bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2026–01–25
27 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. The transition from monocyte to tissue-resident macrophage requires DHPS.
  2. NCOA1 is a gatekeeper of the sexually dimorphic thermogenic activity of white adipose tissue.
  3. Unraveling CD8 lineage decisions reveals that functionally distinct CD8+ T cells are selected by different MHC-I thymic peptides.
  4. Nature Aging coming of age.
  5. Longitudinal analysis of body weight reveals homeostatic and adaptive traits linked to lifespan in diversity outbred mice.
  6. IL-21 mediates crosstalk between T cells and NK cells during the remission of type 1 diabetes.
  7. Integrative epigenetics and transcriptomics identify aging genes in human blood.
  8. The price of prestige.
  9. Past, present and future perspectives on the science of aging.
  10. Voice Assistant for Older Adults With Type 2 Diabetes.
  11. Spatiotemporal regulation of energetic charge dictates T cell function.
  12. Anti-CD3 mAb treatment reshapes infiltrating T and β cells in the islets in autoimmune diabetes.
  13. Glucocorticoids to Manage Cytokine Release Syndrome During Teplizumab Therapy for New-Onset Type 1 Diabetes.
  14. Silencing lipid catabolism determines longevity in response to fasting.
  15. Higher Food Preservative Intake Linked With Type 2 Diabetes.
  16. Diversity and immune dynamics of choroid plexus macrophages are shaped by distinct developmental origins.
  17. Clinically relevant variants from the Mexican biobank show striking diversity across Hispanic people.
  18. Deficiency of Microglial-Derived Spp1 Exacerbates Age-Related Memory Decline by Impairing Mitochondrial Complex I Function.
  19. Immune cells in circulation serve as living biomarkers for inflammatory diseases.
  20. Aging Reshapes γ/δ T-Cell Immunity Through a Type I Interferon-Foxo1 Axis.
  21. Cre Driver Efficiency in Myeloid Lineages Across Tissues and in a Model of Myocardial Injury.
  22. Identification of Or5v1/Olfr110 as an oxylipin receptor and anti-obesity target.
  23. Anti-FAP CAR T cells produced in vivo reduce fibrosis and restore liver homeostasis in metabolic dysfunction-associated steatohepatitis.
  24. Heterogeneous sympathetic control of brown adipose tissue.
  25. Mitochondrial retrograde signal through GCN5L1 transition-mediated PPARγ stabilization promotes MASLD development.
  26. Platelet-derived integrin- and tetraspanin-enriched tethers exacerbate severe inflammation.
  27. NGF promotes, in an autocrine-paracrine manner, metabolic and anti-inflammatory pathways in human and mouse adipocytes.
  1. Nature. 2026 Jan 21.
    The transition from monocyte to tissue-resident macrophage requires DHPS.
    Gustavo E Carrizo, Pianpian Lin, Seung Hyun Lee, Kevin Shenderov, Camille Blériot, Minsun Cha, Lena Schimmelpfennig, Zhen Shen, Nikki van Teijlingen Bakker, Katarzyna M Grzes, Beth Kelly, Niloufar Safinia, Kate L Schole, Yaarub Musa, Gerhard Mittler, Yoh Zen, Edward J Pearce, Florent Ginhoux, David E Sanin, Daniel J Puleston, Erika L Pearce.
      Tissue-resident macrophages (RTMs) form during embryogenesis, self-renew locally, and regulate tissue homeostasis by clearing dead cells and debris1-6. During tissue damage, however, bone-marrow-derived monocytes enter tissues and differentiate into RTMs, repairing the tissue and replenishing macrophages in the niche1. The universal cell-intrinsic mechanisms that control the monocyte-to-RTM transition and the maintenance of mature RTMs across tissues remain elusive3. Here we show that deoxyhypusine synthase (DHPS), an enzyme that mediates spermidine-dependent hypusine modification of translation factor eIF5A5,7, is required for RTM differentiation and maintenance. Mice with myeloid cell lack of DHPS (Dhps-ΔM mice) had a global defect in RTMs across tissues, resulting in persistent but ultimately futile monocyte influx. Transcriptional analyses of DHPS-deficient macrophages indicated a block in their ability to differentiate into mature RTMs, whereas proteomics revealed defects in cell adhesion and signalling pathways. Sequencing of ribosome-engaged transcripts identified a subset of mRNAs involved in cell adhesion and signalling that rely on DHPS for efficient translation. Imaging of DHPS-deficient macrophages in tissues showed differences in morphology and tissue interactions, which were correlated with their failed RTM differentiation. DHPS-deficient macrophages were also defective in critical homeostatic RTM functions including efferocytosis and tissue maintenance. Together, our results demonstrate a cell-intrinsic, tissue-agnostic pathway that drives differentiation of monocyte-derived macrophages into RTMs.
    DOI:  https://doi.org/10.1038/s41586-025-09972-2
  2. Nat Commun. 2026 Jan 20. 17(1): 717
    NCOA1 is a gatekeeper of the sexually dimorphic thermogenic activity of white adipose tissue.
    Mounia Tannour-Louet, Didier F Pisani, Hichem Bouguerra, Alycia Zedda, Marine Bourcier, Noura Lamghari, Nadine Gautier, Benoit Chaput, Elodie Riant, Anne Bouloumié, Emilie Montastier, Nathalie Viguerie, Dominique Langin, Ez-Zoubir Amri, Pierre Gourdy, Jean-François Tanti, Mireille Cormont, Jean-François Louet.
      Premenopausal women preferentially store fat in subcutaneous depots, which provides protection against cardiometabolic disease. Their white adipose tissue also exhibits a more thermogenic, brown-like profile compared with that of men, yet the mechanisms underlying this sex-specific benefit remain unclear. Here, we show that Nuclear Receptor Coactivator 1 is highly expressed in human subcutaneous fat, with further induction during the conversion of white to beige adipocytes and in response to caloric restriction. Loss of Nuclear Receptor Coactivator 1 in subcutaneous adipocytes revealed a cell-autonomous role in promoting beiging by directly regulating the thermogenic factor Uncoupling Protein 1 and sex-dependent mitochondrial gene networks activated by cold and adrenergic stimulation. Acting together with GATA binding protein 3, it establishes elevated basal thermogenic tone in female subcutaneous fat. Female mice lacking this coregulator progressively developed obesity and glucose intolerance, and a male-like fat distribution, with increased visceral fat and reduced beige adipocytes. These findings identify Nuclear Receptor Coactivator 1 as a sex-specific determinant of adipose tissue remodelling and female metabolic resilience.
    DOI:  https://doi.org/10.1038/s41467-025-65229-6
  3. Nat Immunol. 2026 Jan 19.
    Unraveling CD8 lineage decisions reveals that functionally distinct CD8+ T cells are selected by different MHC-I thymic peptides.
    Miho Shinzawa, Nicole Ramos, Khanh Bui, William Hajjar, Assiatu Crossman, Xiongfong Chen, Margaret Cam, Yousuke Takahama, Alfred Singer.
      Thymocytes signaled by T cell antigen receptors to undergo positive selection acquire different functional fates while migrating through the thymus, but how this occurs remains uncertain. We now report that encoding CD8 co-receptors in both Cd4 and Cd8 gene loci modulates major histocompatibility complex (MHC-I) class I T cell antigen receptor signaling duration to generate all potential CD8+ T cell subsets. Strikingly, such mice revealed that functionally different CD8+ T cells are selected by different MHC-I thymic peptides. Thymocytes signaled by β5t-peptides produced by thymoproteasomes exclusively expressed in the thymic cortex invariably become cytotoxic CD8+ T cells indicating their signaling ceases when thymocytes leave the cortex; whereas thymocytes signaled by nonβ5t-peptides expressed throughout the thymus become either helper or innate memory CD8+ T cells because their signaling persists or recurs outside the cortex. Thus, it is because of their different thymic distributions that different MHC-I peptides select functionally different CD8+ T cells, integrating peptide specificity and CD8+ T cell function during positive selection and thymocyte migration.
    DOI:  https://doi.org/10.1038/s41590-025-02411-4
  4. Nat Aging. 2026 Jan;6(1): 1
    Nature Aging coming of age.
      
    DOI:  https://doi.org/10.1038/s43587-025-01062-2
  5. Nat Commun. 2026 Jan 19.
    Longitudinal analysis of body weight reveals homeostatic and adaptive traits linked to lifespan in diversity outbred mice.
    G V Prateek, Zhenghao Chen, Kevin Wright, Andrea Di Francesco, Vladimir Jojic, Gary A Churchill, Anil Raj.
      Dense temporal measurements of physiological health, using simple and consistent assays, are essential to characterize biological processes associated with aging and evaluate the effectiveness of interventions on these processes. We measured body weight in 960 genetically diverse female mice, every 7-10 days over the full course of their lifespan. We used a state space model to characterize the trajectories of body weight throughout life and derived novel traits capturing the dynamics of body weight, 10 of which were both heritable and associated with lifespan. Genetic mapping of these body weight-derived traits identified 5 genomic loci, none of which were previously mapped to body weight. We observed that the ability to maintain stable body weight, despite fluctuations in energy intake and expenditure, was positively associated with lifespan in an age-dependent manner and mapped to a genomic locus linked to energy homeostasis. Our results highlight how dense longitudinal measurements of physiological phenotypes offer new insights into the biology of aging.
    DOI:  https://doi.org/10.1038/s41467-026-68392-6
  6. Nat Metab. 2026 Jan 21.
    IL-21 mediates crosstalk between T cells and NK cells during the remission of type 1 diabetes.
    Kang Lei, Xinyu Li, Ting Zhong, Rong Tang, Qiaolin Deng, Paul E Love, Zhiguang Zhou, Bin Zhao, Xia Li.
      The innate immune system is increasingly recognized as a contributor to the development of type 1 diabetes (T1D), but the role of natural killer (NK) cells remains largely unclear. Here, we identify an expanded subset of transcriptionally active CD226+CD56dimCD16+ NK cells at the onset of T1D that contracts in remission. Using single-cell RNA sequencing integrated with cross-sectional and longitudinal analyses in patients with T1D, we show that CD226+ NK cell frequency correlates with disease progression. CD226+ NK cells exhibit enhanced cytotoxicity, inflammation and glucose metabolism. Mechanistically, CD161+CD4+ T cells promote pathogenic NK cell generation through interleukin-21 (IL-21) and mTOR signalling. Inhibition of this pathway by CD226 blockade, IL-21 receptor fusion protein, IL-21 knockout or mTOR inhibition attenuates NK cell activation, reduces pancreatic infiltration and delays diabetes onset in female mice. Our data reveal a mechanistic link, bridging adaptive and innate immunity, in the progression and remission of T1D that could potentially be exploited in T1D immunotherapy.
    DOI:  https://doi.org/10.1038/s42255-025-01439-y
  7. Nat Commun. 2026 Jan 19. 17(1): 725
    Integrative epigenetics and transcriptomics identify aging genes in human blood.
    Mahdi Moqri, Kejun Ying, Jesse R Poganik, Chiara Herzog, Qingwen Chen, Mehrnoosh Emamifar, Alexander Tyshkovskiy, Alec Eames, Jure Mur, Dmitrii Glubokov, Benyamin Matei-Dediu, Ludger Goeminne, Wayne Mitchell, Daniel L McCartney, Lucas A Salas, Riccardo E Marioni, Jessica A Lasky-Su, Michael P Snyder, Vadim N Gladyshev.
      Recent epigenome-wide studies have identified a large number of genomic regions that consistently exhibit changes in their methylation status with aging across diverse populations, but the functional consequences of these changes are largely unknown. On the other hand, transcriptomic changes are more easily interpreted than epigenetic alterations, but previously identified age-related gene expression changes have shown limited replicability across populations. Here, we develop an approach that leverages high-resolution multi-omic data for an integrative analysis of epigenetic and transcriptomic age-related changes and identify genomic regions associated with both epigenetic and transcriptomic age-dependent changes in blood. Our results show that these multi-omic aging genes in blood are enriched for adaptive immune functions, replicate more robustly across diverse populations and are more strongly associated with aging-related outcomes compared to the genes identified using epigenetic or transcriptomic data alone. These multi-omic aging genes may serve as targets for epigenetic editing to facilitate cellular rejuvenation.
    DOI:  https://doi.org/10.1038/s41467-025-67369-1
  8. Science. 2026 Jan 22. 391(6783): 418
    The price of prestige.
    Zvonimir Marelja.
      
    DOI:  https://doi.org/10.1126/science.aef5344
  9. Nat Aging. 2026 Jan;6(1): 6-22
    Past, present and future perspectives on the science of aging.
    Fabrisia Ambrosio, Maxim N Artyomov, Steven N Austad, Nir Barzilai, Juan Carlos Izpisua Belmonte, Daniel W Belsky, Bérénice A Benayoun, Anne Brunet, Handan Melike Dönertaş, Dena B Dubal, Evandro F Fang, Jerome N Feige, Linda P Fried, David Furman, Xu Gao, Vadim N Gladyshev, Vera Gorbunova, Myriam Gorospe, Jing-Dong J Han, Oskar Hansson, Eiji Hara, Steve Horvath, Nancy Y Ip, George A Kuchel, Matt Kaeberlein, Dudley W Lamming, Becca R Levy, Guang-Hui Liu, Jinkook Lee, Terrie E Moffitt, Tohru Minamino, Linda Partridge, Parminder Raina, Thomas A Rando, John W Rowe, Michal Schwartz, Andrew J Scott, Felipe Sierra, David A Sinclair, Charlotte E Teunissen, Bruno Vellas, Eric Verdin, Keenan A Walker, Ashley E Webb, Tony Wyss-Coray, Ming Xu, Jin-Tai Yu, Alex Zhavoronkov, Yahyah Aman, Anna Kriebs, Qingzhong Ren, Hannah Walters, Sebastien Thuault.
      
    DOI:  https://doi.org/10.1038/s43587-025-01046-2
  10. JAMA Netw Open. 2026 Jan 02. 9(1): e2553483
    Voice Assistant for Older Adults With Type 2 Diabetes.
    Nestoras Mathioudakis.
      
    DOI:  https://doi.org/10.1001/jamanetworkopen.2025.53483
  11. Nat Commun. 2026 Jan 21. 17(1): 770
    Spatiotemporal regulation of energetic charge dictates T cell function.
    Aleksandra S Chikina, Béatrice Corre, Fabrice Lemaître, Philippe Bousso.
      Immune cell functions are dictated by their differentiation state and regulated by transcriptional and epigenetic changes. Immune cell differentiation also controls the preferential metabolic pathways used for energy production. However, whether the energy charge of individual immune cells itself varies across time and space and regulates cell function remains to be fully understood. Here, we show that T cells harbor distinct energetic resources and function in different anatomical locations and times of the day. To monitor ATP: ADP ratio, an indicator of cellular energetic resources, we rely on SPICE-Met, a method that dissects energy metabolism in complex cell populations in vivo. We find that cells with the highest glycolytic capacity, including effector T cells and NK cells, exhibit the highest ATP: ADP ratio. Importantly, effector T cells but not naïve T cells display higher energetic charge when present in the blood compared to lymph nodes due to differential glucose availability. Energetic resources are also regulated in a circadian manner, being highest at the early rest phase. Importantly, differences in energetic charge are directly translated at the level of T cell function, impacting IFN-γ production. Thus, modulation of energetic charge and nutrient availability dictates immune cell function across time and space.
    DOI:  https://doi.org/10.1038/s41467-026-68559-1
  12. JCI Insight. 2026 Jan 23. pii: e192755. [Epub ahead of print]11(2):
    Anti-CD3 mAb treatment reshapes infiltrating T and β cells in the islets in autoimmune diabetes.
    Ying Wu, Maxwell Spurrell, Ana Lledó-Delgado, Songyan Deng, Dejiang Wang, Yang Liu, Mahsa Nouri Barkestani, Ana Luisa Perdigoto, Kevan C Herold.
      Treatment with anti-CD3 monoclonal antibody (mAb) can delay or prevent type 1 diabetes in mice and humans by modulating the immune-mediated destruction of β cells. A single course of treatment may have lasting efficacy, but the mechanisms that account for these prolonged effects, i.e., "operational tolerance," are not clear. Here, we used paired single-cell RNA and T cell receptor sequencing to characterize islet-infiltrating T cells and their counterpart in paired pancreatic lymph nodes from anti-CD3 mAb-treated nonobese diabetic (NOD) mice in remission. We found that after anti-CD3 mAb treatment, T cells that infiltrate the islets are more heterogeneous and have hybrid features including characteristics of T stem cell-like memory and reduced effector function compared with those from untreated prediabetic NOD mice. Autoantigen-reactive CD8+ T cells persist after treatment, but they also show features of stemness and reduced pathogenicity. Our findings describe the reshaping of islet-infiltrating and autoreactive T cells and β cells that lead to operational, but tenuous, tolerance to autoimmune diabetes following anti-CD3 mAb treatment.
    Keywords:  Diabetes; Endocrinology; Immunology; T cells; Tolerance
    DOI:  https://doi.org/10.1172/jci.insight.192755
  13. Diabetes Care. 2026 Jan 20. pii: dc252494. [Epub ahead of print]
    Glucocorticoids to Manage Cytokine Release Syndrome During Teplizumab Therapy for New-Onset Type 1 Diabetes.
    Aye Khine, Srinath Sanda, Christine Torok, Zoe Quandt, Stephen E Gitelman.
      
    DOI:  https://doi.org/10.2337/dc25-2494
  14. Nat Commun. 2026 Jan 22.
    Silencing lipid catabolism determines longevity in response to fasting.
    Lexus Tatge, Juhee Kim, Rene Solano Fonseca, Kyle Feola, Jordan M Wall, Gupse Otuzoglu, Ann C Johnson, Kielen R Zuurbier, Jaeyoung Oh, Shaghayegh T Beheshti, Victor A Lopez, Anthony J Daley, Emma G Werner, Patrick Metang, Sonja L B Arneaud, Abigail Watterson, Jeffrey G McDonald, Vincent S Tagliabracci, Michael E French, Peter M Douglas.
      Oscillations between lipid anabolism and catabolism are essential for maintaining cellular health during metabolic fluctuations. Fasting, a conserved determinant of aging, improves disease outcomes and extends lifespan, yet the relative contributions of lipid catabolism versus its attenuation to fasting-induced longevity remain unresolved. The metabolic flexibility of C. elegans under variable nutrient availability provides a powerful system to address this question. We show that lifespan extension from fasting depends not on sustained activation of lipid catabolism, but on its silencing upon nutrient replenishment. The fasting-responsive nuclear hormone receptor NHR-49 activates β-oxidation; however, unlike classical ligand-regulated receptors, NHR-49 is regulated through ligand-independent mechanisms involving cofactor-mediated transcriptional attenuation and protein turnover. We identify casein kinase 1 alpha 1 (KIN-19) as a key regulator of metabolic plasticity and fasting-induced longevity that silences β-oxidation via primed phosphorylation of NHR-49. Thus, cooperative ligand-independent silencing of this conserved nuclear hormone receptor promotes fasting-associated longevity.
    DOI:  https://doi.org/10.1038/s41467-026-68764-y
  15. JAMA. 2026 Jan 23.
    Higher Food Preservative Intake Linked With Type 2 Diabetes.
    Samantha Anderer.
      
    DOI:  https://doi.org/10.1001/jama.2025.23033
  16. Nat Neurosci. 2026 Jan 21.
    Diversity and immune dynamics of choroid plexus macrophages are shaped by distinct developmental origins.
    Siling Du, Khai M Nguyen, Alina Ulezko Antonova, Jose L Fachi, Patrick Fernandes Rodrigues, Alice Verdiani, Martina Molgora, Igor Smirnov, Jasmin Herz, Tornike Mamuladze, Jennifer Ponce, Amanda Swain, Mattia Bugatti, Susan Gilfillan, Marina Cella, William Vermi, Jonathan Kipnis, Marco Colonna, Simone Brioschi.
      The choroid plexus forms a key barrier and signaling interface between the brain and peripheral circulation, yet its immune landscape remains incompletely understood. Using single-cell transcriptomics combined with lineage and spatial tracing methods, we identified three biologically distinct populations of choroid plexus macrophages, defined by differential expression of CD163, MHCII or CD9. These subsets arise from separate hematopoietic waves, occupy distinct anatomical niches and differentially rely on CSF1 and IL-34 for survival. We found that TGFβ signaling is essential to maintain their tissue-specific identities, and deletion of Tgfbr2 in these cells induces broad phenotypic reprogramming. During neuroinflammation, choroid plexus macrophages mount type I interferon responses and secrete chemokines that recruit CD8+ T cells. Finally, analysis of human choroid plexus reveals macrophage subsets corresponding to those found in mice, indicating evolutionary conservation of their molecular and immune features. Together, these findings define the developmental origin, niche specialization and immune dynamics of choroid plexus macrophages.
    DOI:  https://doi.org/10.1038/s41593-025-02158-z
  17. Nat Med. 2026 Jan 21.
    Clinically relevant variants from the Mexican biobank show striking diversity across Hispanic people.
      
    DOI:  https://doi.org/10.1038/s41591-025-04129-0
  18. Aging Cell. 2026 Feb;25(2): e70378
    Deficiency of Microglial-Derived Spp1 Exacerbates Age-Related Memory Decline by Impairing Mitochondrial Complex I Function.
    Meiling Wang, Yumin Chang, Aojie He, Jing Yang, Ang Li, Hongqin Wang, Kah-Leong Lim, Xing Guo, Chengwu Zhang, Li Lu.
      Age-related memory decline is a hallmark of brain aging and a primary risk factor for neurodegenerative disorders. Microglia play a crucial role in preserving memory function by maintaining brain homeostasis through phagocytosis, yet the specific mechanisms governing this protective function remain elusive. In the present study, we identified a population of Secreted Phosphoprotein 1 (Spp1)-positive microglia in both aged mouse and human brains. To investigate the role of microglial Spp1 in aging, we generated microglia-specific Spp1 knockout (Spp1-cKO) mice. We demonstrate that Spp1 deficiency selectively precipitates memory deficits in aged mice, without affecting memory function in young mice, indicating an age-dependent reliance on Spp1 signaling. Microglial phagocytic capacity positively correlates with Spp1 levels and is diminished by Spp1 deficiency. Mechanistically, Spp1 deficiency leads to the downregulation of the AKT/mitochondrial complex I pathway, thereby compromising microglial oxidative phosphorylation and function. Notably, microglia-specific overexpression of Spp1 partially ameliorates the age-related phenotypes induced by Spp1 deficiency. In conclusion, this study is the first to reveal the crucial role of microglial Spp1 in brain aging and to uncover its underlying mechanism, providing novel insights into age-related memory decline.
    Keywords:  ATP; Spp1; age‐related memory decline; microglia; mitochondrial complex I
    DOI:  https://doi.org/10.1111/acel.70378
  19. Nat Med. 2026 Jan 22.
    Immune cells in circulation serve as living biomarkers for inflammatory diseases.
      
    DOI:  https://doi.org/10.1038/s41591-025-04136-1
  20. Aging Cell. 2026 Feb;25(2): e70389
    Aging Reshapes γ/δ T-Cell Immunity Through a Type I Interferon-Foxo1 Axis.
    Aurélie Durand, Sarah Porte, Eryang Xing, Christian Wu, Agnès Le Bon, Cédric Auffray, Bruno Lucas, Bruno Martin.
      Aging is associated with profound alterations in immune cell composition and function, yet the impact on peripheral γ/δ T-cell subsets remains incompletely understood. Here, we show that the peripheral γ/δ T-cell compartment is markedly remodeled with age in mice. Specifically, innate-like Ly-6C- CD44hi γ/δ T cells expand in secondary lymphoid organs (SLOs) of aged mice, while adaptive-like subsets decline. This age-related shift is accompanied by enhanced functionality, with Ly-6C- CD44hi γ/δ T cells from aged SLOs displaying increased IL-17 production both ex vivo and in vivo following LPS challenge. Mechanistically, this functional remodeling correlates with a significant decrease in the expression of the transcription factor Foxo1 in Ly-6C- CD44hi γ/δ T cells. Type I interferon signaling contributes to the age-dependent downregulation of Foxo1, as Ly-6C- CD44hi γ/δ T cells from aged mice lacking the IFN-α receptor maintain Foxo1 expression and exhibit reduced IL-17 production. Collectively, our findings reveal that aging, through type I interferon-driven modulation of Foxo1, promotes the expansion and enhanced pro-inflammatory activity of innate-like γ/δ T cells. These changes may reinforce immune surveillance in secondary lymphoid organs but could also contribute to age-associated immune dysregulation and inflammation.
    Keywords:  Foxo1; aging; type I IFNs; γ/δ T cells
    DOI:  https://doi.org/10.1111/acel.70389
  21. FASEB J. 2026 Jan 31. 40(2): e71497
    Cre Driver Efficiency in Myeloid Lineages Across Tissues and in a Model of Myocardial Injury.
    Shuaibo Huang, Violeta Chitu, Fenglan Zhu, Jinghang Zhang, Ming Liu, E Richard Stanley, Nikolaos G Frangogiannis.
      Myeloid cell subpopulations are critically implicated in homeostasis and disease. The Cre-lox system offers powerful tools for dissecting their functions; however, interpretation of the findings is dependent on characterization of the efficacy and specificity of the Cre drivers employed. We systematically assessed the recombination efficiency and cellular specificity of two widely used myeloid Cre drivers, LysM-Cre, and CX3CR1CreER, using flow cytometry and histological analyses in healthy tissues and in a model of myocardial infarction. LysM-Cre achieved near-complete recombination (98%-100%) in neutrophils and macrophages, showed moderate efficiency in monocytes, but also labeled a fraction of non-myeloid leukocytes and approximately 10% of septal cardiomyocytes. CX3CR1CreER had high efficiency in macrophages (except for hepatic macrophages), lower sensitivity in monocytes and negligible activity in neutrophils. In myocardial infarction, a second course of tamoxifen after injury significantly enhanced macrophage targeting in the infarct zone. In conclusion, both the macrophage-specific inducible CX3CR1CreER and the highly sensitive, but less specific constitutively active LysM-Cre represent valuable tools for studying myeloid cell biology. Limitations of the CX3CR1CreER include limited recombination efficiency in macrophages with low CX3CR1 expression (e.g., liver macrophages) and the need for extended tamoxifen induction protocols in conditions associated with extensive recruitment of monocyte-derived macrophages.
    DOI:  https://doi.org/10.1096/fj.202503615R
  22. Cell. 2026 Jan 21. pii: S0092-8674(25)01429-1. [Epub ahead of print]
    Identification of Or5v1/Olfr110 as an oxylipin receptor and anti-obesity target.
    Xiao-Yan Ge, Jie Cheng, Li-Jun Zhang, Lu-Lu Guo, Rui Xiang, Yan Lu, Shang-Lei Ning, Kai-Yu Wang, Kong-Kai Zhu, Ming-Xin Gao, Yue Li, Yu-Song Zhang, Nai-Kang Rong, Xiang Han, Ming-Hui Zhang, Le Fang, Yun-Fei Xu, Su-Wen Zhao, Qian Li, Fan Yang, Yong Hao, Ren-Jie Chai, Xiao Yu, Ji-Chun Yang, Jin-Peng Sun.
      Oxylipins are important metabolic messengers for normal life activities, and olfactory receptors (ORs) are known for their low affinity for odor and are not considered oxylipin receptors. By developing the "anonymous receptor identification by reverse-G-protein pull-down" (ARIG) method, we identify orphan OR Or5v1/Olfr110 as an oxylipin 12(S)-hydroxyeicosapentaenoic acid (12(S)-HEPE) receptor. The serum from obese patients with increased BMI showed lower Or5v1/Olfr110-Gs activation compared with normal people. Systemic Or5v1/Olfr110 deficiency or liver-specific Or5v1/Olfr110 deficiency impaired glucose homeostasis, even after stimulation with 12(S)-HEPE. Engagement of 12(S)-HEPE with Olfr110 activated Gs-PKA-pATF2-Cpt1α signaling to reduce obesity through promotion of fatty acid oxidation in liver. Structural aided development of synthetic agonist HOR1-C59 improved glucose homeostasis, which is dependent on Or5v1/Olfr110 expression. Overall, we revealed that a high-affinity oxylipin-sensing OR plays key roles in metabolism. The beneficial effects of HOR1-C59 underscore the therapeutic value of small synthetic compounds that target ORs for disease treatment.
    Keywords:  GPCR signal transduction; drug development; obesity; olfactory receptor
    DOI:  https://doi.org/10.1016/j.cell.2025.12.016
  23. Sci Transl Med. 2026 Jan 21. 18(833): eadx0368
    Anti-FAP CAR T cells produced in vivo reduce fibrosis and restore liver homeostasis in metabolic dysfunction-associated steatohepatitis.
    Chittampalli N Yashaswini, Bruno Cogliati, Tianyue Qin, Tran To, Thomas Williamson, Tyler E Papp, Kenneth Li, Raisa Rasul, Li Chen, Adi Lightstone, Haig Aghajanian, Hamideh Parhiz, Shuang Wang, Joel G Rurik, Jonathan A Epstein, Scott L Friedman.
      Hepatic fibrosis is a key predictor of mortality in liver disease, driven by fibrogenic hepatic stellate cells (HSCs). Targeting these fibrogenic cells may therefore offer a therapeutic approach for hepatic fibrosis. We previously showed that in vivo-generated chimeric antigen receptor (CAR) T cells targeting fibroblast activation protein alpha (FAP) reduced murine cardiac fibrosis. Here, we explored the antifibrotic potential of this in vivo-generated anti-FAP CAR T cell therapy in metabolic dysfunction-associated steatohepatitis (MASH), a highly prevalent disease with no approved antifibrotic therapies. We first established that FAP expression in both human and murine MASH is specific to HSCs. We then used flow cytometry, Sirius Red morphometry, digital pathology analysis, and single nuclear RNA sequencing to assess the impact of anti-FAP CAR T cell therapy on murine MASH. Anti-CD5-targeted lipid nanoparticles carrying anti-FAPCAR messenger RNA transiently generated activated anti-FAP CAR T cells, which substantially reduced fibrosis by depleting profibrogenic HSCs. They also modulated immune cells, endothelial cells, and hepatocytes in a non-cell autonomous manner to mitigate inflammation and restore hepatic homeostasis. These findings highlight the potential of in vivo CAR T therapy to attenuate a highly morbid and pervasive liver disease, not only by directly reducing fibrosis but also through indirect effects on other cell types.
    DOI:  https://doi.org/10.1126/scitranslmed.adx0368
  24. Nat Metab. 2026 Jan 20.
    Heterogeneous sympathetic control of brown adipose tissue.
    Xun Huang, Li Ye.
      
    DOI:  https://doi.org/10.1038/s42255-025-01435-2
  25. JCI Insight. 2026 Jan 23. pii: e196695. [Epub ahead of print]11(2):
    Mitochondrial retrograde signal through GCN5L1 transition-mediated PPARγ stabilization promotes MASLD development.
    Jiaqi Zhang, Danni Wang, Qiqi Tang, Yaoshu Yue, Xin Lu, Xiuya Hu, Yitong Han, Jiarun Chen, Zihan Wang, Xue Bai, Kai Zhang, Yongsheng Chang, Longhao Sun, Lu Zhu, Lingdi Wang.
      Mitochondrial retrograde signaling plays crucial roles in maintaining metabolic homeostasis via regulating genome modification and oxidative responsive gene expression. In this study, we identified GCN5L1, a protein localized in both mitochondria and cytoplasm, and demonstrated its specific translocation from mitochondria to cytoplasm during lipid overload and high-fat diet feeding. Using transcriptome and proteome analyses, we identified that cytoplasmic GCN5L1 binds to and promotes the acetylation of PPARγ at lysine 289 (K289). This acetylation protected PPARγ from ubiquitination-mediated degradation by proteasome. GCN5L1 translocation enhanced protein stability of PPARγ and subsequently promoted lipid accumulation in both cultured cells and murine models. Our study further reveals that PPARγ-K289 mutation reduces the ubiquitination of PPARγ and exacerbates liver steatosis in mice. These findings unveil a mitochondrial retrograde signaling during lipid overload, which regulates the crucial lipogenic transcriptional factor. This discovery elucidates an unrecognized mitochondrial function and mechanism underlying hepatic lipid synthesis.
    Keywords:  Cell biology; Hepatology; Mitochondria; Signal transduction
    DOI:  https://doi.org/10.1172/jci.insight.196695
  26. Science. 2026 Jan 22. 391(6783): eadu2825
    Platelet-derived integrin- and tetraspanin-enriched tethers exacerbate severe inflammation.
    Charly Kusch, David Stegner, Lukas J Weiss, Paquita Nurden, Philipp Burkard, Denise Johnson, Wolfgang Bergmeier, Ceylan Onursal, Stefano Navarro, Christian Hackenbroch, Dennis Pfeiffer, Sabrina Ivana Bonfiglio, Mara Meub, Carina Gross, Joachim Schenk, Valeria Fumagalli, Kristina Mott, Markus Bender, Matteo Iannacone, Oliver Andres, Wolfgang Kastenmüller, Katrin G Heinze, Markus Sauer, Harald Schulze, Klaus Ley, Alan T Nurden, Bernhard Nieswandt.
      Platelet integrin αIIbβ3 is essential for hemostasis, thrombosis, and inflammation. We found that ligation of αIIbβ3 by von Willebrand factor or fibrin under flow triggered its accumulation in plasma membrane extensions or "platelet-derived integrin- and tetraspanin-enriched tethers" (PITTs). PITTs remained anchored to leukocytes or endothelial cells, whereas the partially αIIbβ3-deficient platelet body detached. Although still responsive to stimuli, αIIbβ3-deficient platelets did not support thrombus formation. PITTs promoted leukocyte activation and vascular inflammation in mouse models of infection and endotoxemia, and αIIbβ3 blockade reduced immune-mediated tissue damage. In patients with sepsis, COVID-19, or severe infections, PITT formation and platelet αIIbβ3 loss correlated with disease severity and adverse outcomes. We propose that PITTs are proinflammatory structures that amplify immune responses while contributing to platelet dysfunction in thrombo-inflammatory disease.
    DOI:  https://doi.org/10.1126/science.adu2825
  27. J Clin Endocrinol Metab. 2026 Jan 20. pii: dgag017. [Epub ahead of print]
    NGF promotes, in an autocrine-paracrine manner, metabolic and anti-inflammatory pathways in human and mouse adipocytes.
    Michail Deiktakis, Elias Athanasakis, Ioannis Charalampopoulos, Achille Gravanis, Christos Tsatsanis, Maria Venihaki, Andrew N Margioris, Eirini Dermitzaki.
       CONTEXT: Nerve Growth Factor (NGF) affects sympathetic neurons' development and survival. NGF is also found in non-neural cell lineages that are implicated in immune-endocrine interactions associated with metabolic diseases. Although NGF is expressed in white adipose tissue (WAT), little is known about the regulation of its expression and role in adipocytes.
    OBJECTIVE: To determine whether NGF and its receptors are expressed in human adipocytes and demonstrate their role in adipocyte metabolic and inflammatory phenotypes.
    DESIGN: The expression of NGF and its receptors TrkA and p75NTR and their effects on metabolic and inflammatory responses were examined in freshly isolated adipocytes from human abdominal WAT and mouse 3T3L1 cells.
    RESULTS: TrkA and p75NTR were expressed in both human and mouse adipocytes and pre-adipocytes. NGF was secreted by human white adipocytes and their exogenous exposure to NGF increased mitochondrial mass and activity, PPAR-gamma, CEBPA and adiponectin levels. Additionally, NGF increased lipolysis in human WAT explants and suppressed lipids accumulation, LPL and pro-inflammatory mediators IL-6 and IL-8 in human white adipocytes. The pro-inflammatory factor LPS down-regulated the levels of NGF receptors in human white adipocytes. NGF also affected mitochondrial activity in both human and mouse pre-adipocytes and TrkA appeared to mediate, at least partially, the effects of NGF on adipocytes.
    CONCLUSIONS: Our data suggests that NGF is produced locally within the adipose tissue where it up-regulates mitochondrial function while it suppresses the pro-inflammatory phenotype of human and mouse adipocytes.
    Keywords:  adipocyte; inflammation; metabolism; obesity
    DOI:  https://doi.org/10.1210/clinem/dgag017
This page is being maintained by Thomas Krichel. It was last updated on 2026‒01‒25 at 6:17.