bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–01–19
33 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Lessons from Lebanon.
  2. Got flu? Promising drug shortens symptoms.
  3. Heterochromatic gene silencing controls CD4+ T cell susceptibility to regulatory T cell-mediated suppression in a murine allograft model.
  4. Gasdermin pores on extracellular vesicles spread cell death.
  5. GD3 ganglioside checkpoints in immune surveillance of senescent cells.
  6. Mitotic chromatin marking governs the segregation of DNA damage.
  7. Revealed: the fatty cells that are the 'bubble wrap' of the body.
  8. Deciphering functional tumor-immune crosstalk through highly multiplexed imaging and deep visual proteomics.
  9. MethylTree: exploring epimutations for accurate and non-invasive lineage tracing.
  10. High-resolution, noninvasive single-cell lineage tracing in mice and humans based on DNA methylation epimutations.
  11. Nuclear adenine activates hnRNPA2B1 to enhance antibacterial innate immunity.
  12. How the brain cleans itself during deep sleep.
  13. Chaperoning RNA into granules.
  14. Meta AI creates speech-to-speech translator that works in dozens of languages.
  15. Tripotency in human pancreas.
  16. Inhibited peroxidase activity of peroxiredoxin 1 by palmitic acid exacerbates nonalcoholic steatohepatitis in male mice.
  17. New obesity definition sidelines BMI to focus on health.
  18. 'Transcriptotype' explains phenotypic variability of inborn errors of immunity.
  19. Restimulation by macrophages exhausts T cells.
  20. Living the life emerita/emeritus.
  21. Absence of MCJ/DnaJC15 promotes brown adipose tissue thermogenesis.
  22. Neuronal-ILC2 interactions regulate pancreatic glucagon and glucose homeostasis.
  23. The Human Microglia Atlas (HuMicA) unravels changes in disease-associated microglia subsets across neurodegenerative conditions.
  24. Systems immunology integrates the complex endotypes of recessive dystrophic epidermolysis bullosa.
  25. Mind matters: investigating academia's 'mental health crisis'.
  26. Somatic mutation as an explanation for epigenetic aging.
  27. Semaglutide alleviates knee osteoarthritis pain in persons with obesity.
  28. Chimeric antigen receptor macrophages (CAR-M) sensitize HER2+ solid tumors to PD1 blockade in pre-clinical models.
  29. Bioenergetic adaptations of small intestinal epithelial cells reduce cell differentiation enhancing intestinal permeability in obese mice.
  30. Proteomic signature of HIV-associated subclinical left atrial remodeling and incident heart failure.
  31. Increased SOAT2 expression in aged regulatory T cells is associated with altered cholesterol metabolism and reduced anti-tumor immunity.
  32. Daily briefing: New obesity definition sidelines BMI to focus on health.
  33. Impact of rare non-coding variants on human diseases through alternative polyadenylation outliers.
  1. Science. 2025 Jan 17. 387(6731): 338
    Lessons from Lebanon.
    Peter Kfoury.
      
    DOI:  https://doi.org/10.1126/science.adv8869
  2. Nature. 2025 Jan 15.
    Got flu? Promising drug shortens symptoms.
      
    Keywords:  Medical research
    DOI:  https://doi.org/10.1038/d41586-025-00041-2
  3. Nat Commun. 2025 Jan 10. 16(1): 566
    Heterochromatic gene silencing controls CD4+ T cell susceptibility to regulatory T cell-mediated suppression in a murine allograft model.
    Julie Noguerol, Karl Laviolette, Margot Zahm, Adeline Chaubet, Ambrine Sahal, Claire Détraves, Romain Torres, Clothilde Demont, Véronique Adoue, Carine Joffre, Florence Cammas, Joost Pm van Meerwijk, Olivier P Joffre.
      Protective immune responses require close interactions between conventional (Tconv) and regulatory T cells (Treg). The extracellular mediators and signaling events that regulate the crosstalk between these CD4+ T cell subsets have been extensively characterized. However, how Tconv translate Treg-dependent suppressive signals at the chromatin level remains largely unknown. Here we show, using a murine bone marrow allograft model in which graft rejection is coordinated by CD4+ T cells and can be inhibited by Treg, that Treg-mediated T cell suppression involves Heterochromatin Protein 1 α (HP1α)-dependent gene silencing. Unexpectedly, our screen also reveals that T cells deficient for HP1γ or the methyltransferase SUV39H1 are better repressed by Treg than their wild-type counterparts. Mechanistically, our transcriptional and epigenetic profiling identifies HP1γ as a negative regulator of a gene network functionally associated with T-cell exhaustion, including those encoding the inhibitory receptors PD-1 and LAG-3. In conclusion, we identify HP1 variants as rheostats that finely tune the balance between tolerance and immunity. While HP1α converts immunosuppressive signals into heterochromatin-dependent gene silencing mechanisms, HP1γ adjusts Tconv sensitivity to inhibitory environmental signals.
    DOI:  https://doi.org/10.1038/s41467-025-55848-4
  4. Nat Rev Immunol. 2025 Jan 14.
    Gasdermin pores on extracellular vesicles spread cell death.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-025-01133-w
  5. Nat Aging. 2025 Jan 15.
    GD3 ganglioside checkpoints in immune surveillance of senescent cells.
    Julia Majewska, Valery Krizhanovsky.
      
    DOI:  https://doi.org/10.1038/s43587-025-00803-7
  6. Nat Commun. 2025 Jan 16. 16(1): 746
    Mitotic chromatin marking governs the segregation of DNA damage.
    Juliette Ferrand, Juliette Dabin, Odile Chevallier, Matteo Kane-Charvin, Ariana Kupai, Joel Hrit, Scott B Rothbart, Sophie E Polo.
      The faithful segregation of intact genetic material and the perpetuation of chromatin states through mitotic cell divisions are pivotal for maintaining cell function and identity across cell generations. However, most exogenous mutagens generate long-lasting DNA lesions that are segregated during mitosis. How this segregation is controlled is unknown. Here, we uncover a mitotic chromatin-marking pathway that governs the segregation of UV-induced damage in human cells. Our mechanistic analyses reveal two layers of control: histone ADP-ribosylation, and the incorporation of newly synthesized histones at UV damage sites, that both prevent local mitotic phosphorylations on histone H3 serine residues. Functionally, this chromatin-marking pathway controls the segregation of UV damage in the cell progeny with consequences on daughter cell fate. We propose that this mechanism may help preserve the integrity of stem cell compartments during asymmetric cell divisions.
    DOI:  https://doi.org/10.1038/s41467-025-56090-8
  7. Nature. 2025 Jan 09.
    Revealed: the fatty cells that are the 'bubble wrap' of the body.
    Max Kozlov.
      
    Keywords:  Cell biology
    DOI:  https://doi.org/10.1038/d41586-025-00012-7
  8. Mol Cell. 2025 Jan 08. pii: S1097-2765(24)01041-4. [Epub ahead of print]
    Deciphering functional tumor-immune crosstalk through highly multiplexed imaging and deep visual proteomics.
    Xiang Zheng, Andreas Mund, Matthias Mann.
      Deciphering the intricate tumor-immune interactions within the microenvironment is crucial for advancing cancer immunotherapy. Here, we introduce mipDVP, an advanced approach integrating highly multiplexed imaging, single-cell laser microdissection, and sensitive mass spectrometry to spatially profile the proteomes of distinct cell populations in a human colorectal and tonsil cancer with high sensitivity. In a colorectal tumor-a representative cold tumor-we uncovered spatial compartmentalization of an immunosuppressive macrophage barrier that potentially impedes T cell infiltration. Spatial proteomic analysis revealed distinct functional states of T cells in different tumor compartments. In a tonsil cancer sample-a hot tumor-we identified significant proteomic heterogeneity among cells influenced by proximity to cytotoxic T cell subtypes. T cells in the tumor parenchyma exhibit metabolic adaptations to hypoxic regions. Our spatially resolved, highly multiplexed strategy deciphers the complex cellular interplay within the tumor microenvironment, offering valuable insights for identifying immunotherapy targets and predictive signatures.
    Keywords:  cancer; deep visual proteomics; immunotherapy; mass spectrometry; multiplexed imaging; spatial medicine; spatial proteomics; tumor microenvironment; tumor-infiltrating lymphocytes
    DOI:  https://doi.org/10.1016/j.molcel.2024.12.023
  9. Nat Methods. 2025 Jan 16.
    MethylTree: exploring epimutations for accurate and non-invasive lineage tracing.
      
    DOI:  https://doi.org/10.1038/s41592-024-02568-0
  10. Nat Methods. 2025 Jan 16.
    High-resolution, noninvasive single-cell lineage tracing in mice and humans based on DNA methylation epimutations.
    Mengyang Chen, Ruijiang Fu, Yiqian Chen, Li Li, Shou-Wen Wang.
      In vivo lineage tracing holds great potential to reveal fundamental principles of tissue development and homeostasis. However, current lineage tracing in humans relies on extremely rare somatic mutations, which has limited temporal resolution and lineage accuracy. Here, we developed a generic lineage-tracing tool based on frequent epimutations on DNA methylation, enabled by our computational method MethylTree. Using single-cell genome-wide DNA methylation datasets with known lineage and phenotypic labels, MethylTree reconstructed lineage histories at nearly 100% accuracy across different cell types, developmental stages, and species. We demonstrated the epimutation-based single-cell multi-omic lineage tracing in mouse and human blood, where MethylTree recapitulated the differentiation hierarchy in hematopoiesis. Applying MethylTree to human embryos, we revealed early fate commitment at the four-cell stage. In native mouse blood, we identified ~250 clones of hematopoietic stem cells. MethylTree opens the door for high-resolution, noninvasive and multi-omic lineage tracing in humans and beyond.
    DOI:  https://doi.org/10.1038/s41592-024-02567-1
  11. Cell Metab. 2025 Jan 10. pii: S1550-4131(24)00482-0. [Epub ahead of print]
    Nuclear adenine activates hnRNPA2B1 to enhance antibacterial innate immunity.
    Shihao Zhang, Zenghui Cui, Danni Zhang, Deyu Zhang, Ke Jin, Zemeng Li, Bo Li, Boyi Cong, Juan Liu, Lei Wang, Mingyue Wen, Xuetao Cao.
      Bacterial infection reprograms cellular metabolism and epigenetic status, but how the metabolic-epigenetic crosstalk empowers host antibacterial defense remains unclear. Here, we report that heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is a sensor for metabolite adenine to launch an antimicrobial innate response through increasing Il1b transcription. Myeloid cell-specific Hnrnpa2b1-cKO mice are more susceptible to bacterial infection, while interleukin 1 beta (IL-1β) supplementation rescues the phenotype. Through a large-scale metabolites-hnRNPA2B1 interaction screen, we reveal that adenine directly binds and activates hnRNPA2B1 to mediate innate antibacterial response. Mechanistically, adenine directly recruits hnRNPA2B1 to Il1b enhancers, and hnRNPA2B1 increases Il1b enhancer chromatin accessibility through binding and recruiting nucleolin and fat mass and obesity-associated protein (FTO) to mediate Il1b enhancer DNA N6-methyladenosine (6mA) demethylation. Furthermore, bacterial infection elevates nuclear adenine at the early stage of infection, and in vivo adenine administration protects mice from death upon bacterial infection through the hnRNPA2B1-IL-1β circuit. Our findings offer new insights into metabolic-epigenetic crosstalk relevant to antibacterial innate immunity and indicate potential approaches for treating bacterial infections.
    Keywords:  DNA N(6)-methyladenosine; adenine; antibacterial immunity; hnRNPA2B1; interleukin 1; nucleolin
    DOI:  https://doi.org/10.1016/j.cmet.2024.11.014
  12. Nature. 2025 Jan;637(8046): 521
    How the brain cleans itself during deep sleep.
      
    Keywords:  Brain
    DOI:  https://doi.org/10.1038/d41586-025-00007-4
  13. Nat Cell Biol. 2025 Jan;27(1): 4
    Chaperoning RNA into granules.
    Daryl J V David.
      
    DOI:  https://doi.org/10.1038/s41556-024-01602-9
  14. Nature. 2025 Jan 15.
    Meta AI creates speech-to-speech translator that works in dozens of languages.
    Davide Castelvecchi.
      
    Keywords:  Computer science; Language
    DOI:  https://doi.org/10.1038/d41586-025-00045-y
  15. Nat Cell Biol. 2025 Jan;27(1): 4
    Tripotency in human pancreas.
    Stylianos Lefkopoulos.
      
    DOI:  https://doi.org/10.1038/s41556-024-01601-w
  16. Nat Commun. 2025 Jan 11. 16(1): 598
    Inhibited peroxidase activity of peroxiredoxin 1 by palmitic acid exacerbates nonalcoholic steatohepatitis in male mice.
    Wen Yin, Heng Xu, Zhonghao Bai, Yue Wu, Yan Zhang, Rui Liu, Zhangzhao Wang, Bei Zhang, Jing Shen, Hao Zhang, Xin Chen, Danting Ma, Xiaofeng Shi, Lihui Yan, Chang Zhang, Hualiang Jiang, Kaixian Chen, Dean Guo, Wenyan Niu, Huiyong Yin, Weiping J Zhang, Cheng Luo, Xiangyang Xie.
      Reactive oxygen species exacerbate nonalcoholic steatohepatitis (NASH) by oxidizing macromolecules; yet how they promote NASH remains poorly understood. Here, we show that peroxidase activity of global hepatic peroxiredoxin (PRDX) is significantly decreased in NASH, and palmitic acid (PA) binds to PRDX1 and inhibits its peroxidase activity. Using three genetic models, we demonstrate that hepatic PRDX1 protects against NASH in male mice. Mechanistically, PRDX1 suppresses STAT signaling and protects mitochondrial function by scavenging hydrogen peroxide, and mitigating the oxidation of protein tyrosine phosphatases and lipid peroxidation. We further identify rosmarinic acid (RA) as a potent agonist of PRDX1. As revealed by the complex crystal structure, RA binds to PRDX1 and stabilizes its peroxidatic cysteine. RA alleviates NASH through specifically activating PRDX1's peroxidase activity. Thus, beyond revealing the molecular mechanism underlying PA promoting oxidative stress and NASH, our study suggests that boosting PRDX1's peroxidase activity is a promising intervention for treating NASH.
    DOI:  https://doi.org/10.1038/s41467-025-55939-2
  17. Nature. 2025 Jan 14.
    New obesity definition sidelines BMI to focus on health.
    Giorgia Guglielmi.
      
    Keywords:  Obesity; Public health
    DOI:  https://doi.org/10.1038/d41586-025-00123-1
  18. Nat Rev Immunol. 2025 Jan 14.
    'Transcriptotype' explains phenotypic variability of inborn errors of immunity.
    Alexandra Flemming.
      
    DOI:  https://doi.org/10.1038/s41577-025-01134-9
  19. Immunity. 2025 Jan 14. pii: S1074-7613(24)00574-0. [Epub ahead of print]58(1): 12-14
    Restimulation by macrophages exhausts T cells.
    Fernando Fernández-García, Barbara B Maier.
      Inhibiting T cell exhaustion is an attractive cancer immunotherapy strategy. In this issue of Immunity, Waibl Polania et al. examine the microenvironmental signals regulating terminal T cell exhaustion and find that antigen presentation by tumor-associated macrophages, not tumor cells, drives terminal T cell exhaustion in glioblastoma.
    DOI:  https://doi.org/10.1016/j.immuni.2024.12.010
  20. Nat Methods. 2025 Jan 15.
    Living the life emerita/emeritus.
    Vivien Marx.
      
    DOI:  https://doi.org/10.1038/s41592-024-02592-0
  21. Nat Commun. 2025 Jan 13. 16(1): 229
    Absence of MCJ/DnaJC15 promotes brown adipose tissue thermogenesis.
    Beatriz Cicuéndez, Alfonso Mora, Juan Antonio López, Andrea Curtabbi, Javier Pérez-García, Begoña Porteiro, Daniel Jimenez-Blasco, Pedro Latorre-Muro, Paula Vo, Madison Jerome, Beatriz Gómez-Santos, Rafael Romero-Becerra, Magdalena Leiva, Elena Rodríguez, Marta León, Luis Leiva-Vega, Noemi Gómez-Lado, Jorge L Torres, Lourdes Hernández-Cosido, Pablo Aguiar, Miguel Marcos, Martin Jastroch, Andreas Daiber, Patricia Aspichueta, Juan Pedro Bolaños, Jessica B Spinelli, Pere Puigserver, José Antonio Enriquez, Jesús Vázquez, Cintia Folgueira, Guadalupe Sabio.
      Obesity poses a global health challenge, demanding a deeper understanding of adipose tissue (AT) and its mitochondria. This study describes the role of the mitochondrial protein Methylation-controlled J protein (MCJ/DnaJC15) in orchestrating brown adipose tissue (BAT) thermogenesis. Here we show how MCJ expression decreases during obesity, as evident in human and mouse adipose tissue samples. MCJKO mice, even without UCP1, a fundamental thermogenic protein, exhibit elevated BAT thermogenesis. Electron microscopy unveils changes in mitochondrial morphology resembling BAT activation. Proteomic analysis confirms these findings and suggests involvement of the eIF2α mediated stress response. The pivotal role of eIF2α is scrutinized by in vivo CRISPR deletion of eIF2α in MCJKO mice, abrogating thermogenesis. These findings uncover the importance of MCJ as a regulator of BAT thermogenesis, presenting it as a promising target for obesity therapy.
    DOI:  https://doi.org/10.1038/s41467-024-54353-4
  22. Science. 2025 Jan 17. 387(6731): eadi3624
    Neuronal-ILC2 interactions regulate pancreatic glucagon and glucose homeostasis.
    Marko Šestan, Bruno Raposo, Miguel Rendas, David Brea, Roksana Pirzgalska, Ana Rasteiro, Maria Aliseychik, Inês Godinho, Hélder Ribeiro, Tania Carvalho, Stephan Wueest, Daniel Konrad, Henrique Veiga-Fernandes.
      The immune system shapes body metabolism, while interactions between peripheral neurons and immune cells control tissue homeostasis and immunity. However, whether peripheral neuroimmune interactions orchestrate endocrine system functions remains unexplored. After fasting, mice lacking type 2 innate lymphoid cells (ILC2s) displayed disrupted glucose homeostasis, impaired pancreatic glucagon secretion, and inefficient hepatic gluconeogenesis. Additionally, intestinal ILC2s were found in the pancreas, which was dependent on their expression of the adrenergic beta 2 receptor. Targeted activation of catecholaminergic intestinal neurons promoted the accumulation of ILC2s in the pancreas. Our work provides evidence that immune cells can be regulated by neuronal signals in response to fasting, activating an inter-organ communication route that promotes pancreatic endocrine function and regulation of blood glucose levels.
    DOI:  https://doi.org/10.1126/science.adi3624
  23. Nat Commun. 2025 Jan 16. 16(1): 739
    The Human Microglia Atlas (HuMicA) unravels changes in disease-associated microglia subsets across neurodegenerative conditions.
    Ricardo Martins-Ferreira, Josep Calafell-Segura, Bárbara Leal, Javier Rodríguez-Ubreva, Elena Martínez-Saez, Elisabetta Mereu, Paulo Pinho E Costa, Ariadna Laguna, Esteban Ballestar.
      Dysregulated microglia activation, leading to neuroinflammation, is crucial in neurodegenerative disease development and progression. We constructed an atlas of human brain immune cells by integrating nineteen single-nucleus RNA-seq and single-cell RNA-seq datasets from multiple neurodegenerative conditions, comprising 241 samples from patients with Alzheimer's disease, autism spectrum disorder, epilepsy, multiple sclerosis, Lewy body diseases, COVID-19, and healthy controls. The integrated Human Microglia Atlas (HuMicA) included 90,716 nuclei/cells and revealed nine populations distributed across all conditions. We identified four subtypes of disease-associated microglia and disease-inflammatory macrophages, recently described in mice, and shown here to be prevalent in human tissue. The high versatility of microglia is evident through changes in subset distribution across various pathologies, suggesting their contribution in shaping pathological phenotypes. A GPNMB-high subpopulation was expanded in AD and MS. In situ hybridization corroborated this increase in AD, opening the question on the relevance of this population in other pathologies.
    DOI:  https://doi.org/10.1038/s41467-025-56124-1
  24. Nat Commun. 2025 Jan 14. 16(1): 664
    Systems immunology integrates the complex endotypes of recessive dystrophic epidermolysis bullosa.
    Nell Hirt, Enzo Manchon, Qian Chen, Clara Delaroque, Aurelien Corneau, Patrice Hemon, Safaa Saker-Delye, Pauline Bataille, Jean-David Bouaziz, Emmanuelle Bourrat, Alain Hovnanian, Helene Le Buanec, Fawzi Aoudjit, Hicham El Costa, Nabila Jabrane-Ferrat, Reem Al-Daccak.
      Endotypes are characterized by the immunological, inflammatory, metabolic, and remodelling pathways that explain the mechanisms underlying the clinical presentation (phenotype) of a disease. Recessive dystrophic epidermolysis bullosa (RDEB) is a severe blistering disease caused by COL7A1 pathogenic variants. Although underscored by animal studies, the endotypes of human RDEB are poorly understood. To fill this gap, we apply systems immunology approaches using single-cell high-dimensional techniques to capture the signature of peripheral immune cells and the diversity of metabolic profiles in RDEB adults, sampled outside of any opportunistic infection and active cancer. Our study, demonstrates the particular inflammation and immunity characteristics of RDEB adults, with activated / effector T and dysfunctional natural killer cell signatures, concomitant with an overall pro-inflammatory lipid signature. Artificial intelligence prediction models and principal component analysis stress that RDEB is not solely confined to cutaneous issues but has complex systemic endotypes marked by immune dysregulation and hyperinflammation. By characterising the phenotype-endotype association in RDEB adults, our study lays the groundwork for translational interventions that could by lessening inflammation, alleviate the everlasting suffering of RDEB patients, while awaiting curative genetic therapies.
    DOI:  https://doi.org/10.1038/s41467-025-55934-7
  25. Nature. 2025 Jan 10.
    Mind matters: investigating academia's 'mental health crisis'.
    Adam Levy.
      
    Keywords:  Careers; Institutions; Psychiatric disorders; Psychology
    DOI:  https://doi.org/10.1038/d41586-024-04240-1
  26. Nat Aging. 2025 Jan 13.
    Somatic mutation as an explanation for epigenetic aging.
    Zane Koch, Adam Li, Daniel S Evans, Steven Cummings, Trey Ideker.
      DNA methylation marks have recently been used to build models known as epigenetic clocks, which predict calendar age. As methylation of cytosine promotes C-to-T mutations, we hypothesized that the methylation changes observed with age should reflect the accrual of somatic mutations, and the two should yield analogous aging estimates. In an analysis of multimodal data from 9,331 human individuals, we found that CpG mutations indeed coincide with changes in methylation, not only at the mutated site but with pervasive remodeling of the methylome out to ±10 kilobases. This one-to-many mapping allows mutation-based predictions of age that agree with epigenetic clocks, including which individuals are aging more rapidly or slowly than expected. Moreover, genomic loci where mutations accumulate with age also tend to have methylation patterns that are especially predictive of age. These results suggest a close coupling between the accumulation of sporadic somatic mutations and the widespread changes in methylation observed over the course of life.
    DOI:  https://doi.org/10.1038/s43587-024-00794-x
  27. Nat Aging. 2025 Jan 14.
    Semaglutide alleviates knee osteoarthritis pain in persons with obesity.
    Yahyah Aman.
      
    DOI:  https://doi.org/10.1038/s43587-025-00809-1
  28. Nat Commun. 2025 Jan 15. 16(1): 706
    Chimeric antigen receptor macrophages (CAR-M) sensitize HER2+ solid tumors to PD1 blockade in pre-clinical models.
    Stefano Pierini, Rashid Gabbasov, Maria Cecilia Oliveira-Nunes, Rehman Qureshi, Alison Worth, Shuo Huang, Karan Nagar, Crystal Griffin, Lurong Lian, Yumi Yashiro-Ohtani, Kayleigh Ross, Christopher Sloas, Michael Ball, Benjamin Schott, Poonam Sonawane, Linara Cornell, Daniel Blumenthal, Sotheavy Chhum, Nicholas Minutolo, Kerri Ciccaglione, Lauren Shaw, Isaac Zentner, Hyam Levitsky, Olga Shestova, Saar Gill, Bindu Varghese, Daniel Cushing, Sabrina Ceeraz DeLong, Sascha Abramson, Thomas Condamine, Michael Klichinsky.
      We previously developed human CAR macrophages (CAR-M) and demonstrated redirection of macrophage anti-tumor function leading to tumor control in immunodeficient xenograft models. Here, we develop clinically relevant fully immunocompetent syngeneic models to evaluate the potential for CAR-M to remodel the tumor microenvironment (TME), induce T cell anti-tumor immunity, and sensitize solid tumors to PD1/PDL1 checkpoint inhibition. In vivo, anti-HER2 CAR-M significantly reduce tumor burden, prolong survival, remodel the TME, increase intratumoral T cell and natural killer (NK) cell infiltration, and induce antigen spreading. CAR-M therapy protects against antigen-negative relapses in a T cell dependent fashion, confirming long-term anti-tumor immunity. In HER2+ solid tumors with limited sensitivity to anti-PD1 (aPD1) monotherapy, the combination of CAR-M and aPD1 significantly improves tumor growth control, survival, and remodeling of the TME in pre-clinical models. These results demonstrate synergy between CAR-M and T cell checkpoint blockade and provide a strategy to potentially enhance response to aPD1 therapy for patients with non-responsive tumors.
    DOI:  https://doi.org/10.1038/s41467-024-55770-1
  29. Mol Metab. 2025 Jan 13. pii: S2212-8778(25)00005-5. [Epub ahead of print] 102098
    Bioenergetic adaptations of small intestinal epithelial cells reduce cell differentiation enhancing intestinal permeability in obese mice.
    Thomas Guerbette, Vincent Ciesielski, Manon Brien, Daniel Catheline, Roselyne Viel, Mégane Bostoen, Jean-Baptiste Perrin, Agnès Burel, Régis Janvier, Vincent Rioux, Annaïg Lan, Gaëlle Boudry.
       BACKGROUND: Obesity and overweight are associated with low-grade inflammation induced by adipose tissue expansion and perpetuated by altered intestinal homeostasis, including increased epithelial permeability. Intestinal epithelium functions are supported by intestinal epithelial cells (IEC) mitochondria function.
    METHODS AND RESULTS: Here, we report that diet-induced obesity (DIO) in mice induces lipid metabolism adaptations favoring lipid storage in IEC together with reduced number, altered dynamics and diminished oxidative phosphorylation activity of IEC mitochondria. Using the jejunal epithelial cell line IPEC-J2, we showed that IEC lipid metabolism and oxidative stress machinery adaptations preceded mitochondrial bioenergetic ones. Moreover, we unraveled the intricate link between IEC energetic status and proliferation / differentiation balance since enhancing mitochondrial function with the AMPK activator AICAR in jejunal organoids reduced proliferation and initiated IEC differentiation and conversely. We confirmed that the reduced IEC mitochondrial function observed in DIO mice was associated with increased proliferation and reduced differentiation, promoting expression of the permissive Cldn2 in the jejunal epithelium of DIO mice.
    CONCLUSIONS: Our study provides new insights into metabolic adaptations of IEC in obesity by revealing that excess lipid intake diminishes mitochondrial number in IEC, reducing IEC differentiation that contribute to increased epithelial permeability.
    Keywords:  high fat diet; intestine; lipid metabolism; mitochondria; obesity
    DOI:  https://doi.org/10.1016/j.molmet.2025.102098
  30. Nat Commun. 2025 Jan 12. 16(1): 610
    Proteomic signature of HIV-associated subclinical left atrial remodeling and incident heart failure.
    Tess E Peterson, Virginia S Hahn, Ruin Moaddel, Min Zhu, Sabina A Haberlen, Frank J Palella, Michael Plankey, Joel S Bader, Joao A C Lima, Robert E Gerszten, Jerome I Rotter, Stephen S Rich, Susan R Heckbert, Gregory D Kirk, Damani A Piggott, Luigi Ferrucci, Joseph B Margolick, Todd T Brown, Katherine C Wu, Wendy S Post.
      People living with HIV are at higher risk of heart failure and associated left atrial remodeling compared to people without HIV. Mechanisms are unclear but have been linked to inflammation and premature aging. Here we obtain plasma proteomics concurrently with cardiac magnetic resonance imaging in two independent study populations to identify parallels between HIV-related and aging-related immune dysfunction that could contribute to atrial remodeling and clinical heart failure. We discover a plasma proteomic signature that may in part reflect or contribute to HIV-associated atrial remodeling, many features of which are associated with older age and time to incident heart failure among an independent community-based cohort without HIV. This proteomic profile was statistically enriched for immune checkpoint proteins, tumor necrosis factor signaling, ephrin signaling, and extracellular matrix organization, identifying possible shared pathways in HIV and aging that may contribute to risk of heart failure.
    DOI:  https://doi.org/10.1038/s41467-025-55911-0
  31. Nat Commun. 2025 Jan 13. 16(1): 630
    Increased SOAT2 expression in aged regulatory T cells is associated with altered cholesterol metabolism and reduced anti-tumor immunity.
    Mingjiong Zhang, Jiahua Cui, Haoyan Chen, Yifan Cheng, Qiaoyu Chen, Feng Zong, Xiao Lu, Lang Qin, Yu Han, Xingwang Kuai, Yuxing Zhang, Minjie Chu, Shuangshuang Wu, Jianqing Wu.
      Immune functions decline with aging, leading to increased susceptibility to various diseases including tumors. Exploring aging-related molecular targets in elderly patients with cancer is thus highly sought after. Here we find that an ER transmembrane enzyme, sterol O-acyltransferase 2 (SOAT2), is overexpressed in regulatory T (Treg) cells from elderly patients with lung squamous cell carcinoma (LSCC), while radiomics analysis of LSCC patients associates increased SOAT2 expression with reduced immune infiltration and poor prognosis. Mechanically, ex vivo human and mouse Treg cell data and in vivo mouse tumor models suggest that SOAT2 overexpression in Treg cells promotes cholesterol metabolism by activating the SREBP2-HMGCR-GGPP pathway, leading to enhanced Treg suppresser functions but reduced CD8+ T cell proliferation, migration, homeostasis and anti-tumor immunity. Our study thus identifies a potential mechanism responsible for altered Treg function in the context of immune aging, and also implicates SOAT2 as a potential target for tumor immunotherapy.
    DOI:  https://doi.org/10.1038/s41467-025-56002-w
  32. Nature. 2025 Jan 15.
    Daily briefing: New obesity definition sidelines BMI to focus on health.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-025-00147-7
  33. Nat Commun. 2025 Jan 16. 16(1): 682
    Impact of rare non-coding variants on human diseases through alternative polyadenylation outliers.
    Xudong Zou, Zhaozhao Zhao, Yu Chen, Kewei Xiong, Zeyang Wang, Shuxin Chen, Hui Chen, Gong-Hong Wei, Shuhua Xu, Wei Li, Ting Ni, Lei Li.
      Although rare non-coding variants (RVs) play crucial roles in complex traits and diseases, understanding their mechanisms and identifying disease-associated RVs continue to be major challenges. Here we constructed a comprehensive atlas of alternative polyadenylation (APA) outliers (aOutliers), including 1334 3' UTR and 200 intronic aOutliers, from 15,201 samples across 49 human tissues. These aOutliers exhibit unique characteristics from transcription or splicing outliers, with a pronounced RV enrichment. Mechanistically, aOutlier-RVs alter poly(A) signals and splicing sites, and perturbation indeed triggers APA events. Furthermore, we developed a Bayesian-based APA RV prediction model, which successfully pinpointed a specific set of 1799 RVs impacting 278 genes with significantly large disease effect sizes. Notably, we observed a convergence effect between rare and common cancer variants, exemplified by regulation in the DDX18 gene. Together, this study introduced an APA-enhanced framework for genome annotation, underscoring APA's role in uncovering functional RVs linked to complex traits and diseases.
    DOI:  https://doi.org/10.1038/s41467-024-55407-3
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