bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–06–29
23 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Hormone helps mice live longer and avoid obesity.
  2. Death Glitch.
  3. Lipids rewire T cell exhaustion.
  4. Capturing dynamic rather than static risk for improved monitoring of type 1 diabetes progression.
  5. Cancer cells get power boost by stealing mitochondria from nerves.
  6. Neuronal transfer of mitochondria to tumour cells promotes cancer spread.
  7. Microprotein SMIM26 drives oxidative metabolism via serine-responsive mitochondrial translation.
  8. Insulin neoantigen elicits memory T cell activation in diabetes.
  9. The E3 ubiquitin ligase Cul5 regulates hematopoietic stem cell function for steady-state hematopoiesis in mice.
  10. The mitochondrial methylation potential gates mitoribosome assembly.
  11. Polyunsaturated fatty acid-induced metabolic exhaustion and ferroptosis impair the anti-tumour function of MAIT cells in MASLD.
  12. Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy.
  13. GLP-1 and amylin receptor multiagonism with amycretin for obesity management.
  14. Dietary control of peripheral adipose storage capacity through membrane lipid remodelling.
  15. Microglia promote inflammatory cell death upon neuronal mitochondrial impairment during neurodegeneration.
  16. Epigenetic attenuation of interferon signaling is associated with aging-related improvements in systemic lupus erythematosus.
  17. A lysosomal surveillance response to stress extends healthspan.
  18. Obesity drives depot-specific vascular remodeling in male white adipose tissue.
  19. Restriction of innate Tγδ17 cell plasticity by an AP-1 regulatory axis.
  20. Apolipoprotein M attenuates age-related macular degeneration phenotypes via sphingosine-1-phosphate signaling and lysosomal lipid catabolism.
  21. Granzyme K+ CD8 T cells slow tauopathy progression by targeting microglia.
  22. Gut microbiota-specific T cells induce neuroinflammation through molecular mimicry.
  23. Diabetes-Related Distress and Glycemic Dysregulation in Everyday Life With Type 1 Diabetes: Which Comes First?
  1. Nature. 2025 Jun 25.
    Hormone helps mice live longer and avoid obesity.
      
    Keywords:  Ageing
    DOI:  https://doi.org/10.1038/d41586-025-01896-1
  2. Science. 2025 Jun 26. 388(6754): 1379
    Death Glitch.
      
    DOI:  https://doi.org/10.1126/science.adz3936
  3. Nat Immunol. 2025 Jun 27.
    Lipids rewire T cell exhaustion.
    Marie-Elen Tuchel, Annette Oxenius.
      
    DOI:  https://doi.org/10.1038/s41590-025-02177-9
  4. Nat Med. 2025 Jun 26.
    Capturing dynamic rather than static risk for improved monitoring of type 1 diabetes progression.
      
    DOI:  https://doi.org/10.1038/s41591-025-03825-1
  5. Nature. 2025 Jun 25.
    Cancer cells get power boost by stealing mitochondria from nerves.
    Traci Watson.
      
    Keywords:  Cancer; Cell biology; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-01941-z
  6. Nature. 2025 Jun 25.
    Neuronal transfer of mitochondria to tumour cells promotes cancer spread.
    Anand K Singh, Yuan Pan.
      
    Keywords:  Cancer; Medical research; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-025-01718-4
  7. Mol Cell. 2025 Jun 20. pii: S1097-2765(25)00472-1. [Epub ahead of print]
    Microprotein SMIM26 drives oxidative metabolism via serine-responsive mitochondrial translation.
    Jiemin Nah, Sreya Mahendran, Baptiste Kerouanton, Liang Cui, Daniella H Hock, Alfredo Cabrera-Orefice, Kyle Dunlap, David Robinson, Desmond W H Tung, Sze Huey Leong, Kiat-Yi Tan, Sonia P Chothani, Jingjing Sun, Agnieszka Dziegowska, Grazyna Leszczynska, Owen J L Rackham, Ilka Wittig, Peter Dedon, Gregory S Ducker, David A Stroud, Lena Ho.
      Mitochondrial small open reading frame (ORF)-encoded microproteins (SEPs) are key regulators and components of the electron transport chain (ETC). Although ETC complex I assembly is tightly coupled to nutrient availability, including serine, the coordinating mechanism remains unknown. A genome-wide CRISPR screen targeting SEPs revealed that deletion of the LINC00493-encoded microprotein SMIM26 sensitizes cells to one-carbon restriction. SMIM26 interacts with mitochondrial serine transporters SFXN1/2 and the mitoribosome, forming a functional triad that facilitates translation of the complex I subunit mt-ND5. SMIM26 loss impairs serine import, reduces folate intermediates, and disrupts key mitochondrial tRNA modifications (τm5U and τm5s²U), resulting in ND5 translation failure and complex I deficiency. SMIM26 deletion is embryonic lethal in mice and impedes tumor growth in a xenograft model of folate-dependent acute myeloid leukemia. These findings define SMIM26 as a critical integrator of one-carbon flux and complex I biogenesis and establish a paradigm for localized mitochondrial translation through transporter-ribosome interactions.
    Keywords:  complex I; electron transport chain; micropeptides; mitochondria; mitochondrial translation; one-carbon pathway; oxidative phosphorylation; small ORF-encoded peptides
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.033
  8. Nat Rev Immunol. 2025 Jun 25.
    Insulin neoantigen elicits memory T cell activation in diabetes.
    Boyan K Tsankov, Dana J Philpott.
      
    DOI:  https://doi.org/10.1038/s41577-025-01202-0
  9. J Clin Invest. 2025 Jun 26. pii: e180913. [Epub ahead of print]
    The E3 ubiquitin ligase Cul5 regulates hematopoietic stem cell function for steady-state hematopoiesis in mice.
    Siera A Tomishima, Dale D Kim, Nadia Porter, Ipsita Guha, Asif A Dar, Yohaniz Ortega-Burgos, Jennifer Roof, Hossein Fazelinia, Lynn A Spruce, Christopher S Thom, Robert L Bowman, Paula M Oliver.
      The balance of hematopoietic stem cell (HSC) self-renewal versus differentiation is essential to ensure long-term repopulation capacity while allowing response to events that require increased hematopoietic output. Proliferation and differentiation of HSCs and their progeny is controlled by the JAK/STAT pathway downstream of cytokine signaling. E3 ubiquitin ligases, like Cullin 5 (Cul5), can regulate JAK/STAT signaling by degrading signaling intermediates. Here we report that mice lacking Cul5 in hematopoietic cells (Cul5Vav-Cre) have increased numbers of HSPCs, splenomegaly, and extramedullary hematopoiesis. Differentiation in Cul5Vav-Cre mice is myeloid- and megakaryocyte-biased, resulting in leukocytosis, anemia and thrombocytosis. Cul5Vav-Cre mice increased HSC proliferation and circulation, associated with a decrease in CXCR4 surface expression. In bone marrow cells, we identified LRRC41 co-immunoprecipitated with CUL5, and vice versa, supporting that CRL5 forms a complex with LRRC41. We identified an accumulation of LRRC41 and STAT5 in Cul5Vav-Cre HSCs during IL-3 stimulation, supporting their regulation by Cul5. Whole cell proteome (WCP) analysis of HSPCs from Cul5Vav-Cre bone marrow identified upregulation of many STAT5 target genes and associated pathways. Finally, JAK1/2 inhibition with ruxolitinib normalized hematopoiesis in Cul5Vav-Cre mice. These studies demonstrate the function of Cul5 in HSC function, stem cell fate decisions, and regulation of IL-3 signaling.
    Keywords:  Bone marrow differentiation; Hematology; Hematopoietic stem cells; Immunology; Stem cells; Ubiquitin-proteosome system
    DOI:  https://doi.org/10.1172/JCI180913
  10. Nat Commun. 2025 Jun 25. 16(1): 5388
    The mitochondrial methylation potential gates mitoribosome assembly.
    Ruth I C Glasgow, Vivek Singh, Lucía Peña-Pérez, Alissa Wilhalm, Marco F Moedas, David Moore, Florian A Rosenberger, Xinping Li, Ilian Atanassov, Mira Saba, Miriam Cipullo, Joanna Rorbach, Anna Wedell, Christoph Freyer, Alexey Amunts, Anna Wredenberg.
      S-adenosylmethionine (SAM) is the principal methyl donor in cells and is essential for mitochondrial gene expression, influencing RNA modifications, translation, and ribosome biogenesis. Using direct long-read RNA sequencing in mouse tissues and embryonic fibroblasts, we show that processing of the mitochondrial ribosomal gene cluster fails in the absence of mitochondrial SAM, leading to an accumulation of unprocessed precursors. Proteomic analysis of ribosome fractions revealed these precursors associated with processing and assembly factors, indicating stalled biogenesis. Structural analysis by cryo-electron microscopy demonstrated that SAM-dependent methylation is required for peptidyl transferase centre formation during mitoribosome assembly. Our findings identify a critical role for SAM in coordinating mitoribosomal RNA processing and large subunit maturation, linking cellular methylation potential to mitochondrial translation capacity.
    DOI:  https://doi.org/10.1038/s41467-025-60977-x
  11. J Hepatol. 2025 Jun 19. pii: S0168-8278(25)02273-1. [Epub ahead of print]
    Polyunsaturated fatty acid-induced metabolic exhaustion and ferroptosis impair the anti-tumour function of MAIT cells in MASLD.
    Sebastian Deschler, Junika Pohl-Topcu, Lukas Ramsauer, Philippa Meiser, Sophia Erlacher, Robin P Schenk, H Carlo Maurer, Peng Shen, Juliane Kager, Joseph Zink, Karyna Pistrenko, Enric Redondo Monte, Julius Weber, Lena Wasmaier, Melanie Laschinger, Norbert Hüser, Fabian Geisler, Douglas Thorburn, Hanno Nieß, Gabriela M Wiedemann, Hans Zischka, Mathias Heikenwälder, Karin Kleigrewe, Carolin Mogler, Jan P Böttcher, Percy A Knolle, Roland M Schmid, Katrin Böttcher.
       BACKGROUND & AIMS: Mucosal-associated invariant T (MAIT) cells constitute a highly abundant innate-like T cell population in the human liver that is critical for immune surveillance of hepatic cancers but often dysfunctional in human hepatocellular carcinoma (HCC) for unclear reasons. Here, we sought to determine mechanisms that drive MAIT cells dysfunction in metabolic dysfunction-associated steatotic liver disease (MASLD), a chronic liver disease predisposing patients for HCC development.
    METHODS: We studied MAIT cell functionality, metabolism and anti-cancer activity directly ex vivo in patients with MASLD, as well as in co-culture models mimicking MASLD. (Single-cell) RNA sequencing was used for translation into clinical cohorts of patients with MASLD and MASLD-associated HCC.
    RESULTS: We show that MAIT cells have lost their effector functions in patients with MASLD. We uncover that MAIT cell dysfunction is caused by MASLD-associated polyunsaturated fatty acids (PUFAs), which selectively accumulate in MAIT cells but not conventional CD8+ T cells or NK cells. Mechanistically, PUFAs drive MAIT cell dysfunction through intracellular formation of lipid peroxides that promote a state of 'metabolic exhaustion' characterised by compromised mitochondrial respiration and glycolysis in MAIT cells. Excessive signalling through this MASLD-PUFA-lipid peroxide axis results in MAIT cell death by ferroptosis. Interference with PUFA-induced lipid peroxide formation in MAIT cells reversed their metabolic exhaustion and prevented ferroptotic MAIT cell death, thereby restoring MAIT cell effector function and anti-cancer activity. In patients with HCC, high enrichment of the MAIT cell-PUFA gene signature linked to MAIT cell dysfunction was associated with poor survival.
    CONCLUSIONS: Our findings uncover a novel immunometabolic axis that serves as a functional barrier for MAIT cell-mediated anti-cancer immunity and could be exploited for enhancement of immunotherapy. IMPACT AND IMPLICATIONS: ; This study identifies a novel immunometabolic axis by which polyunsaturated fatty acids (PUFAs) accumulating in MASLD liver tissue drive MAIT cell dysfunction through lipid peroxide-induced metabolic exhaustion and ferroptosis, thereby impairing their anti-tumour activity. These findings reveal how MASLD creates an immune-permissive environment that may facilitate HCC development and -progression. Targeting the PUFA-lipid peroxide axis could restore MAIT cell function and enhance current immunotherapeutic anti-cancer strategies.
    Keywords:  HCC; MAIT cells; MASLD; ferroptosis; immunometabolism; lipid peroxidation
    DOI:  https://doi.org/10.1016/j.jhep.2025.06.006
  12. Nat Commun. 2025 Jun 25. 16(1): 5377
    Metabolic reprogramming of the neovascular niche promotes regenerative angiogenesis in proliferative retinopathy.
    Gael Cagnone, Sheetal Pundir, Charlotte Betus, Tapan Agnihotri, Anli Ren, Jin Sung -Kim, Noémie-Rose Harvey, Emilie Heckel, Mei Xi Chen, Anu Situ, Perrine Gaub, Nicholas Kim, Ashim Das, Severine Leclerc, Florian Wünnemann, Louis Berillon, Gregor Andelfinger, Sergio Crespo-Garcia, Alexandre Dubrac, Flavio A Rezende, Clary B Clish, Bruno Maranda, José Carlos Rivera, Lois E H Smith, Przemyslaw Sapieha, Jean-Sébastien Joyal.
      Healthy blood vessels supply neurons to preserve metabolic function. In blinding proliferative retinopathies (PRs), pathological neovascular tufts often emerge in lieu of needed physiological revascularization. Here we show that metabolic shifts in the neovascular niche define angiogenic fate. Fatty acid oxidation (FAO) metabolites accumulated in human and murine retinopathy samples. Neovascular tufts with a distinct single-cell transcriptional signature highly expressed FAO enzymes. The deletion of Sirt3, an FAO regulator, shifted the neovascular niche metabolism from FAO to glycolysis and suppressed tuft formation. This metabolic transition increased Vegf expression in astrocytes and reprogrammed pathological neovessels to a physiological phenotype, hastening vascular regeneration of the ischemic retina and improving vision. Hence, strategies to change the metabolic environment of vessels could promote a regenerative phenotype in vascular diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60061-4
  13. Lancet. 2025 Jun 20. pii: S0140-6736(25)01250-4. [Epub ahead of print]
    GLP-1 and amylin receptor multiagonism with amycretin for obesity management.
    Bernard Khoo, Tricia M-M Tan.
      
    DOI:  https://doi.org/10.1016/S0140-6736(25)01250-4
  14. Nat Metab. 2025 Jun 27.
    Dietary control of peripheral adipose storage capacity through membrane lipid remodelling.
    Marcus J Tol, Yuta Shimanaka, Alexander H Bedard, Jennifer Sapia, Liujuan Cui, Mariana Colaço-Gaspar, Peter Hofer, Alessandra Ferrari, Kevin Qian, John P Kennelly, Stephen D Lee, Yajing Gao, Xu Xiao, Jie Gao, Julia J Mack, Thomas A Weston, Kevin J Williams, Baolong Su, Calvin Pan, Aldons J Lusis, Daniel P Pike, Alex Reed, Natalia Milosevich, Benjamin F Cravatt, Makoto Arita, Stephen G Young, David A Ford, Rudolf Zechner, Stefano Vanni, Peter Tontonoz.
      Genetic and dietary cues are known drivers of obesity, yet how they converge at the molecular level is incompletely understood. Here we show that PPARγ supports hypertrophic expansion of adipose tissue via transcriptional control of LPCAT3, an endoplasmic reticulum (ER)-resident O-acyltransferase that selectively enriches diet-derived omega-6 polyunsaturated fatty acids (n-6 PUFAs) in the membrane lipidome. In mice fed a high-fat diet, lowering membrane n-6 PUFA levels through genetic or dietary interventions results in aberrant adipose triglyceride (TG) turnover, ectopic fat deposition and insulin resistance. Additionally, we detail a non-canonical adaptive response in 'lipodystrophic' Lpcat3-/- adipose tissues that engages a futile lipid cycle to increase metabolic rate and offset lipid overflow to ectopic sites. Live-cell imaging, lipidomics and molecular dynamics simulations reveal that adipocyte LPCAT3 activity enriches n-6 arachidonate in the phosphatidylethanolamine (PE)-dense ER-lipid droplet interface. Functionally, this localized PE remodelling optimizes TG storage by driving the formation of large droplets that exhibit greater resistance to adipose TG lipase activity. These findings highlight the PPARγ-LPCAT3 axis as a mechanistic link between dietary n-6 PUFA intake, adipose expandability and systemic energy balance.
    DOI:  https://doi.org/10.1038/s42255-025-01320-y
  15. Nat Struct Mol Biol. 2025 Jun 25.
    Microglia promote inflammatory cell death upon neuronal mitochondrial impairment during neurodegeneration.
    Guangyan Miao, Tina M Fortier, Haibo Liu, Dorothy P Schafer, Katherine A Fitzgerald, Junhao Mao, Eric H Baehrecke.
      The failure to clear dysfunctional mitochondria, cell death and inflammation have been linked in neurodegenerative disease, but their relationship and role in these conditions is not fully understood. Loss of Vps13d prevents clearance of mitochondria, and mutations in human VPS13D have been associated with neurological movement disorders. To investigate the relationship between mitochondrial health, inflammation and neurodegeneration, we created a conditional Vps13d-knockout mouse. Loss of Vps13d in excitatory neurons resulted in behavioral changes and neurodegeneration. Vacuolar protein sorting 13D (VPS13D) deficiency also caused mitochondrial ultrastructural defects and dysfunction in neurons followed by gasdermin E processing, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon response cGAMP interactor (STING) signaling, microglial activation and cell death. Gasdermin E localization with mitochondria in Vps13d-mutant neurons was required for elevated extracellular mitochondrial DNA that promoted activation of microglia. Depletion of microglia suppressed cell death and behavioral phenotypes but not mitochondrial changes in the neuron-specific Vps13d-knockout model, indicating that microglia promote cell death in this model of neurodegenerative disease.
    DOI:  https://doi.org/10.1038/s41594-025-01602-9
  16. Sci Transl Med. 2025 Jun 25. 17(804): eadt5550
    Epigenetic attenuation of interferon signaling is associated with aging-related improvements in systemic lupus erythematosus.
    Rithwik Narendra, Hoang Van Phan, Sarah L Patterson, Ana Almonte-Loya, Emily C Lydon, Cristina Lanata, Christina Love, Joonsuk Park, Michiko Shimoda, Lisa Barcellos, Honey Mekonen, Angela Detweiler, Padmini Deosthale, Norma Neff, Lindsey A Criswell, Lenka Maliskova, Walter Eckalbar, Gabriela K Fragiadakis, Jinoos Yazdany, Maria Dall'Era, Patricia Katz, Chun Jimmie Ye, Marina Sirota, Charles R Langelier.
      In the general population, aging is associated with an increase in systemic inflammation and chronic disease burden. However, in systemic lupus erythematosus (SLE), older age is uniquely associated with a decrease in disease activity, suggesting a distinct relationship between aging and inflammation. Using a multiomic approach, we compared aging-related changes in the peripheral blood immune profiles of 287 patients with SLE and 928 healthy controls. In patients with SLE, aging correlated with lower expression of interferon (IFN)-stimulated genes (ISGs) across multiple cell types, decreased plasma IFN-α2, and differential genome methylation. Both patients with SLE and controls demonstrated age-related declines in naïve T cells, but only patients with SLE exhibited increases in CD56dim natural killer cells with older age. Of the genes both down-regulated and hypermethylated with older age, ISGs were disproportionately represented, suggesting a role for epigenetic silencing. Altogether, we found that patients with SLE exhibit unique aging-related decreases in IFN signaling that correlate with improved disease activity.
    DOI:  https://doi.org/10.1126/scitranslmed.adt5550
  17. Nat Cell Biol. 2025 Jun 26.
    A lysosomal surveillance response to stress extends healthspan.
    Terytty Yang Li, Arwen W Gao, Rendan Yang, Yu Sun, Yuxuan Lei, Xiaoxu Li, Lin Chen, Yasmine J Liu, Rachel N Arey, Kimberly Morales, Raya B Liu, Wenzheng Wang, Ang Zhou, Tong-Jin Zhao, Weisha Li, Amélia Lalou, Qi Wang, Tanes Lima, Riekelt H Houtkooper, Johan Auwerx.
      Lysosomes are cytoplasmic organelles central for the degradation of macromolecules to maintain cellular homoeostasis and health. However, how lysosomal activity can be boosted to counteract ageing and ageing-related diseases remains elusive. Here we reveal that silencing specific vacuolar H+-ATPase subunits (for example, vha-6), which are essential for intestinal lumen acidification in Caenorhabditis elegans, extends lifespan by ~60%. This longevity phenotype can be explained by an adaptive transcriptional response typified by induction of a set of transcripts involved in lysosomal function and proteolysis, which we termed the lysosomal surveillance response (LySR). LySR activation is characterized by boosted lysosomal activity and enhanced clearance of protein aggregates in worm models of Alzheimer's disease, Huntington's disease and amyotrophic lateral sclerosis, thereby improving fitness. The GATA transcription factor ELT-2 governs the LySR programme and its associated beneficial effects. Activating the LySR pathway may therefore represent an attractive mechanism to reduce proteotoxicity and, as such, potentially extend healthspan.
    DOI:  https://doi.org/10.1038/s41556-025-01693-y
  18. Nat Commun. 2025 Jun 25. 16(1): 5392
    Obesity drives depot-specific vascular remodeling in male white adipose tissue.
    Sana S Hasan, David John, Martina Rudnicki, Ibrahim AlZaim, Daniel Eberhard, Iris Moll, Jacqueline Taylor, Christian Klein, Maximilian von Heesen, Lena-Christin Conradi, Ralf H Adams, Eckhard Lammert, Joanna Kalucka, Christiana Ruhrberg, Stefanie Dimmeler, Andreas Fischer.
      Obesity-driven pathological expansion of white adipose tissue (WAT) is a key driver of endothelial dysfunction. However, early vascular alterations associated with over-nutrition also serve to exacerbate WAT dysfunction. Here, we conduct a single-cell transcriptomic analysis of WAT endothelium to delineate endothelial heterogeneity and elucidate vascular alterations and its consequence in a male murine model of obesity. We demarcate depot-specific differences in subcutaneous (sWAT) and visceral WAT (vWAT) endothelium through in sillico analysis and further corroboration of our findings. Moreover, we identify a sWAT-specific fenestrated endothelial cell (EC) subtype, which declines in obese conditions. Utilizing systemic anti-VEGFA blockade and genetic Vegfa manipulation, we demonstrate that VEGFA is necessary for maintaining fenestration in sWAT. Additionally, we detect this fenestrated EC subtype in male human WAT, which undergoes reduction in individuals with obesity. Collectively, this atlas serves as a valuable tool for future studies to decipher the functional significance of different WAT EC subtypes.
    DOI:  https://doi.org/10.1038/s41467-025-60910-2
  19. Nat Immunol. 2025 Jun 27.
    Restriction of innate Tγδ17 cell plasticity by an AP-1 regulatory axis.
    Morgan E Parker, Naren U Mehta, Tzu-Chieh Liao, William H Tomaszewski, Stephanie A Snyder, Julia Busch, Maria Ciofani.
      Interleukin-17 (IL-17)-producing γδ T (Tγδ17) cells are innate-like mediators of intestinal barrier immunity. Although IL-17-producing helper T cell and group 3 innate lymphoid cell plasticity have been extensively studied, the mechanisms governing Tγδ17 cell effector flexibility remain undefined. Here, we combined type 3 fate mapping with single-cell ATAC-sequencing/RNA-sequencing multiome profiling to define the cellular features and regulatory networks underlying Tγδ17 cell plasticity. During homeostasis, Tγδ17 cell effector identity was stable across tissues, including for intestinal T-bet+ Tγδ17 cells that restrained interferon-γ production. However, Salmonella enterica subsp. enterica serovar Typhimurium infection induced intestinal Vγ6+ Tγδ17 cell conversion into type 1 effectors, with loss of IL-17A production and partial RORγt downregulation. Multiome analysis revealed a trajectory along Vγ6+ Tγδ17 cell effector conversion, with TIM-3 marking ex-Tγδ17 cells with enhanced type 1 functionality. Last, we characterized and validated a critical AP-1 regulatory axis centered around JUNB and FOSL2 that controls Vγ6+ Tγδ17 cell plasticity by stabilizing type 3 identity and restricting type 1 effector conversion.
    DOI:  https://doi.org/10.1038/s41590-025-02206-7
  20. Nat Commun. 2025 Jun 24. 16(1): 5331
    Apolipoprotein M attenuates age-related macular degeneration phenotypes via sphingosine-1-phosphate signaling and lysosomal lipid catabolism.
    Tae Jun Lee, Andrea Santeford, Kristen M Pitts, Carla Valenzuela Ripoll, Ryo Terao, Zhen Guo, Mualla Ozcan, Dagmar Kratky, Christina Christoffersen, Ali Javaheri, Rajendra S Apte.
      Age-related macular degeneration (AMD) is a leading cause of blindness in people over 50. AMD and cardiovascular disease share risk factors including age, impaired lipid metabolism, and extracellular lipid deposition. Because of its importance in age-related diseases, we hypothesize that apolipoprotein M (ApoM), a lipocalin that binds sphingosine-1-phosphate (S1P), might restore lipid homeostasis and retinal function in AMD. In support, we find that human patients with AMD demonstrate significantly reduced ApoM compared to controls. In mice with impaired retinal cholesterol efflux, ApoM improves retinal pigment epithelium (RPE) function and lipotoxicity in an S1P- and S1P receptor 3-dependent manner. Ultrastructural evidence of enhanced melanosome-lipid droplet interactions led us to hypothesize and demonstrate that ApoM-S1P signaling drives RPE-specific lysosomal lipid catabolism. RPE-specific knockout of lysosomal acid lipase recapitulates features of AMD. Our study defines a novel role for ApoM/S1P signaling in AMD driven by RPE lipotoxicity, mediated by cell-autonomous lysosomal lipid catabolism.
    DOI:  https://doi.org/10.1038/s41467-025-60830-1
  21. Nat Immunol. 2025 Jun 24.
    Granzyme K+ CD8 T cells slow tauopathy progression by targeting microglia.
    Hannah D Mason, Yvonne L Latour, Christopher T Boughter, Kory R Johnson, Dragan Maric, Cayce E Dorrier, Vivian A Guedes, Chen Lai, Patrick C Duncker, Alexis M Johnson, Monica Manglani, Jessica M Gill, Daniel P Perl, Martin Meier-Schellersheim, Dorian B McGavern.
      Neurodegenerative diseases activate innate and adaptive immune responses that can either slow or accelerate disease progression. Here, we sought to define beneficial immune pressures that emerge during tauopathy development in mice and humans. Using mice that express mutant human tau in neurons, we observed that microglia slowed tauopathy development by controlling the spread of phosphorylated tau (pTau) in the central nervous system and blood. However, over time microglia converted into distressed antigen-presenting cells, acquired neuronal transcripts and were targeted by resident, clonally expanded CD8+ T cells. These cells did not express traditional effector molecules, such as IFNγ, TNF or granzymes a/b/c, but instead deposited granzyme K (GZMK) onto microglia and were regulated by immune checkpoint proteins (TIGIT, PD-1), as blockade of TIGIT and PD-1 enhanced disease progression. GZMK+CD8+ T cells also targeted microglia in pTau-rich human brain lesions resulting from age, Alzheimer's disease or chronic traumatic encephalopathy. Deletion of CD8+ T cells in mice promoted the emergence of distressed microglia containing neuronal transcripts, markedly enhanced pTau spread and accelerated neurological decline. These data demonstrate that GZMK+CD8+ T cells are a signature of tauopathy development and could potentially be harnessed to slow disease progression.
    DOI:  https://doi.org/10.1038/s41590-025-02198-4
  22. Nat Rev Immunol. 2025 Jun 24.
    Gut microbiota-specific T cells induce neuroinflammation through molecular mimicry.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-025-01201-1
  23. Diabetes Care. 2025 Jun 24. pii: dc250559. [Epub ahead of print]
    Diabetes-Related Distress and Glycemic Dysregulation in Everyday Life With Type 1 Diabetes: Which Comes First?
    Jeffrey S Gonzalez, Claire J Hoogendoorn, Raymond Hernandez, Stefan Schneider, Fayel Mustafiz, Megha Siddhanta, Elizabeth A Pyatak.
       OBJECTIVE: In an observational study, we paired ecological momentary assessment (EMA) and continuous glucose monitoring (CGM) to examine lagged effects of glycemic regulation on diabetes-related distress (DD), and vice versa, among adults with type 1 diabetes (T1D).
    RESEARCH DESIGN AND METHODS: Participants (N = 182; median ± SD age 40 ± 14 years; 54% women; 41% Latino; 29% White and 15% Black) wore a blinded CGM device for 14 days and completed five to six EMA surveys per day. We tested expected associations between momentary DD ratings and relevant patient-reported outcomes on validated questionnaires. Using multilevel cross-lagged modeling, we evaluated within-person lagged effects of CGM metrics (mean glucose mean; percentage of time in range [TIR; i.e., 70-180 mg/dL] and percentages of time 181-250, >250, and <70 mg/dL; and coefficient of variation [CV]) over 3-h periods on DD rated 0-100 at the end of that interval and 3 h later. We also examined lagged effects of DD on subsequent CGM metrics.
    RESULTS: Momentary DD ratings were significantly associated with results of questionnaires for DD, well-being, functional and mental health, and quality of life. Higher mean glucose, less TIR, greater percentage of time 181-250 and >250 mg/dL, and higher CV over 3 h each predicted greater DD at the end of that interval; higher 3-h mean glucose also predicted more DD 3 h later (P < 0.05). Greater DD unexpectedly predicted a lower percentage of time in hypoglycemia over the next 3 h (P < 0.05) but predicted no other CGM metrics.
    CONCLUSIONS: Findings support the validity of EMA of DD in adults with T1D and suggest glucose dysregulation is linked to subsequent increased DD over the short term, not vice versa. These findings have implications for interventions targeting DD.
    DOI:  https://doi.org/10.2337/dc25-0559
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