of actin-R12C-mediated RLR priming, enabling HIV-1 to escape immune control.
    DOI:  https://doi.org/10.1038/s41467-025-67028-5
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