bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2025–02–02
24 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Single-cell profiling of the immune landscape across the human lifespan.
  2. Reproducibility and transparency: what's going on and how can we help.
  3. Multiomics reveals that triacylglycerol mobilization helps drive recovery from mitochondrial stress.
  4. A mutation in LXRα uncovers a role for cholesterol sensing in limiting metabolic dysfunction-associated steatohepatitis.
  5. Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically.
  6. Liver-innervating vagal sensory neurons are indispensable for the development of hepatic steatosis and anxiety-like behavior in diet-induced obese mice.
  7. Epigenetic modification increases skeletal muscle resilience to metabolic stress.
  8. An inter-organ neuro-immuno-endocrine circuit for glucose homeostasis.
  9. FAM43A coordinates mtDNA replication and mitochondrial biogenesis in response to mtDNA depletion.
  10. Four lessons COVID taught us about the immune system.
  11. Recognizing ultra-processed foods in grocery stores.
  12. OXCT1 succinylation and activation by SUCLA2 promotes ketolysis and liver tumor growth.
  13. Platelet-white cell ratio is more strongly associated with mortality than other common risk ratios derived from complete blood counts.
  14. AAV capsid prioritization in normal and steatotic human livers maintained by machine perfusion.
  15. Early transcriptional effects of inflammatory cytokines reveal highly redundant cytokine networks.
  16. Single cell profiling of circulating autoreactive CD4 T cells from patients with autoimmune liver diseases suggests tissue imprinting.
  17. Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer's disease.
  18. Daily briefing: What went wrong at 23andMe.
  19. Inflammatory signatures of microglia in hypercortisolemia-related depression.
  20. Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.
  21. Unlocking drug modes of action with multi-dimensional high-throughput metabolic profiling.
  22. The TRPV1-PKM2-SREBP1 axis maintains microglial lipid homeostasis in Alzheimer's disease.
  23. Statistical identification of cell type-specific spatially variable genes in spatial transcriptomics.
  24. Monocytes and interstitial macrophages contribute to hypoxic pulmonary hypertension.
  1. Nat Immunol. 2025 Feb;26(2): 172-173
    Single-cell profiling of the immune landscape across the human lifespan.
      
    DOI:  https://doi.org/10.1038/s41590-024-02058-7
  2. Nat Commun. 2025 Jan 27. 16(1): 1082
    Reproducibility and transparency: what's going on and how can we help.
      
    DOI:  https://doi.org/10.1038/s41467-024-54614-2
  3. Nat Cell Biol. 2025 Jan 24.
    Multiomics reveals that triacylglycerol mobilization helps drive recovery from mitochondrial stress.
      
    DOI:  https://doi.org/10.1038/s41556-024-01603-8
  4. Nat Commun. 2025 Jan 28. 16(1): 1102
    A mutation in LXRα uncovers a role for cholesterol sensing in limiting metabolic dysfunction-associated steatohepatitis.
    Alexis T Clark, Lillian Russo-Savage, Luke A Ashton, Niki Haghshenas, Nicolas A Amselle, Ira G Schulman.
      Liver x receptor alpha (LXRα) functions as an intracellular cholesterol sensor that regulates lipid metabolism at the transcriptional level in response to the direct binding of cholesterol derivatives. We have generated mice with a mutation in LXRα that reduces activity in response to endogenous cholesterol derived LXR ligands while still allowing transcriptional activation by synthetic agonists. The mutant LXRα functions as a dominant negative that shuts down cholesterol sensing. When fed a high fat, high cholesterol diet LXRα mutant mice rapidly develop pathologies associated with Metabolic Dysfunction-Associated Steatohepatitis (MASH) including ballooning hepatocytes, liver inflammation, and fibrosis. Strikingly LXRα mutant mice have decreased liver triglycerides but increased liver cholesterol. Therefore, elevated cholesterol in the liver may play a critical role in the development of MASH. Reengaging LXR signaling by treatment with synthetic agonist reverses MASH in LXRα mutant mice suggesting that LXRα normally functions to impede the development of liver disease.
    DOI:  https://doi.org/10.1038/s41467-025-56565-8
  5. Nat Commun. 2025 Jan 25. 16(1): 1030
    Genetic variation in IL-4 activated tissue resident macrophages determines strain-specific synergistic responses to LPS epigenetically.
    Mingming Zhao, Dragana Jankovic, Verena M Link, Camila Oliveira Silva Souza, Katherine M Hornick, Oyebola Oyesola, Yasmine Belkaid, Justin Lack, Png Loke.
      How macrophages in the tissue environment integrate multiple stimuli depends on the genetic background of the host, but this is still poorly understood. We investigate IL-4 activation of male C57BL/6 and BALB/c strain specific in vivo tissue-resident macrophages (TRMs) from the peritoneal cavity. C57BL/6 TRMs are more transcriptionally responsive to IL-4 stimulation, with induced genes associated with more super enhancers, induced enhancers, and topologically associating domains (TAD) boundaries. IL-4-directed epigenomic remodeling reveals C57BL/6 specific enrichment of NF-κB, IRF, and STAT motifs. Additionally, IL-4-activated C57BL/6 TRMs demonstrate an augmented synergistic response upon in vitro lipopolysaccharide (LPS) exposure, despite naïve BALB/c TRMs displaying a more robust transcriptional response to LPS. Single-cell RNA sequencing (scRNA-seq) analysis of mixed bone marrow chimeras indicates that transcriptional differences and synergy are cell intrinsic within the same tissue environment. Hence, genetic variation alters IL-4-induced cell intrinsic epigenetic reprogramming resulting in strain specific synergistic responses to LPS exposure.
    DOI:  https://doi.org/10.1038/s41467-025-56379-8
  6. Nat Commun. 2025 Jan 24. 16(1): 991
    Liver-innervating vagal sensory neurons are indispensable for the development of hepatic steatosis and anxiety-like behavior in diet-induced obese mice.
    Jiyeon Hwang, Sangbhin Lee, Junichi Okada, Li Liu, Jeffrey E Pessin, Streamson C Chua, Gary J Schwartz, Young-Hwan Jo.
      The visceral organ-brain axis, mediated by vagal sensory neurons, is essential for maintaining various physiological functions. Here, we investigate the impact of liver-projecting vagal sensory neurons on energy balance, hepatic steatosis, and anxiety-like behavior in mice under obesogenic conditions. A small subset of vagal sensory neurons innervate the liver and project centrally to the nucleus of the tractus solitarius, area postrema, and dorsal motor nucleus of the vagus, and peripherally to the periportal areas in the liver. The loss of these neurons prevents diet-induced obesity, and these outcomes are associated with increased energy expenditure. Although males and females exhibit improved glucose homeostasis following disruption of liver-projecting vagal sensory neurons, only male mice display increased insulin sensitivity. Furthermore, the loss of liver-projecting vagal sensory neurons limits the progression of hepatic steatosis. Intriguingly, mice lacking liver-innervating vagal sensory neurons also exhibit less anxiety-like behavior compared to control mice. Modulation of the liver-brain axis may aid in designing effective treatments for both psychiatric and metabolic disorders associated with obesity and MAFLD.
    DOI:  https://doi.org/10.1038/s41467-025-56328-5
  7. Nat Metab. 2025 Jan 27.
    Epigenetic modification increases skeletal muscle resilience to metabolic stress.
      
    DOI:  https://doi.org/10.1038/s42255-024-01211-8
  8. Nat Rev Immunol. 2025 Jan 28.
    An inter-organ neuro-immuno-endocrine circuit for glucose homeostasis.
    Kirsty Minton.
      
    DOI:  https://doi.org/10.1038/s41577-025-01139-4
  9. J Cell Biol. 2025 Mar 03. pii: e202311082. [Epub ahead of print]224(3):
    FAM43A coordinates mtDNA replication and mitochondrial biogenesis in response to mtDNA depletion.
    Alva G Sainz, Gladys R Rojas, Alexandra G Moyzis, Matthew P Donnelly, Kailash C Mangalhara, Melissa A Johnson, Pau B Esparza-Moltó, Kym J Grae, Reuben J Shaw, Gerald S Shadel.
      Mitochondrial retrograde signaling (MRS) pathways relay the functional status of mitochondria to elicit homeostatic or adaptive changes in nuclear gene expression. Budding yeast have "intergenomic signaling" pathways that sense the amount of mitochondrial DNA (mtDNA) independently of oxidative phosphorylation (OXPHOS), the primary function of genes encoded by mtDNA. However, MRS pathways that sense the amount of mtDNA in mammalian cells remain poorly understood. We found that mtDNA-depleted IMR90 cells can sustain OXPHOS for a significant amount of time, providing a robust model system to interrogate human intergenomic signaling. We identified FAM43A, a largely uncharacterized protein, as a CHK2-dependent early responder to mtDNA depletion. Depletion of FAM43A activates a mitochondrial biogenesis program, resulting in an increase in mitochondrial mass and mtDNA copy number via CHK2-mediated upregulation of the p53R2 form of ribonucleotide reductase. We propose that FAM43A performs a checkpoint-like function to limit mitochondrial biogenesis and turnover under conditions of mtDNA depletion or replication stress.
    DOI:  https://doi.org/10.1083/jcb.202311082
  10. Nature. 2025 Jan 27.
    Four lessons COVID taught us about the immune system.
    Heidi Ledford.
      
    DOI:  https://doi.org/10.1038/d41586-025-00128-w
  11. Nat Med. 2025 Jan 30.
    Recognizing ultra-processed foods in grocery stores.
    Karen O'Leary.
      
    Keywords:  Machine Learning; Nutrition; Public health
    DOI:  https://doi.org/10.1038/d41591-025-00007-x
  12. Mol Cell. 2025 Jan 21. pii: S1097-2765(24)01066-9. [Epub ahead of print]
    OXCT1 succinylation and activation by SUCLA2 promotes ketolysis and liver tumor growth.
    Dong Guo, Qiujing Yu, Yingying Tong, Xu Qian, Ying Meng, Fei Ye, Xiaoming Jiang, Lihui Wu, Qingqing Yang, Suyao Li, Min Li, Qingang Wu, Liwei Xiao, Xuxiao He, Rongxuan Zhu, Guijun Liu, Dou Nie, Shudi Luo, Leina Ma, Ren-An Jin, Zhihua Liu, Xiao Liang, Dong Yan, Zhimin Lu.
      Ketone bodies generated in hepatocytes in the adult liver are used for nonhepatic tissues as an energy source. However, ketolysis is reactivated in hepatocellular carcinoma (HCC) cells with largely unelucidated mechanisms. Here, we demonstrate that 3-oxoacid CoA-transferase 1 (OXCT1), a rate-limiting enzyme in ketolysis, interacts with SUCLA2 upon IGF1 stimulation in HCC cells. This interaction results from ERK2-mediated SUCLA2 S124 phosphorylation and subsequent PIN1-mediated cis-trans isomerization of SUCLA2. OXCT1-associated SUCLA2 generates succinyl-CoA, which not only serves as a substrate for OXCT1 but also directly succinylates OXCT1 at K421 and activates OXCT1. SUCLA2-regulated OXCT1 activation substantially enhances ketolysis, HCC cell proliferation, and tumor growth in mice. Notably, treatment with acetohydroxamic acid, an OXCT1 inhibitor used clinically for urinary infection, inhibits liver tumor growth in mice and significantly enhances lenvatinib therapy. Our findings highlight the role of SUCLA2-coupled regulation of OXCT1 succinylation in ketolysis and unveil an unprecedented strategy for treating HCC by interrupting ketolysis.
    Keywords:  OXCT1; SUCLA2; ketolysis; ketone body; succinyl-CoA; succinylation; tumorigenesis
    DOI:  https://doi.org/10.1016/j.molcel.2024.12.025
  13. Nat Commun. 2025 Jan 28. 16(1): 1113
    Platelet-white cell ratio is more strongly associated with mortality than other common risk ratios derived from complete blood counts.
    Brody H Foy, Jonathan C T Carlson, Aaron D Aguirre, John M Higgins.
      Complete blood count indices and their ratios are associated with adverse clinical outcomes for many acute illnesses, but the mechanisms generating these associations are not fully understood. Recent identification of a consistent pattern of white blood cell and platelet count co-regulation during acute inflammatory recovery provides a potentially unifying explanation. Here we show that the platelet-to-white-cell ratio, which was selected based on this conserved recovery pattern, is more strongly associated with mortality than other blood count markers and ratios in four important illnesses involving acute inflammation: COVID-19, acute heart failure, myocardial infarction, and stroke. Patients recovering well from these acute illnesses tend to follow a joint white cell and platelet trajectory that can be reduced to this one-dimensional ratio. The platelet-to-white-cell ratio's association with prognosis is consistent with recently identified inflammatory dynamics and may provide a convenient and interpretable summary of patient inflammatory state.
    DOI:  https://doi.org/10.1038/s41467-025-56251-9
  14. Nat Biotechnol. 2025 Jan 29.
    AAV capsid prioritization in normal and steatotic human livers maintained by machine perfusion.
    Jae-Jun Kim, Simone N T Kurial, Pervinder K Choksi, Miguel Nunez, Tyler Lunow-Luke, Jan Bartel, Julia Driscoll, Chris L Her, Simaron Dhillon, William Yue, Abhishek Murti, Tin Mao, Julian N Ramos, Amita Tiyaboonchai, Markus Grompe, Aras N Mattis, Shareef M Syed, Bruce M Wang, Jacquelyn J Maher, Garrett R Roll, Holger Willenbring.
      Therapeutic efficacy and safety of adeno-associated virus (AAV) liver gene therapy depend on capsid choice. To predict AAV capsid performance under near-clinical conditions, we established side-by-side comparison at single-cell resolution in human livers maintained by normothermic machine perfusion. AAV-LK03 transduced hepatocytes much more efficiently and specifically than AAV5, AAV8 and AAV6, which are most commonly used clinically, and AAV-NP59, which is better at transducing human hepatocytes engrafted in immune-deficient mice. AAV-LK03 preferentially transduced periportal hepatocytes in normal liver, whereas AAV5 targeted pericentral hepatocytes in steatotic liver. AAV5 and AAV8 transduced liver sinusoidal endothelial cells as efficiently as hepatocytes. AAV capsid and steatosis influenced vector episome formation, which determines gene therapy durability, with AAV5 delaying concatemerization. Our findings inform capsid choice in clinical AAV liver gene therapy, including consideration of disease-relevant hepatocyte zonation and effects of steatosis, and facilitate the development of AAV capsids that transduce hepatocytes or other therapeutically relevant cell types in the human liver with maximum efficiency and specificity.
    DOI:  https://doi.org/10.1038/s41587-024-02523-6
  15. J Exp Med. 2025 Apr 07. pii: e20241207. [Epub ahead of print]222(4):
    Early transcriptional effects of inflammatory cytokines reveal highly redundant cytokine networks.
    Immunological Genome Project Consortium
      Inflammatory cytokines are fundamental mediators of the organismal response to injury, infection, or other harmful stimuli. To elucidate the early and mostly direct transcriptional signatures of inflammatory cytokines, we profiled all immunologic cell types by RNAseq after systemic exposure to IL1β, IL6, and TNFα. Our results revealed a significant overlap in the responses, with broad divergence between myeloid and lymphoid cells, but with very few cell-type-specific responses. Pathway and motif analysis identified several main controllers (NF-κB, IRF8, and PU.1), but the largest portion of the response appears to be mediated by MYC, which was also implicated in the response to γc cytokines. Indeed, inflammatory and γc cytokines elicited surprisingly similar responses (∼50% overlap in NK cells). Significant overlap with interferon-induced responses was observed, paradoxically in lymphoid but not myeloid cell types. These results point to a highly redundant cytokine network, with intertwined effects between disparate cytokines and cell types.
    DOI:  https://doi.org/10.1084/jem.20241207
  16. Nat Commun. 2025 Jan 29. 16(1): 1161
    Single cell profiling of circulating autoreactive CD4 T cells from patients with autoimmune liver diseases suggests tissue imprinting.
    Anaïs Cardon, Thomas Guinebretière, Chuang Dong, Laurine Gil, Sakina Ado, Pierre-Jean Gavlovsky, Martin Braud, Richard Danger, Christoph Schultheiß, Aurélie Doméné, Perrine Paul-Gilloteaux, Caroline Chevalier, Laura Bernier, Jean-Paul Judor, Cynthia Fourgeux, Astrid Imbert, Marion Khaldi, Edouard Bardou-Jacquet, Laure Elkrief, Adrien Lannes, Christine Silvain, Matthieu Schnee, Florence Tanne, Fabienne Vavasseur, Lucas Brusselle, Sophie Brouard, William W Kwok, Jean-François Mosnier, Ansgar W Lohse, Jeremie Poschmann, Mascha Binder, Jérôme Gournay, Sophie Conchon, Pierre Milpied, Amédée Renand.
      Autoimmune liver diseases (AILD) involve dysregulated CD4 T cell responses against liver self-antigens, but how these autoreactive T cells relate to liver tissue pathology remains unclear. Here we perform single-cell transcriptomic and T cell receptor analyses of circulating, self-antigen-specific CD4 T cells from patients with AILD and identify a subset of liver-autoreactive CD4 T cells with a distinct B-helper transcriptional profile characterized by PD-1, TIGIT and HLA-DR expression. These cells share clonal relationships with expanded intrahepatic T cells and exhibit transcriptional signatures overlapping with tissue-resident T cells in chronically inflamed environments. Using a mouse model, we demonstrate that, following antigen recognition in the liver, CD4 T cells acquire an exhausted phenotype, play a crucial role in liver damage, and are controlled by immune checkpoint pathways. Our findings thus suggest that circulating autoreactive CD4 T cells in AILD are imprinted by chronic antigen exposure to promote liver inflammation, thereby serving as a potential target for developing biomarkers and therapies for AILD.
    DOI:  https://doi.org/10.1038/s41467-025-56363-2
  17. Nat Commun. 2025 Jan 28. 16(1): 1126
    Polygenic burden of short tandem repeat expansions promotes risk for Alzheimer's disease.
    Michael H Guo, Wan-Ping Lee, Badri Vardarajan, Gerard D Schellenberg, Jennifer E Phillips-Cremins.
      Studies of the genetics of Alzheimer's disease (AD) have largely focused on single nucleotide variants and short insertions/deletions. However, most of the disease heritability has yet to be uncovered, suggesting that there is substantial genetic risk conferred by other forms of genetic variation. There are over one million short tandem repeats (STRs) in the genome, and their link to AD risk has not been assessed. As pathogenic expansions of STR cause over 30 neurologic diseases, it is important to ascertain whether STRs may also be implicated in AD risk. Here, we genotype 312,731 polymorphic STR tracts genome-wide using PCR-free whole genome sequencing data from 2981 individuals (1489 AD case and 1492 control individuals). We implement an approach to identify STR expansions as STRs with tract lengths that are outliers from the population. We then test for differences in aggregate burden of expansions in case versus control individuals. AD patients harbor a 1.19-fold increase of STR expansions compared to healthy elderly controls (p = 8.27×10-3, two-sided Mann-Whitney test). Individuals carrying >30 STR expansions have a 3.69-fold higher odds of having AD and have more severe AD neuropathology. AD STR expansions are highly enriched within active promoters in post-mortem hippocampal brain tissues and particularly within SINE-VNTR-Alu (SVA) retrotransposons. Together, these results demonstrate that expanded STRs within active promoter regions of the genome associate with risk of AD.
    DOI:  https://doi.org/10.1038/s41467-025-56400-0
  18. Nature. 2025 Jan 24.
    Daily briefing: What went wrong at 23andMe.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-025-00247-4
  19. Cell Insight. 2025 Apr;4(2): 100222
    Inflammatory signatures of microglia in hypercortisolemia-related depression.
    Yanxiang Zhao, Yingying Huang, Zhangyuzi Deng, Ying Cao, Jing Yang.
      
    DOI:  https://doi.org/10.1016/j.cellin.2024.100222
  20. Cell Death Dis. 2025 Jan 25. 16(1): 40
    Ferroptosis triggers mitochondrial fragmentation via Drp1 activation.
    Lohans Pedrera, Laura Prieto Clemente, Alina Dahlhaus, Sara Lotfipour Nasudivar, Sofya Tishina, Daniel Olmo González, Jenny Stroh, Fatma Isil Yapici, Randhwaj Pratap Singh, Nils Grotehans, Thomas Langer, Ana J García-Sáez, Silvia von Karstedt.
      Constitutive mitochondrial dynamics ensure quality control and metabolic fitness of cells, and their dysregulation has been implicated in various human diseases. The large GTPase Dynamin-related protein 1 (Drp1) is intimately involved in mediating constitutive mitochondrial fission and has been implicated in mitochondrial cell death pathways. During ferroptosis, a recently identified type of regulated necrosis driven by excessive lipid peroxidation, mitochondrial fragmentation has been observed. Yet, how this is regulated and whether it is involved in ferroptotic cell death has remained unexplored. Here, we provide evidence that Drp1 is activated upon experimental induction of ferroptosis and promotes cell death execution and mitochondrial fragmentation. Using time-lapse microscopy, we found that ferroptosis induced mitochondrial fragmentation and loss of mitochondrial membrane potential, but not mitochondrial outer membrane permeabilization. Importantly, Drp1 accelerated ferroptotic cell death kinetics. Notably, this function was mediated by the regulation of mitochondrial dynamics, as overexpression of Mitofusin 2 phenocopied the effect of Drp1 deficiency in delaying ferroptosis cell death kinetics. Mechanistically, we found that Drp1 is phosphorylated and activated after induction of ferroptosis and that it translocates to mitochondria. Further activation at mitochondria through the phosphatase PGAM5 promoted ferroptotic cell death. Remarkably, Drp1 depletion delayed mitochondrial and plasma membrane lipid peroxidation. These data provide evidence for a functional role of Drp1 activation and mitochondrial fragmentation in the acceleration of ferroptotic cell death, with important implications for targeting mitochondrial dynamics in diseases associated with ferroptosis.
    DOI:  https://doi.org/10.1038/s41419-024-07312-2
  21. Nat Biotechnol. 2025 Jan 28.
    Unlocking drug modes of action with multi-dimensional high-throughput metabolic profiling.
      
    DOI:  https://doi.org/10.1038/s41587-024-02525-4
  22. Cell Death Dis. 2025 Jan 14. 16(1): 14
    The TRPV1-PKM2-SREBP1 axis maintains microglial lipid homeostasis in Alzheimer's disease.
    Xudong Sha, Jiayuan Lin, Kexin Wu, Jia Lu, Zhihua Yu.
      Microglia are progressively activated by inflammation and exhibit phagocytic dysfunction in the pathogenesis of neurodegenerative diseases. Lipid-droplet-accumulating microglia were identified in the aging mouse and human brain; however, little is known about the formation and role of lipid droplets in microglial neuroinflammation of Alzheimer's disease (AD). Here, we report a striking buildup of lipid droplets accumulation in microglia in the 3xTg mouse brain. Moreover, we observed significant upregulation of PKM2 and sterol regulatory element binding protein 1 (SREBP1) levels, which were predominantly localized in microglia of 3xTg mice. PKM2 dimerization was necessary for SREBP1 activation and lipogenesis of lipid droplet-accumulating microglia. RNA sequencing analysis of microglia isolated from 3xTg mice exhibited transcriptomic changes in lipid metabolism, innate inflammation, and phagocytosis dysfunction; these changes were improved with capsaicin-mediated pharmacological activation of TRPV1 via inhibition of PKM2 dimerization and reduction of SREBP1 activation. Lipid droplet-accumulating microglia exhibited increased mitochondrial injury accompanied by impaired mitophagy, which was abrogated upon of TRPV1 activation. Capsaicin also rescued neuronal loss, tau pathology, and memory impairment in 3xTg mice. Our study suggests that TRPV1-PKM2-SREBP1 axis regulation of microglia lipid metabolism could be a therapeutic approach to alleviate the consequences of AD.
    DOI:  https://doi.org/10.1038/s41419-024-07328-8
  23. Nat Commun. 2025 Jan 26. 16(1): 1059
    Statistical identification of cell type-specific spatially variable genes in spatial transcriptomics.
    Lulu Shang, Peijun Wu, Xiang Zhou.
      An essential task in spatial transcriptomics is identifying spatially variable genes (SVGs). Here, we present Celina, a statistical method for systematically detecting cell type-specific SVGs (ct-SVGs)-a subset of SVGs exhibiting distinct spatial expression patterns within specific cell types. Celina utilizes a spatially varying coefficient model to accurately capture each gene's spatial expression pattern in relation to the distribution of cell types across tissue locations, ensuring effective type I error control and high power. Celina proves powerful compared to existing methods in single-cell resolution spatial transcriptomics and stands as the only effective solution for spot-resolution spatial transcriptomics. Applied to five real datasets, Celina uncovers ct-SVGs associated with tumor progression and patient survival in lung cancer, identifies metagenes with unique spatial patterns linked to cell proliferation and immune response in kidney cancer, and detects genes preferentially expressed near amyloid-β plaques in an Alzheimer's model.
    DOI:  https://doi.org/10.1038/s41467-025-56280-4
  24. J Clin Invest. 2025 Jan 30. pii: e176865. [Epub ahead of print]
    Monocytes and interstitial macrophages contribute to hypoxic pulmonary hypertension.
    Rahul Kumar, Kevin Nolan, Biruk Kassa, Neha Chanana, Tsering Palmo, Kavita Sharma, Kanika Singh, Claudia Mickael, Dara Fonseca Balladares, Julia Nilsson, Amit Prabhakar, Aastha Mishra, Michael H Lee, Linda Sanders, Sushil Kumar, Ari B Molofsky, Kurt R Stenmark, Dean Sheppard, Rubin M Tuder, Mohit D Gupta, Tashi Thinlas, Qadar Pasha, Brian B Graham.
      Hypoxia is a major cause of pulmonary hypertension (PH) worldwide, and it is likely that interstitial pulmonary macrophages contribute to this vascular pathology. We observed in hypoxia-exposed mice an increase in resident interstitial macrophages, which expanded through proliferation and expressed the monocyte recruitment ligand CCL2. We also observed an increase in CCR2+ macrophages through recruitment, which express the protein thrombospondin-1 that functionally activates TGF-beta to cause vascular disease. Blockade of monocyte recruitment with either CCL2 neutralizing antibody treatment or CCR2 deficiency in the bone marrow compartment suppressed hypoxic PH. These data were supported by analysis of plasma samples from humans who travelled from low (225m) to high (3500m) elevation, revealing an increase in thrombospondin-1 and TGF-beta expression following ascent, which was blocked by dexamethasone prophylaxis. In the hypoxic mouse model, dexamethasone prophylaxis recapitulated these findings by mechanistically suppressing CCL2 expression and CCR2+ monocyte recruitment. These data suggest a pathologic cross-talk between two discrete interstitial macrophage populations, which can be therapeutically targeted.
    Keywords:  Chemokines; Hypoxia; Inflammation; Monocytes; Vascular biology
    DOI:  https://doi.org/10.1172/JCI176865
This page is being maintained by Thomas Krichel. It was last updated on 2025‒02‒02 at 7:02.