bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–08–11
29 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Blocking IL-11 improves healthspan and lifespan in mice.
  2. Blood tests could soon predict your risk of Alzheimer's.
  3. Neutrophil-microglia interactions in AD.
  4. Light-responsive adipose-hypothalamus axis controls metabolic regulation.
  5. Gasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS-STING activation.
  6. The UK launched a metascience unit. Will other countries follow suit?
  7. Your microwave oven has its own microbiome.
  8. Protein droplets spread to seal tight junctions.
  9. DNA strands show symmetry in damage tolerance but asymmetries in repair efficiency.
  10. SLC25A48 controls mitochondrial choline import and metabolism.
  11. Neuro-intestinal acetylcholine signalling regulates the mitochondrial stress response in Caenorhabditis elegans.
  12. Age-related epithelial defects limit thymic function and regeneration.
  13. How the stressed-out brain can weaken the immune system.
  14. A plastic aggrecan barrier modulated by peripheral energy state gates metabolic signal access to arcuate neurons.
  15. Molecular mimicry in multisystem inflammatory syndrome in children.
  16. Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.
  17. How migrating cells define their back to move forward.
  18. Coral giants sound the alarm for the Great Barrier Reef.
  19. PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity.
  20. Non-classical monocytes have the support of the whole vascular tree.
  21. Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity.
  22. scTab: Scaling cross-tissue single-cell annotation models.
  23. Cxcr4 regulates a pool of adipocyte progenitors and contributes to adiposity in a sex-dependent manner.
  24. Data reveal how doctors take women's pain less seriously than men's.
  25. The interferon γ pathway enhances pluripotency and X-chromosome reactivation in iPSC reprogramming.
  26. A pattern emerges in chromatin aging: AP-1 steals the show.
  27. Intermittent clearance of p21-highly-expressing cells extends lifespan and confers sustained benefits to health and physical function.
  28. HIF-1α is required to differentiate the neonatal Macrophage protein secretome from adults.
  29. Basic neuroscience is integral to transgender people's health care.
  1. Nat Aging. 2024 Aug 08.
    Blocking IL-11 improves healthspan and lifespan in mice.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-024-00699-9
  2. Nature. 2024 Aug;632(8024): 243-245
    Blood tests could soon predict your risk of Alzheimer's.
    Alison Abbott.
      
    Keywords:  Alzheimer's disease; Medical research; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-02535-x
  3. Nat Neurosci. 2024 Aug;27(8): 1444
    Neutrophil-microglia interactions in AD.
    Leonie Welberg.
      
    DOI:  https://doi.org/10.1038/s41593-024-01732-1
  4. Nat Commun. 2024 Aug 08. 15(1): 6768
    Light-responsive adipose-hypothalamus axis controls metabolic regulation.
    Tadataka Tsuji, Vladimir Tolstikov, Yang Zhang, Tian Lian Huang, Henrique Camara, Meghan Halpin, Niven R Narain, King-Wai Yau, Matthew D Lynes, Michael A Kiebish, Yu-Hua Tseng.
      Light is fundamental for biological life, with most mammals possessing light-sensing photoreceptors in various organs. Opsin3 is highly expressed in adipose tissue which has extensive communication with other organs, particularly with the brain through the sympathetic nervous system (SNS). Our study reveals a new light-triggered crosstalk between adipose tissue and the hypothalamus. Direct blue-light exposure to subcutaneous white fat improves high-fat diet-induced metabolic abnormalities in an Opsin3-dependent manner. Metabolomic analysis shows that blue light increases circulating levels of histidine, which activates histaminergic neurons in the hypothalamus and stimulates brown adipose tissue (BAT) via SNS. Blocking central actions of histidine and denervating peripheral BAT blunts the effects of blue light. Human white adipocytes respond to direct blue light stimulation in a cell-autonomous manner, highlighting the translational relevance of this pathway. Together, these data demonstrate a light-responsive metabolic circuit involving adipose-hypothalamus communication, offering a potential strategy to alleviate obesity-induced metabolic abnormalities.
    DOI:  https://doi.org/10.1038/s41467-024-50866-0
  5. Nat Commun. 2024 Aug 05. 15(1): 6640
    Gasdermin-E-mediated pyroptosis drives immune checkpoint inhibitor-associated myocarditis via cGAS-STING activation.
    Si-Jia Sun, Xiao-Dong Jiao, Zhi-Gang Chen, Qi Cao, Jia-Hui Zhu, Qi-Rui Shen, Yi Liu, Zhen Zhang, Fang-Fang Xu, Yu Shi, Jie Tong, Shen-Xi Ouyang, Jiang-Tao Fu, Yi Zhao, Jun Ren, Dong-Jie Li, Fu-Ming Shen, Pei Wang.
      Immune checkpoint inhibitor (ICI)-induced myocarditis involves intensive immune/inflammation activation; however, its molecular basis is unclear. Here, we show that gasdermin-E (GSDME), a gasdermin family member, drives ICI-induced myocarditis. Pyroptosis mediated by GSDME, but not the canonical GSDMD, is activated in myocardial tissue of mice and cancer patients with ICI-induced myocarditis. Deficiency of GSDME in male mice alleviates ICI-induced cardiac infiltration of T cells, macrophages, and monocytes, as well as mitochondrial damage and inflammation. Restoration of GSDME expression specifically in cardiomyocytes, rather than myeloid cells, in GSDME-deficient mice reproduces ICI-induced myocarditis. Mechanistically, quantitative proteomics reveal that GSDME-dependent pyroptosis promotes cell death and mitochondrial DNA release, which in turn activates cGAS-STING signaling, triggering a robust interferon response and myocardial immune/inflammation activation. Pharmacological blockade of GSDME attenuates ICI-induced myocarditis and improves long-term survival in mice. Our findings may advance the understanding of ICI-induced myocarditis and suggest that targeting the GSDME-cGAS-STING-interferon axis may help prevent and manage ICI-associated myocarditis.
    DOI:  https://doi.org/10.1038/s41467-024-50996-5
  6. Nature. 2024 Aug 07.
    The UK launched a metascience unit. Will other countries follow suit?
    Dalmeet Singh Chawla.
      
    Keywords:  Funding; Government; Policy; Publishing
    DOI:  https://doi.org/10.1038/d41586-024-02469-4
  7. Nature. 2024 Aug 08.
    Your microwave oven has its own microbiome.
    Alix Soliman.
      
    Keywords:  Microbiology; Public health
    DOI:  https://doi.org/10.1038/d41586-024-02553-9
  8. Nature. 2024 Aug 07.
    Protein droplets spread to seal tight junctions.
    Alexander Ludwig.
      
    Keywords:  Biophysics; Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-02234-7
  9. Nature. 2024 Aug 07.
    DNA strands show symmetry in damage tolerance but asymmetries in repair efficiency.
      
    Keywords:  Cancer; Genetics; Genomics
    DOI:  https://doi.org/10.1038/d41586-024-02561-9
  10. Cell Metab. 2024 Aug 01. pii: S1550-4131(24)00281-X. [Epub ahead of print]
    SLC25A48 controls mitochondrial choline import and metabolism.
    Anthony R P Verkerke, Xu Shi, Mark Li, Yusuke Higuchi, Tadashi Yamamuro, Daisuke Katoh, Hiroshi Nishida, Christopher Auger, Ichitaro Abe, Robert E Gerszten, Shingo Kajimura.
      Choline is an essential nutrient for the biosynthesis of phospholipids, neurotransmitters, and one-carbon metabolism with a critical step being its import into mitochondria. However, the underlying mechanisms and biological significance remain poorly understood. Here, we report that SLC25A48, a previously uncharacterized mitochondrial inner-membrane carrier protein, controls mitochondrial choline transport and the synthesis of choline-derived methyl donors. We found that SLC25A48 was required for brown fat thermogenesis, mitochondrial respiration, and mitochondrial membrane integrity. Choline uptake into the mitochondrial matrix via SLC25A48 facilitated the synthesis of betaine and purine nucleotides, whereas loss of SLC25A48 resulted in increased production of mitochondrial reactive oxygen species and imbalanced mitochondrial lipids. Notably, human cells carrying a single nucleotide polymorphism on the SLC25A48 gene and cancer cells lacking SLC25A48 exhibited decreased mitochondrial choline import, increased oxidative stress, and impaired cell proliferation. Together, this study demonstrates that SLC25A48 regulates mitochondrial choline catabolism, bioenergetics, and cell survival.
    Keywords:  bioenergetics; brown adipose tissue; cancer metabolism; choline; mitochondria; purine nucleotides
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.010
  11. Nat Commun. 2024 Aug 03. 15(1): 6594
    Neuro-intestinal acetylcholine signalling regulates the mitochondrial stress response in Caenorhabditis elegans.
    Rebecca Cornell, Wei Cao, Bernie Harradine, Rasoul Godini, Ava Handley, Roger Pocock.
      Neurons coordinate inter-tissue protein homeostasis to systemically manage cytotoxic stress. In response to neuronal mitochondrial stress, specific neuronal signals coordinate the systemic mitochondrial unfolded protein response (UPRmt) to promote organismal survival. Yet, whether chemical neurotransmitters are sufficient to control the UPRmt in physiological conditions is not well understood. Here, we show that gamma-aminobutyric acid (GABA) inhibits, and acetylcholine (ACh) promotes the UPRmt in the Caenorhabditis elegans intestine. GABA controls the UPRmt by regulating extra-synaptic ACh release through metabotropic GABAB receptors GBB-1/2. We find that elevated ACh levels in animals that are GABA-deficient or lack ACh-degradative enzymes induce the UPRmt through ACR-11, an intestinal nicotinic α7 receptor. This neuro-intestinal circuit is critical for non-autonomously regulating organismal survival of oxidative stress. These findings establish chemical neurotransmission as a crucial regulatory layer for nervous system control of systemic protein homeostasis and stress responses.
    DOI:  https://doi.org/10.1038/s41467-024-50973-y
  12. Nat Immunol. 2024 Aug 07.
    Age-related epithelial defects limit thymic function and regeneration.
    Anastasia I Kousa, Lorenz Jahn, Kelin Zhao, Angel E Flores, Dante Acenas, Emma Lederer, Kimon V Argyropoulos, Andri L Lemarquis, David Granadier, Kirsten Cooper, Michael D'Andrea, Julie M Sheridan, Jennifer Tsai, Lisa Sikkema, Amina Lazrak, Katherine Nichols, Nichole Lee, Romina Ghale, Florent Malard, Hana Andrlova, Enrico Velardi, Salma Youssef, Marina Burgos da Silva, Melissa Docampo, Roshan Sharma, Linas Mazutis, Verena C Wimmer, Kelly L Rogers, Susan DeWolf, Brianna Gipson, Antonio L C Gomes, Manu Setty, Dana Pe'er, Laura Hale, Nancy R Manley, Daniel H D Gray, Marcel R M van den Brink, Jarrod A Dudakov.
      The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.
    DOI:  https://doi.org/10.1038/s41590-024-01915-9
  13. Nature. 2024 Aug 08.
    How the stressed-out brain can weaken the immune system.
    Sara Reardon.
      
    Keywords:  Brain; Immunology; Microbiome; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-02557-5
  14. Nat Commun. 2024 Aug 07. 15(1): 6701
    A plastic aggrecan barrier modulated by peripheral energy state gates metabolic signal access to arcuate neurons.
    Laura Kuczynski-Noyau, Sixtine Karmann, Paolo Alberton, Ines Martinez-Corral, Sreekala Nampoothiri, Florent Sauvé, Tori Lhomme, Carmelo Quarta, Suneel S Apte, Sébastien Bouret, Attila Aszodi, Sowmyalakshmi Rasika, Philippe Ciofi, Julie Dam, Vincent Prévot, Virginie Mattot.
      The hypothalamic arcuate nucleus (ARH) contains neurons vital for maintaining energy homeostasis that sense and respond to changes in blood-borne metabolic hormones. Despite its juxtaposition to the median eminence (ME), a circumventricular organ lacking a blood-brain barrier and thus exposed to circulating molecules, only a few ventral ARH neurons perceive these extravasating metabolic signals due to a poorly understood ME/ARH diffusion barrier. Here, we show in male mice that aggrecan, a perineural-net proteoglycan deposited by orexigenic ARH neurons, creates a peculiar ventrodorsal diffusion gradient. Fasting enhances aggrecan deposition more dorsally, reinforcing the diffusion barrier, particularly around neurons adjacent to fenestrated capillary loops that enter the ARH. The disruption of aggrecan deposits results in unregulated diffusion of blood-borne molecules into the ARH and impairs food intake. Our findings reveal the molecular nature and plasticity of the ME/ARH diffusion barrier, and indicate its physiological role in hypothalamic metabolic hormone sensing.
    DOI:  https://doi.org/10.1038/s41467-024-50798-9
  15. Nature. 2024 Aug 07.
    Molecular mimicry in multisystem inflammatory syndrome in children.
    Overcoming COVID-19 Network Investigators
      Multisystem inflammatory syndrome in children (MIS-C) is a severe, post-infectious sequela of SARS-CoV-2 infection1,2, yet the pathophysiological mechanism connecting the infection to the broad inflammatory syndrome remains unknown. Here we leveraged a large set of samples from patients with MIS-C to identify a distinct set of host proteins targeted by patient autoantibodies including a particular autoreactive epitope within SNX8, a protein involved in regulating an antiviral pathway associated with MIS-C pathogenesis. In parallel, we also probed antibody responses from patients with MIS-C to the complete SARS-CoV-2 proteome and found enriched reactivity against a distinct domain of the SARS-CoV-2 nucleocapsid protein. The immunogenic regions of the viral nucleocapsid and host SNX8 proteins bear remarkable sequence similarity. Consequently, we found that many children with anti-SNX8 autoantibodies also have cross-reactive T cells engaging both the SNX8 and the SARS-CoV-2 nucleocapsid protein epitopes. Together, these findings suggest that patients with MIS-C develop a characteristic immune response to the SARS-CoV-2 nucleocapsid protein that is associated with cross-reactivity to the self-protein SNX8, demonstrating a mechanistic link between the infection and the inflammatory syndrome, with implications for better understanding a range of post-infectious autoinflammatory diseases.
    DOI:  https://doi.org/10.1038/s41586-024-07722-4
  16. Cell Metab. 2024 Aug 01. pii: S1550-4131(24)00278-X. [Epub ahead of print]
    Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.
    Yiming Zhang, Cassandra B Higgins, Stefani Tica, Joshua A Adams, Jiameng Sun, Shannon C Kelly, Xiaoyu Zong, Dennis J Dietzen, Terri Pietka, Samuel J Ballentine, Leah Shriver, Gary Patti, Yin Cao, Brian J DeBosch.
      Urea cycle impairment and its relationship to obesity and inflammation remained elusive, partly due to the dramatic clinical presentation of classical urea cycle defects. We generated mice with hepatocyte-specific arginase 2 deletion (Arg2LKO) and revealed a mild compensated urea cycle defect. Stable isotope tracing and respirometry revealed hepatocyte urea and TCA cycle flux defects, impaired mitochondrial oxidative metabolism, and glutamine anaplerosis despite normal energy and glucose homeostasis during early adulthood. Yet during middle adulthood, chow- and diet-induced obese Arg2LKO mice develop exaggerated glucose and lipid derangements, which are reversible by replacing the TCA cycle oxidative substrate nicotinamide adenine dinucleotide. Moreover, serum-based hallmarks of urea, TCA cycle, and mitochondrial derangements predict incident fibroinflammatory liver disease in 106,606 patients nearly a decade in advance. The data reveal hierarchical urea-TCA cycle control via ARG2 to drive oxidative metabolism. Moreover, perturbations in this circuit may causally link urea cycle compromise to fibroinflammatory liver disease.
    Keywords:  arginase; diabetes; fasting; metabolic dysfunction-associated steatohepatitis; metabolic dysfunction-associated steatotic liver disease; nicotinamide adenine dinucleotide; nicotinamide riboside; obesity; tricarboxylic acid cycle; urea cycle
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.007
  17. Nature. 2024 Aug 07.
    How migrating cells define their back to move forward.
      
    Keywords:  Cell biology; Molecular biology
    DOI:  https://doi.org/10.1038/d41586-024-02572-6
  18. Nature. 2024 Aug;632(8024): 265-266
    Coral giants sound the alarm for the Great Barrier Reef.
    Miriam Pfeiffer.
      
    Keywords:  Climate change; Climate sciences; Environmental sciences
    DOI:  https://doi.org/10.1038/d41586-024-02329-1
  19. Nature. 2024 Aug 07.
    PTER is a N-acetyltaurine hydrolase that regulates feeding and obesity.
    Wei Wei, Xuchao Lyu, Andrew L Markhard, Sipei Fu, Rachel E Mardjuki, Peter E Cavanagh, Xianfeng Zeng, Jakub Rajniak, Nannan Lu, Shuke Xiao, Meng Zhao, Maria Dolores Moya-Garzon, Steven D Truong, Jonathan Chiu-Chun Chou, Lianna W Wat, Saranya Chidambaranathan-Reghupaty, Laetitia Coassolo, Duo Xu, Fangfang Shen, Wentao Huang, Cuauhtemoc B Ramirez, Cholsoon Jang, Lingyin Li, Katrin J Svensson, Michael A Fischbach, Jonathan Z Long.
      Taurine is a conditionally essential micronutrient and one of the most abundant amino acids in humans1-3. In endogenous taurine metabolism, dedicated enzymes are involved in the biosynthesis of taurine from cysteine and in the downstream metabolism of secondary taurine metabolites4,5. One taurine metabolite is N-acetyltaurine6. Levels of N-acetyltaurine are dynamically regulated by stimuli that alter taurine or acetate flux, including endurance exercise7, dietary taurine supplementation8 and alcohol consumption6,9. So far, the identities of the enzymes involved in N-acetyltaurine metabolism, and the potential functions of N-acetyltaurine itself, have remained unknown. Here we show that the body mass index associated orphan enzyme phosphotriesterase-related (PTER)10 is a physiological N-acetyltaurine hydrolase. In vitro, PTER catalyses the hydrolysis of N-acetyltaurine to taurine and acetate. In mice, PTER is expressed in the kidney, liver and brainstem. Genetic ablation of Pter in mice results in complete loss of tissue N-acetyltaurine hydrolysis activity and a systemic increase in N-acetyltaurine levels. After stimuli that increase taurine levels, Pter knockout mice exhibit reduced food intake, resistance to diet-induced obesity and improved glucose homeostasis. Administration of N-acetyltaurine to obese wild-type mice also reduces food intake and body weight in a GFRAL-dependent manner. These data place PTER into a central enzymatic node of secondary taurine metabolism and uncover a role for PTER and N-acetyltaurine in body weight control and energy balance.
    DOI:  https://doi.org/10.1038/s41586-024-07801-6
  20. Nat Rev Immunol. 2024 Aug 08.
    Non-classical monocytes have the support of the whole vascular tree.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-024-01078-6
  21. Dev Cell. 2024 Aug 03. pii: S1534-5807(24)00448-9. [Epub ahead of print]
    Itaconate uptake via SLC13A3 improves hepatic antibacterial innate immunity.
    Chao Chen, Caiyun Liu, Pengkai Sun, Zhenxing Zhang, Zhimin Wang, Ping Liu, Xinjian Li.
      Itaconate is an immunoregulatory metabolite produced by the mitochondrial enzyme immune-responsive gene 1 (IRG1) in inflammatory macrophages. We recently identified an important mechanism by which itaconate is released from inflammatory macrophages. However, it remains unknown whether extracellular itaconate is taken up by non-myeloid cells to exert immunoregulatory functions. Here, we used a custom-designed CRISPR screen to identify the dicarboxylate transporter solute carrier family 13 member 3 (SLC13A3) as an itaconate importer and to characterize the role of SLC13A3 in itaconate-improved hepatic antibacterial innate immunity. Functionally, liver-specific deletion of Slc13a3 impairs hepatic antibacterial innate immunity in vivo and in vitro. Mechanistically, itaconate uptake via SLC13A3 induces transcription factor EB (TFEB)-dependent lysosomal biogenesis and subsequently improves antibacterial innate immunity in mouse hepatocytes. These findings identify SLC13A3 as a key itaconate importer in mouse hepatocytes and will aid in the development of potent itaconate-based antibacterial therapeutics.
    Keywords:  SLC13A3; TFEB; antibacterial innate immunity; importer; itaconate; lysosomal biogenesis
    DOI:  https://doi.org/10.1016/j.devcel.2024.07.011
  22. Nat Commun. 2024 Aug 04. 15(1): 6611
    scTab: Scaling cross-tissue single-cell annotation models.
    Felix Fischer, David S Fischer, Roman Mukhin, Andrey Isaev, Evan Biederstedt, Alexandra-Chloé Villani, Fabian J Theis.
      Identifying cellular identities is a key use case in single-cell transcriptomics. While machine learning has been leveraged to automate cell annotation predictions for some time, there has been little progress in scaling neural networks to large data sets and in constructing models that generalize well across diverse tissues. Here, we propose scTab, an automated cell type prediction model specific to tabular data, and train it using a novel data augmentation scheme across a large corpus of single-cell RNA-seq observations (22.2 million cells). In this context, we show that cross-tissue annotation requires nonlinear models and that the performance of scTab scales both in terms of training dataset size and model size. Additionally, we show that the proposed data augmentation schema improves model generalization. In summary, we introduce a de novo cell type prediction model for single-cell RNA-seq data that can be trained across a large-scale collection of curated datasets and demonstrate the benefits of using deep learning methods in this paradigm.
    DOI:  https://doi.org/10.1038/s41467-024-51059-5
  23. Nat Commun. 2024 Aug 05. 15(1): 6622
    Cxcr4 regulates a pool of adipocyte progenitors and contributes to adiposity in a sex-dependent manner.
    Benjamin M Steiner, Abigail M Benvie, Derek Lee, Yuwei Jiang, Daniel C Berry.
      Sex steroids modulate the distribution of mammalian white adipose tissues. Moreover, WAT remodeling requires adipocyte progenitor cells. Nevertheless, the sex-dependent mechanisms regulating adipocyte progenitors remain undetermined. Here, we uncover Cxcr4 acting in a sexually dimorphic manner to affect a pool of proliferating cells leading to restriction of female fat mass. We find that deletion of Cxcr4 in Pparγ-expressing cells results in female, not male, lipodystrophy, which cannot be restored by high-fat diet consumption. Additionally, Cxcr4 deletion is associated with a loss of a pool of proliferating adipocyte progenitors. Cxcr4 loss is accompanied by the upregulation of estrogen receptor alpha in adipose-derived PPARγ-labelled cells related to estradiol hypersensitivity and stalled adipogenesis. Estrogen removal or administration of antiestrogens restores WAT accumulation and dynamics of adipose-derived cells in Cxcr4-deficient mice. These findings implicate Cxcr4 as a female adipogenic rheostat, which may inform strategies to target female adiposity.
    DOI:  https://doi.org/10.1038/s41467-024-50985-8
  24. Nature. 2024 Aug 05.
    Data reveal how doctors take women's pain less seriously than men's.
    Lilly Tozer.
      
    Keywords:  Health care; Public health
    DOI:  https://doi.org/10.1038/d41586-024-02547-7
  25. Sci Adv. 2024 Aug 09. 10(32): eadj8862
    The interferon γ pathway enhances pluripotency and X-chromosome reactivation in iPSC reprogramming.
    Mercedes Barrero, Aleksey Lazarenkov, Enrique Blanco, Luis G Palma, Anna V López-Rubio, Moritz Bauer, Anna Bigas, Luciano Di Croce, José Luis Sardina, Bernhard Payer.
      Reprogramming somatic cells into induced pluripotent stem cells (iPSCs) requires activation of the pluripotency network and resetting of the epigenome by erasing the epigenetic memory of the somatic state. In female mouse cells, a critical epigenetic reprogramming step is the reactivation of the inactive X chromosome. Despite its importance, a systematic understanding of the regulatory networks linking pluripotency and X-reactivation is missing. Here, we reveal important pathways for pluripotency acquisition and X-reactivation using a genome-wide CRISPR screen during neural precursor to iPSC reprogramming. In particular, we discover that activation of the interferon γ (IFNγ) pathway early during reprogramming accelerates pluripotency acquisition and X-reactivation. IFNγ stimulates STAT3 signaling and the pluripotency network and leads to enhanced TET-mediated DNA demethylation, which consequently boosts X-reactivation. We therefore gain a mechanistic understanding of the role of IFNγ in reprogramming and X-reactivation and provide a comprehensive resource of the molecular networks involved in these processes.
    DOI:  https://doi.org/10.1126/sciadv.adj8862
  26. Cell Metab. 2024 Aug 06. pii: S1550-4131(24)00286-9. [Epub ahead of print]36(8): 1639-1641
    A pattern emerges in chromatin aging: AP-1 steals the show.
    Cian J Lynch, Laia Richart, Manuel Serrano.
      During aging, transcriptional programs of cell identity are partially eroded, reducing cellular fitness and resilience. Patrick et al.1 unveil a general mechanism for this process that consists of the progressive loss of transcription factor AP-1 from cell identity enhancers and its relocation by competition to stress-response elements.
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.015
  27. Cell Metab. 2024 Aug 06. pii: S1550-4131(24)00277-8. [Epub ahead of print]36(8): 1795-1805.e6
    Intermittent clearance of p21-highly-expressing cells extends lifespan and confers sustained benefits to health and physical function.
    Binsheng Wang, Lichao Wang, Nathan S Gasek, Chia-Ling Kuo, Jia Nie, Taewan Kim, Pengyi Yan, Junyu Zhu, Blake L Torrance, Yueying Zhou, Lisa C Flores, Colton Allen, Allison M Andrade, Chun Guo, Rachel L Cohn, Evan R Jellison, Jenna M Bartley, George A Kuchel, Sheng Li, Tamar Pirtskhalava, Tamar Tchkonia, Sumit Yadav, Laura Haynes, James L Kirkland, Yuji Ikeno, Ming Xu.
      A key challenge in aging research is extending lifespan in tandem with slowing down functional decline so that life with good health (healthspan) can be extended. Here, we show that monthly clearance, starting from 20 months, of a small number of cells that highly express p21Cip1 (p21high) improves cardiac and metabolic function and extends both median and maximum lifespans in mice. Importantly, by assessing the health and physical function of these mice monthly until death, we show that clearance of p21high cells improves physical function at all remaining stages of life, suggesting healthspan extension. Mechanistically, p21high cells encompass several cell types with a relatively conserved proinflammatory signature. Clearance of p21high cells reduces inflammation and alleviates age-related transcriptomic signatures of various tissues. These findings demonstrate the feasibility of healthspan extension in mice and indicate p21high cells as a therapeutic target for healthy aging.
    Keywords:  aging; cellular senescence; frailty; inflammation; morbidity compression
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.006
  28. Cell Immunol. 2024 Aug 02. pii: S0008-8749(24)00064-9. [Epub ahead of print]403-404 104861
    HIF-1α is required to differentiate the neonatal Macrophage protein secretome from adults.
    Amanda Becker, Mallory Filipp, Connor Lantz, Kristofor Glinton, Edward B Thorp.
      The immune response to stress diverges with age, with neonatal macrophages implicated in tissue regeneration versus tissue scarring and maladaptive inflammation in adults. Integral to the macrophage stress response is the recognition of hypoxia and pathogen-associated molecular patterns (PAMPs), which are often coupled. The age-specific, cell-intrinsic nature of this stress response remains vague. To uncover age-defined divergences in macrophage crosstalk potential after exposure to hypoxia and PAMPs, we interrogated the secreted proteomes of neonatal versus adult macrophages via non-biased mass spectrometry. Through this approach, we newly identified age-specific signatures in the secretomes of neonatal versus adult macrophages in response to hypoxia and the prototypical PAMP, lipopolysaccharide (LPS). Neonatal macrophages secreted proteins most consistent with an anti-inflammatory, regenerative phenotype protective against apoptosis and oxidative stress, dependent on hypoxia inducible transcription factor-1α (HIF-1α). In contrast, adult macrophages secreted proteins consistent with a pro-inflammatory, glycolytic phenotypic signature consistent with pathogen killing. Taken together, these data uncover fundamental age and HIF-1α dependent macrophage responses that may be targeted to calibrate the innate immune response during stress and inflammation.
    Keywords:  HIF-1α; Immunometabolism; Inflammation; Macrophage; Regeneration
    DOI:  https://doi.org/10.1016/j.cellimm.2024.104861
  29. Nature. 2024 Aug;632(8024): 259
    Basic neuroscience is integral to transgender people's health care.
    Doug P VanderLaan, Philippa Hüpen.
      
    Keywords:  Neuroscience; Public health
    DOI:  https://doi.org/10.1038/d41586-024-02549-5
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