bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–09–15
47 papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. Eggs from older mice regain youth when grown in young cells.
  2. Fat absorption controlled by a brain-gut circuit.
  3. Brain region boosts avoidance of unpleasantness and pain - in mice.
  4. Cell-to-cell tunnels rescue neurons from degeneration.
  5. Mitophagy protects against ferroptosis.
  6. A sex-stratified analysis of the genetic architecture of human brain anatomy.
  7. Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology.
  8. Ferroptosis disseminates afar in development.
  9. Lipid recycling by macrophage cells drives the growth of brain cancer.
  10. The wake.
  11. Fur farming a 'viral highway' that could spark next pandemic, say scientists.
  12. Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity.
  13. Long-term longitudinal analysis of 4,187 participants reveals insights into determinants of clonal hematopoiesis.
  14. Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells.
  15. World's first whole-eye transplant: the innovations that made it possible.
  16. Non-invasive metabolic imaging of brown adipose tissue.
  17. Daily briefing: The Doritos dye that makes mouse tissue transparent.
  18. Human intestinal immuno-organoids.
  19. Cell swelling enhances ligand-driven β-adrenergic signaling.
  20. Adipocyte inflammation is the primary driver of hepatic insulin resistance in a human iPSC-based microphysiological system.
  21. IL-2 delivery to CD8+ T cells during infection requires MRTF/SRF-dependent gene expression and cytoskeletal dynamics.
  22. Stromal cell dysfunction contributes to thymic decline in aging.
  23. Incompetent neck valves threaten the aging brain.
  24. A distinct neuronal ensemble of prelimbic cortex mediates spontaneous pain in rats with peripheral inflammation.
  25. Fly-brain connectome helps to make predictions about neural activity.
  26. Cage-like complexes that protect folding proteins visualized in cells.
  27. HIF-2α drives hepatic Kupffer cell death and proinflammatory recruited macrophage activation in nonalcoholic steatohepatitis.
  28. Heterochromatin: Hiding from the remodeling machines.
  29. Hypothalamic SLC7A14 accounts for aging-reduced lipolysis in white adipose tissue of male mice.
  30. Expansion of tumor-reactive CD8+ T cell clonotypes occurs in the spleen in response to immune checkpoint blockade.
  31. Why do we crumble under pressure? Science has the answer.
  32. The burden of a gene.
  33. Ribotoxic stress drives cell death by UV.
  34. Local administration of regulatory T cells promotes tissue healing.
  35. Solid tumour-induced systemic immunosuppression involves dichotomous myeloid-B cell interactions.
  36. RING1 missense variants reveal sensitivity of DNA damage repair to H2A monoubiquitination dosage during neurogenesis.
  37. A pinch of salt boosts T cell function.
  38. Stepwise de novo establishment of inactive X chromosome architecture in early development.
  39. The brain aged more slowly in monkeys given a cheap diabetes drug.
  40. Efferocytosis drives a tryptophan metabolism pathway in macrophages to promote tissue resolution.
  41. RUNX1 interacts with lncRNA SMANTIS to regulate monocytic cell functions.
  42. Variants in LRRC7 lead to intellectual disability, autism, aggression and abnormal eating behaviors.
  43. IL-1β promotes adipogenesis by directly targeting adipocyte precursors.
  44. Endothelial metabolic control of insulin sensitivity through resident macrophages.
  45. A mouse protozoan boosts antigen-specific mucosal IgA responses in a specific lipid metabolism- and signaling-dependent manner.
  46. Targeting APT2 improves MAVS palmitoylation and antiviral innate immunity.
  47. Structure and mechanism of a phosphotransferase system glucose transporter.
  1. Nature. 2024 Sep 09.
    Eggs from older mice regain youth when grown in young cells.
    Smriti Mallapaty.
      
    Keywords:  Ageing; Cell biology
    DOI:  https://doi.org/10.1038/d41586-024-02872-x
  2. Nature. 2024 Sep 11.
    Fat absorption controlled by a brain-gut circuit.
      
    Keywords:  Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-02932-2
  3. Nature. 2024 Sep 12.
    Brain region boosts avoidance of unpleasantness and pain - in mice.
      
    Keywords:  Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-02876-7
  4. Nature. 2024 Sep 11.
    Cell-to-cell tunnels rescue neurons from degeneration.
    Julia F Riley, Erika L F Holzbaur.
      
    Keywords:  Cell biology; Neurodegeneration
    DOI:  https://doi.org/10.1038/d41586-024-02862-z
  5. Nat Cell Biol. 2024 Sep;26(9): 1374
    Mitophagy protects against ferroptosis.
    Petra Gross.
      
    DOI:  https://doi.org/10.1038/s41556-024-01507-7
  6. Nat Commun. 2024 Sep 13. 15(1): 8041
    A sex-stratified analysis of the genetic architecture of human brain anatomy.
    Rebecca Shafee, Dustin Moraczewski, Siyuan Liu, Travis Mallard, Adam Thomas, Armin Raznahan.
      Large biobanks have dramatically advanced our understanding of genetic influences on human brain anatomy. However, most studies have combined rather than compared male and female participants. Here we screen for sex differences in the common genetic architecture of over 1000 neuroanatomical phenotypes in the UK Biobank and establish a general concordance between male and female participants in heritability estimates, genetic correlations, and variant-level effects. Notable exceptions include higher mean heritability in the female group for regional volume and surface area phenotypes; between-sex genetic correlations that are significantly below 1 in the insula and parietal cortex; and a common variant with stronger effect in male participants mapping to RBFOX1 - a gene linked to multiple neuropsychiatric disorders more common in men. This work suggests that common variant influences on human brain anatomy are largely consistent between males and females, with a few exceptions that will guide future research in growing datasets.
    DOI:  https://doi.org/10.1038/s41467-024-52244-2
  7. Nat Commun. 2024 Sep 10. 15(1): 7918
    Entorhinal cortex vulnerability to human APP expression promotes hyperexcitability and tau pathology.
    Annie M Goettemoeller, Emmie Banks, Prateek Kumar, Viktor J Olah, Katharine E McCann, Kelly South, Christina C Ramelow, Anna Eaton, Duc M Duong, Nicholas T Seyfried, David Weinshenker, Srikant Rangaraju, Matthew J M Rowan.
      Preventative treatment for Alzheimer's Disease (AD) is dire, yet mechanisms underlying early regional vulnerability remain unknown. In AD, one of the earliest pathophysiological correlates to cognitive decline is hyperexcitability, which is observed first in the entorhinal cortex. Why hyperexcitability preferentially emerges in specific regions in AD is unclear. Using regional, cell-type-specific proteomics and electrophysiology in wild-type mice, we uncovered a unique susceptibility of the entorhinal cortex to human amyloid precursor protein (hAPP). Entorhinal hyperexcitability resulted from selective vulnerability of parvalbumin (PV) interneurons, with respect to surrounding excitatory neurons. This effect was partially replicated with an APP chimera containing a humanized amyloid-beta sequence. EC hyperexcitability could be ameliorated by co-expression of human Tau with hAPP at the expense of increased pathological tau species, or by enhancing PV interneuron excitability in vivo. This study suggests early interventions targeting inhibitory neurons may protect vulnerable regions from the effects of APP/amyloid and tau pathology.
    DOI:  https://doi.org/10.1038/s41467-024-52297-3
  8. Nat Cell Biol. 2024 Sep;26(9): 1374
    Ferroptosis disseminates afar in development.
    Zhe Wang.
      
    DOI:  https://doi.org/10.1038/s41556-024-01504-w
  9. Nature. 2024 Sep 11.
    Lipid recycling by macrophage cells drives the growth of brain cancer.
    Lisa Sevenich.
      
    Keywords:  Cancer; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-02868-7
  10. Nature. 2024 Sep 11.
    The wake.
    S R Algernon.
      
    Keywords:  Arts; Culture
    DOI:  https://doi.org/10.1038/d41586-024-02924-2
  11. Nature. 2024 Sep 06.
    Fur farming a 'viral highway' that could spark next pandemic, say scientists.
    Smriti Mallapaty.
      
    DOI:  https://doi.org/10.1038/d41586-024-02871-y
  12. Cell. 2024 Sep 02. pii: S0092-8674(24)00898-5. [Epub ahead of print]
    Small-molecule GSDMD agonism in tumors stimulates antitumor immunity without toxicity.
    Pietro Fontana, Gang Du, Ying Zhang, Haiwei Zhang, Setu M Vora, Jun Jacob Hu, Ming Shi, Ahmet B Tufan, Liam B Healy, Shiyu Xia, Dian-Jang Lee, Zhouyihan Li, Pilar Baldominos, Heng Ru, Hongbo R Luo, Judith Agudo, Judy Lieberman, Hao Wu.
      Gasdermin-mediated inflammatory cell death (pyroptosis) can activate protective immunity in immunologically cold tumors. Here, we performed a high-throughput screen for compounds that could activate gasdermin D (GSDMD), which is expressed widely in tumors. We identified 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB) as a direct and selective GSDMD agonist that activates GSDMD pore formation and pyroptosis without cleaving GSDMD. In mouse tumor models, pulsed and low-level pyroptosis induced by DMB suppresses tumor growth without harming GSDMD-expressing immune cells. Protection is immune-mediated and abrogated in mice lacking lymphocytes. Vaccination with DMB-treated cancer cells protects mice from secondary tumor challenge, indicating that immunogenic cell death is induced. DMB treatment synergizes with anti-PD-1. DMB treatment does not alter circulating proinflammatory cytokine or leukocyte numbers or cause weight loss. Thus, our studies reveal a strategy that relies on a low level of tumor cell pyroptosis to induce antitumor immunity and raise the possibility of exploiting pyroptosis without causing overt toxicity.
    Keywords:  GSDMD; GSDMD agonist; antitumor immunity; cancer; checkpoint blockade; gasdermin; immunogenic cell death; immunotherapy; pyroptosis; tumor
    DOI:  https://doi.org/10.1016/j.cell.2024.08.007
  13. Nat Commun. 2024 Sep 09. 15(1): 7858
    Long-term longitudinal analysis of 4,187 participants reveals insights into determinants of clonal hematopoiesis.
    Md Mesbah Uddin, Seyedmohammad Saadatagah, Abhishek Niroula, Bing Yu, Whitney E Hornsby, Shriienidhie Ganesh, Kim Lannery, Art Schuermans, Michael C Honigberg, Alexander G Bick, Peter Libby, Benjamin L Ebert, Christie M Ballantyne, Pradeep Natarajan.
      Clonal hematopoiesis of indeterminate potential (CHIP) is linked to diverse aging-related diseases, including hematologic malignancy and atherosclerotic cardiovascular disease (ASCVD). While CHIP is common among older adults, the underlying factors driving its development are largely unknown. To address this, we performed whole-exome sequencing on 8,374 blood DNA samples collected from 4,187 Atherosclerosis Risk in Communities Study (ARIC) participants over a median follow-up of 21 years. During this period, 735 participants developed incident CHIP. Splicing factor genes (SF3B1, SRSF2, U2AF1, and ZRSR2) and TET2 CHIP grow significantly faster than DNMT3A non-R882 clones. We find that age at baseline and sex significantly influence the incidence of CHIP, while ASCVD and other traditional ASCVD risk factors do not exhibit such associations. Additionally, baseline synonymous passenger mutations are strongly associated with CHIP status and are predictive of new CHIP clone acquisition and clonal growth over extended follow-up, providing valuable insights into clonal dynamics of aging hematopoietic stem and progenitor cells. This study also reveals associations between germline genetic variants and incident CHIP. Our comprehensive longitudinal assessment yields insights into cell-intrinsic and -extrinsic factors contributing to the development and progression of CHIP clones in older adults.
    DOI:  https://doi.org/10.1038/s41467-024-52302-9
  14. Nat Cell Biol. 2024 Sep 11.
    Ammonia-induced lysosomal and mitochondrial damage causes cell death of effector CD8+ T cells.
    Huafeng Zhang, Jincheng Liu, Wu Yuan, Qian Zhang, Xiao Luo, Yonggang Li, Yue'e Peng, Jingyu Feng, Xiaoyu Liu, Jie Chen, Yabo Zhou, Jiadi Lv, Nannan Zhou, Jingwei Ma, Ke Tang, Bo Huang.
      Ammonia is thought to be a cytotoxin and its increase in the blood impairs cell function. However, whether and how this toxin triggers cell death under pathophysiological conditions remains unclear. Here we show that ammonia induces a distinct form of cell death in effector T cells. We found that rapidly proliferating T cells use glutaminolysis to release ammonia in the mitochondria, which is then translocated to and stored in the lysosomes. Excessive ammonia accumulation increases lysosomal pH and results in the termination of lysosomal ammonia storage and ammonia reflux into mitochondria, leading to mitochondrial damage and cell death, which is characterized by lysosomal alkalization, mitochondrial swelling and impaired autophagic flux. Inhibition of glutaminolysis or blocking lysosomal alkalization prevents ammonia-induced T cell death and improves T cell-based antitumour immunotherapy. These findings identify a distinct form of cell death that differs from previously known mechanisms.
    DOI:  https://doi.org/10.1038/s41556-024-01503-x
  15. Nature. 2024 Sep 09.
    World's first whole-eye transplant: the innovations that made it possible.
    Julian Nowogrodzki.
      
    Keywords:  Immunology; Medical research
    DOI:  https://doi.org/10.1038/d41586-024-02906-4
  16. Nat Methods. 2024 Sep;21(9): 1580
    Non-invasive metabolic imaging of brown adipose tissue.
    Jean Nakhle.
      
    DOI:  https://doi.org/10.1038/s41592-024-02422-3
  17. Nature. 2024 Sep 06.
    Daily briefing: The Doritos dye that makes mouse tissue transparent.
    Flora Graham.
      
    DOI:  https://doi.org/10.1038/d41586-024-02941-1
  18. Nat Genet. 2024 Sep;56(9): 1765
    Human intestinal immuno-organoids.
    Chiara Anania.
      
    DOI:  https://doi.org/10.1038/s41588-024-01927-z
  19. Nat Commun. 2024 Sep 07. 15(1): 7822
    Cell swelling enhances ligand-driven β-adrenergic signaling.
    Alexei Sirbu, Marc Bathe-Peters, Jothi L M Kumar, Asuka Inoue, Martin J Lohse, Paolo Annibale.
      G protein-coupled receptors' conformational landscape can be affected by their local, microscopic interactions within the cell plasma membrane. We employ here a pleiotropic stimulus, namely osmotic swelling, to alter the cortical environment within intact cells and monitor the response in terms of receptor function and downstream signaling. We observe that in osmotically swollen cells the β2-adrenergic receptor, a prototypical GPCR, favors an active conformation, resulting in cAMP transient responses to adrenergic stimulation that have increased amplitude. The results are validated in primary cell types such as adult cardiomyocytes, a model system where swelling occurs upon ischemia-reperfusion injury. Our results suggest that receptors' function is finely modulated by their biophysical context, and specifically that osmotic swelling acts as a potentiator of downstream signaling, not only for the β2-adrenergic receptor, but also for other receptors, hinting at a more general regulatory mechanism.
    DOI:  https://doi.org/10.1038/s41467-024-52191-y
  20. Nat Commun. 2024 Sep 12. 15(1): 7991
    Adipocyte inflammation is the primary driver of hepatic insulin resistance in a human iPSC-based microphysiological system.
    Lin Qi, Marko Groeger, Aditi Sharma, Ishan Goswami, Erzhen Chen, Fenmiao Zhong, Apsara Ram, Kevin Healy, Edward C Hsiao, Holger Willenbring, Andreas Stahl.
      Interactions between adipose tissue, liver and immune system are at the center of metabolic dysfunction-associated steatotic liver disease and type 2 diabetes. To address the need for an accurate in vitro model, we establish an interconnected microphysiological system (MPS) containing white adipocytes, hepatocytes and proinflammatory macrophages derived from isogenic human induced pluripotent stem cells. Using this MPS, we find that increasing the adipocyte-to-hepatocyte ratio moderately affects hepatocyte function, whereas macrophage-induced adipocyte inflammation causes lipid accumulation in hepatocytes and MPS-wide insulin resistance, corresponding to initiation of metabolic dysfunction-associated steatotic liver disease. We also use our MPS to identify and characterize pharmacological intervention strategies for hepatic steatosis and systemic insulin resistance and find that the glucagon-like peptide-1 receptor agonist semaglutide improves hepatocyte function by acting specifically on adipocytes. These results establish our MPS modeling the adipose tissue-liver axis as an alternative to animal models for mechanistic studies or drug discovery in metabolic diseases.
    DOI:  https://doi.org/10.1038/s41467-024-52258-w
  21. Nat Commun. 2024 Sep 11. 15(1): 7956
    IL-2 delivery to CD8+ T cells during infection requires MRTF/SRF-dependent gene expression and cytoskeletal dynamics.
    Diane Maurice, Patrick Costello, Jessica Diring, Francesco Gualdrini, Bruno Frederico, Richard Treisman.
      Paracrine IL-2 signalling drives the CD8 + T cell expansion and differentiation that allow protection against viral infections, but the underlying molecular events are incompletely understood. Here we show that the transcription factor SRF, a master regulator of cytoskeletal gene expression, is required for effective IL-2 signalling during L. monocytogenes infection. Acting cell-autonomously with its actin-regulated cofactors MRTF-A and MRTF-B, SRF is dispensible for initial TCR-mediated CD8+ T cell proliferation, but is required for sustained IL-2 dependent CD8+ effector T cell expansion, and persistence of memory cells. Following TCR activation, Mrtfab-null CD8+ T cells produce IL-2 normally, but homotypic clustering is impaired both in vitro and in vivo. Expression of cytoskeletal structural and regulatory genes, most notably actins, is defective in Mrtfab-null CD8+ T cells. Activation-induced cell clustering in vitro requires F-actin assembly, and Mrtfab-null cell clusters are small, contain less F-actin, and defective in IL-2 retention. Clustering of Mrtfab-null cells can be partially restored by exogenous actin expression. IL-2 mediated CD8+ T cell proliferation during infection thus depends on the control of cytoskeletal dynamics and actin gene expression by MRTF-SRF signalling.
    DOI:  https://doi.org/10.1038/s41467-024-52230-8
  22. Nat Aging. 2024 Sep 06.
    Stromal cell dysfunction contributes to thymic decline in aging.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-024-00711-2
  23. Nat Aging. 2024 Sep 11.
    Incompetent neck valves threaten the aging brain.
    Monica M Santisteban, Costantino Iadecola.
      
    DOI:  https://doi.org/10.1038/s43587-024-00707-y
  24. Nat Commun. 2024 Sep 10. 15(1): 7922
    A distinct neuronal ensemble of prelimbic cortex mediates spontaneous pain in rats with peripheral inflammation.
    Longyu Ma, Lupeng Yue, Shuting Liu, Shi Xu, Jifu Tong, Xiaoyan Sun, Li Su, Shuang Cui, Feng-Yu Liu, You Wan, Ming Yi.
      The absence of a comprehensive understanding of the neural basis of spontaneous pain limits the development of therapeutic strategies targeting this primary complaint of patients with chronic pain. Here we report a distinct neuronal ensemble within the prelimbic cortex which processes signals related to spontaneous pain in rats with chronic inflammatory pain. This neuronal ensemble specifically encodes spontaneous pain-related behaviors, independently of other locomotive and evoked behaviors. Activation of this neuronal ensemble elicits marked spontaneous pain-like behaviors and enhances nociceptive responses, whereas prolonged silencing of its activities alleviates spontaneous pain and promotes overall recovery from inflammatory pain. Notably, afferents from the primary somatosensory cortex and infralimbic cortex bidirectionally modulate the activities of the spontaneous pain-responsive prelimbic cortex neuronal ensemble and pain behaviors. These findings reveal the cortical basis of spontaneous pain at the neuronal level, highlighting a distinct neuronal ensemble within the prelimbic cortex and its associated pain-regulatory brain networks.
    DOI:  https://doi.org/10.1038/s41467-024-52243-3
  25. Nature. 2024 Sep 11.
    Fly-brain connectome helps to make predictions about neural activity.
      
    Keywords:  Machine learning; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-02935-z
  26. Nature. 2024 Sep 11.
    Cage-like complexes that protect folding proteins visualized in cells.
      
    Keywords:  Cell biology; Structural biology
    DOI:  https://doi.org/10.1038/d41586-024-02926-0
  27. Sci Transl Med. 2024 Sep 11. 16(764): eadi0284
    HIF-2α drives hepatic Kupffer cell death and proinflammatory recruited macrophage activation in nonalcoholic steatohepatitis.
    Ishtiaq Jeelani, Jae-Su Moon, Flavia Franco da Cunha, Chanond A Nasamran, Seokhyun Jeon, Xinhang Zhang, Gautam K Bandyopadhyay, Katarzyna Dobaczewska, Zbigniew Mikulski, Mojgan Hosseini, Xiao Liu, Tatiana Kisseleva, David A Brenner, Seema Singh, Rohit Loomba, Minkyu Kim, Yun Sok Lee.
      Proinflammatory hepatic macrophage activation plays a key role in the development of nonalcoholic steatohepatitis (NASH). This involves increased embryonic hepatic Kupffer cell (KC) death, facilitating the replacement of KCs with bone marrow-derived recruited hepatic macrophages (RHMs) that highly express proinflammatory genes. Moreover, phago/efferocytic activity of KCs is diminished in NASH, enhancing liver inflammation. However, the molecular mechanisms underlying these changes in KCs are not known. Here, we show that hypoxia-inducible factor 2α (HIF-2α) mediates NASH-associated decreased KC growth and efferocytosis by enhancing lysosomal stress. At the molecular level, HIF-2α stimulated mammalian target of rapamycin (mTOR)- and extracellular signal-regulated kinase-dependent inhibitory transcription factor EB (TFEB) phosphorylation, leading to decreased lysosomal and phagocytic gene expression. With increased metabolic stress and phago/efferocytic burden in NASH, these changes were sufficient to increase lysosomal stress, causing decreased efferocytosis and lysosomal cell death. Of interest, HIF-2α-dependent TFEB regulation only occurred in KCs but not RHMs. Instead, in RHMs, HIF-2α promoted mitochondrial reactive oxygen species production and proinflammatory activation by increasing ANT2 expression and mitochondrial permeability transition. Consequently, myeloid lineage-specific or KC-specific HIF-2α depletion or the inhibition of mTOR-dependent TFEB inhibition using antisense oligonucleotide treatment protected against the development of NASH in mice. Moreover, treatment with an HIF-2α-specific inhibitor reduced inflammatory and fibrogenic gene expression in human liver spheroids cultured under a NASH-like condition. Together, our results suggest that macrophage subtype-specific effects of HIF-2α collectively contribute to the proinflammatory activation of liver macrophages, leading to the development of NASH.
    DOI:  https://doi.org/10.1126/scitranslmed.adi0284
  28. Mol Cell. 2024 Sep 05. pii: S1097-2765(24)00666-X. [Epub ahead of print]84(17): 3167-3169
    Heterochromatin: Hiding from the remodeling machines.
    Craig L Peterson.
      In this issue of Molecular Cell, Sahu et al.1 find that shielding heterochromatin from SWI/SNF chromatin remodelers is essential to maintain and epigenetically propagate pre-existing heterochromatin domains, whereas SWI/SNF action protects facultative heterochromatic regions from premature silencing.
    DOI:  https://doi.org/10.1016/j.molcel.2024.08.012
  29. Nat Commun. 2024 Sep 11. 15(1): 7948
    Hypothalamic SLC7A14 accounts for aging-reduced lipolysis in white adipose tissue of male mice.
    Xiaoxue Jiang, Kan Liu, Peixiang Luo, Zi Li, Fei Xiao, Haizhou Jiang, Shangming Wu, Min Tang, Feixiang Yuan, Xiaoying Li, Yousheng Shu, Bo Peng, Shanghai Chen, Shihong Ni, Feifan Guo.
      The central nervous system has been implicated in the age-induced reduction in adipose tissue lipolysis. However, the underlying mechanisms remain unclear. Here, we show the expression of SLC7A14 is reduced in proopiomelanocortin (POMC) neurons of aged mice. Overexpression of SLC7A14 in POMC neurons alleviates the aging-reduced lipolysis, whereas SLC7A14 deletion mimics the age-induced lipolysis impairment. Metabolomics analysis reveals that POMC SLC7A14 increased taurochenodeoxycholic acid (TCDCA) content, which mediates the SLC7A14 knockout- or age-induced WAT lipolysis impairment. Furthermore, SLC7A14-increased TCDCA content is dependent on intestinal apical sodium-dependent bile acid transporter (ASBT), which is regulated by intestinal sympathetic afferent nerves. Finally, SLC7A14 regulates the intestinal sympathetic afferent nerves by inhibiting mTORC1 signaling through inhibiting TSC1 phosphorylation. Collectively, our study suggests the function for central SLC7A14 and an upstream mechanism for the mTORC1 signaling pathway. Moreover, our data provides insights into the brain-gut-adipose tissue crosstalk in age-induced lipolysis impairment.
    DOI:  https://doi.org/10.1038/s41467-024-52059-1
  30. Sci Immunol. 2024 Sep 13. 9(99): eadi3487
    Expansion of tumor-reactive CD8+ T cell clonotypes occurs in the spleen in response to immune checkpoint blockade.
    Duncan M Morgan, Brendan L Horton, Vidit Bhandarkar, Richard Van, Teresa Dinter, Maria Zagorulya, J Christopher Love, Stefani Spranger.
      Immune checkpoint blockade (ICB) enhances T cell responses against cancer, leading to long-term survival in a fraction of patients. CD8+ T cell differentiation in response to chronic antigen stimulation is highly complex, and it remains unclear precisely which T cell differentiation states at which anatomic sites are critical for the response to ICB. We identified an intermediate-exhausted population in the white pulp of the spleen that underwent substantial expansion in response to ICB and gave rise to tumor-infiltrating clonotypes. Increased systemic antigen redirected differentiation of this population toward a more circulatory exhausted KLR state, whereas a lack of cross-presented tumor antigen reduced its differentiation in the spleen. An analogous population of exhausted KLR CD8+ T cells in human blood samples exhibited diminished tumor-trafficking ability. Collectively, our data demonstrate the critical role of antigen density within the spleen for the differentiation and expansion of T cell clonotypes in response to ICB.
    DOI:  https://doi.org/10.1126/sciimmunol.adi3487
  31. Nature. 2024 Sep 12.
    Why do we crumble under pressure? Science has the answer.
    Jude Coleman.
      
    DOI:  https://doi.org/10.1038/d41586-024-02956-8
  32. Science. 2024 Sep 13. 385(6714): 1154-1157
    The burden of a gene.
    Jocelyn Kaiser.
      A variant called APOE4 is notorious for its link to Alzheimer's. Can new insights into its function help stave off disease?
    DOI:  https://doi.org/10.1126/science.adt0510
  33. Nat Cell Biol. 2024 Sep;26(9): 1374
    Ribotoxic stress drives cell death by UV.
    Petra Gross.
      
    DOI:  https://doi.org/10.1038/s41556-024-01506-8
  34. Nat Commun. 2024 Sep 09. 15(1): 7863
    Local administration of regulatory T cells promotes tissue healing.
    Bhavana Nayer, Jean L Tan, Yasmin K Alshoubaki, Yen-Zhen Lu, Julien M D Legrand, Sinnee Lau, Nan Hu, Anthony J Park, Xiao-Nong Wang, Daniela Amann-Zalcenstein, Peter F Hickey, Trevor Wilson, Gisela A Kuhn, Ralph Müller, Ajithkumar Vasanthakumar, Shizuo Akira, Mikaël M Martino.
      Regulatory T cells (Tregs) are crucial immune cells for tissue repair and regeneration. However, their potential as a cell-based regenerative therapy is not yet fully understood. Here, we show that local delivery of exogenous Tregs into injured mouse bone, muscle, and skin greatly enhances tissue healing. Mechanistically, exogenous Tregs rapidly adopt an injury-specific phenotype in response to the damaged tissue microenvironment, upregulating genes involved in immunomodulation and tissue healing. We demonstrate that exogenous Tregs exert their regenerative effect by directly and indirectly modulating monocytes/macrophages (Mo/MΦ) in injured tissues, promoting their switch to an anti-inflammatory and pro-healing state via factors such as interleukin (IL)-10. Validating the key role of IL-10 in exogenous Treg-mediated repair and regeneration, the pro-healing capacity of these cells is lost when Il10 is knocked out. Additionally, exogenous Tregs reduce neutrophil and cytotoxic T cell accumulation and IFN-γ production in damaged tissues, further dampening the pro-inflammatory Mo/MΦ phenotype. Highlighting the potential of this approach, we demonstrate that allogeneic and human Tregs also promote tissue healing. Together, this study establishes exogenous Tregs as a possible universal cell-based therapy for regenerative medicine and provides key mechanistic insights that could be harnessed to develop immune cell-based therapies to enhance tissue healing.
    DOI:  https://doi.org/10.1038/s41467-024-51353-2
  35. Nat Cell Biol. 2024 Sep 12.
    Solid tumour-induced systemic immunosuppression involves dichotomous myeloid-B cell interactions.
    Xiaoxin Hao, Yichao Shen, Jun Liu, Angela Alexander, Ling Wu, Zhan Xu, Liqun Yu, Yang Gao, Fengshuo Liu, Hilda L Chan, Che-Hsing Li, Yunfeng Ding, Weijie Zhang, David G Edwards, Nan Chen, Azadeh Nasrazadani, Naoto T Ueno, Bora Lim, Xiang H-F Zhang.
      Solid tumours induce systemic immunosuppression that involves myeloid and T cells. B cell-related mechanisms remain relatively understudied. Here we discover two distinct patterns of tumour-induced B cell abnormality (TiBA; TiBA-1 and TiBA-2), both associated with abnormal myelopoiesis in the bone marrow. TiBA-1 probably results from the niche competition between pre-progenitor-B cells and myeloid progenitors, leading to a global reduction in downstream B cells. TiBA-2 is characterized by systemic accumulation of a unique early B cell population, driven by interaction with excessive neutrophils. Importantly, TiBA-2-associated early B cells foster the systemic accumulation of exhaustion-like T cells. Myeloid and B cells from the peripheral blood of patients with triple-negative breast cancer recapitulate the TiBA subtypes, and the distinct TiBA profile correlates with pathologic complete responses to standard-of-care immunotherapy. This study underscores the inter-patient diversity of tumour-induced systemic changes and emphasizes the need for treatments tailored to different B and myeloid cell abnormalities.
    DOI:  https://doi.org/10.1038/s41556-024-01508-6
  36. Nat Commun. 2024 Sep 10. 15(1): 7931
    RING1 missense variants reveal sensitivity of DNA damage repair to H2A monoubiquitination dosage during neurogenesis.
    C W Ryan, S L Regan, E F Mills, B T McGrath, E Gong, Y T Lai, J B Sheingold, K Patel, T Horowitz, A Moccia, Y C Tsan, A Srivastava, S L Bielas.
      Polycomb repressive complex 1 (PRC1) modifies chromatin through catalysis of histone H2A lysine 119 monoubiquitination (H2AK119ub1). RING1 and RNF2 interchangeably serve as the catalytic subunit within PRC1. Pathogenic missense variants in PRC1 core components reveal functions of these proteins that are obscured in knockout models. While Ring1a knockout models remain healthy, the microcephaly and neuropsychiatric phenotypes associated with a pathogenic RING1 missense variant implicate unappreciated functions. Using an in vitro model of neurodevelopment, we observe that RING1 contributes to the broad placement of H2AK119ub1, and that its targets overlap with those of RNF2. PRC1 complexes harboring hypomorphic RING1 bind target loci but do not catalyze H2AK119ub1, reducing H2AK119ub1 by preventing catalytically active complexes from accessing the locus. This results in delayed DNA damage repair and cell cycle progression in neural progenitor cells (NPCs). Conversely, reduced H2AK119ub1 due to hypomorphic RING1 does not generate differential expression that impacts NPC differentiation. In contrast, hypomorphic RNF2 generates a greater reduction in H2AK119ub1 that results in both delayed DNA repair and widespread transcriptional changes. These findings suggest that the DNA damage response is more sensitive to H2AK119ub1 dosage change than is regulation of gene expression.
    DOI:  https://doi.org/10.1038/s41467-024-52292-8
  37. Nat Immunol. 2024 Sep 09.
    A pinch of salt boosts T cell function.
    Karina L Hajdu, Lorène Rousseau, Ping-Chih Ho.
      
    DOI:  https://doi.org/10.1038/s41590-024-01946-2
  38. Nat Genet. 2024 Sep 10.
    Stepwise de novo establishment of inactive X chromosome architecture in early development.
    Zhenhai Du, Liangjun Hu, Zhuoning Zou, Meishuo Liu, Zihan Li, Xukun Lu, Clair Harris, Yunlong Xiang, Fengling Chen, Guang Yu, Kai Xu, Feng Kong, Qianhua Xu, Bo Huang, Ling Liu, Qiang Fan, Haifeng Wang, Sundeep Kalantry, Wei Xie.
      X chromosome inactivation triggers a dramatic reprogramming of transcription and chromosome architecture. However, how the chromatin organization of inactive X chromosome is established de novo in vivo remains elusive. Here, we identified an Xist-separated megadomain structure (X-megadomains) on the inactive X chromosome in mouse extraembryonic lineages and extraembryonic endoderm (XEN) cell lines, and transiently in the embryonic lineages, before Dxz4-delineated megadomain formation at later stages in a strain-specific manner. X-megadomain boundary coincides with strong enhancer activities and cohesin binding in an Xist regulatory region required for proper Xist activation in early embryos. Xist regulatory region disruption or cohesin degradation impaired X-megadomains in extraembryonic endoderm cells and caused ectopic activation of regulatory elements and genes near Xist, indicating that cohesin loading at regulatory elements promotes X-megadomains and confines local gene activities. These data reveal stepwise X chromosome folding and transcriptional regulation to achieve both essential gene activation and global silencing during the early stages of X chromosome inactivation.
    DOI:  https://doi.org/10.1038/s41588-024-01897-2
  39. Nature. 2024 Sep 12.
    The brain aged more slowly in monkeys given a cheap diabetes drug.
    Max Kozlov.
      
    Keywords:  Ageing; Brain; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-02938-w
  40. Nat Metab. 2024 Sep 06.
    Efferocytosis drives a tryptophan metabolism pathway in macrophages to promote tissue resolution.
    Santosh R Sukka, Patrick B Ampomah, Lancia N F Darville, David Ngai, Xiaobo Wang, George Kuriakose, Yuling Xiao, Jinjun Shi, John M Koomen, Robert H McCusker, Ira Tabas.
      Macrophage efferocytosis prevents apoptotic cell (AC) accumulation and triggers inflammation-resolution pathways. The mechanisms linking efferocytosis to resolution often involve changes in macrophage metabolism, but many gaps remain in our understanding of these processes. We now report that efferocytosis triggers an indoleamine 2,3-dioxygenase-1 (IDO1)-dependent tryptophan (Trp) metabolism pathway that promotes several key resolution processes, including the induction of pro-resolving proteins, such interleukin-10, and further enhancement of efferocytosis. The process begins with upregulation of Trp transport and metabolism, and it involves subsequent activation of the aryl hydrocarbon receptor (AhR) by the Trp metabolite kynurenine (Kyn). Through these mechanisms, macrophage IDO1 and AhR contribute to a proper resolution response in several different mouse models of efferocytosis-dependent tissue repair, notably during atherosclerosis regression induced by plasma low-density lipoprotein (LDL) lowering. These findings reveal an integrated metabolism programme in macrophages that links efferocytosis to resolution, with possible therapeutic implications for non-resolving chronic inflammatory diseases, notably atherosclerosis.
    DOI:  https://doi.org/10.1038/s42255-024-01115-7
  41. Commun Biol. 2024 Sep 13. 7(1): 1131
    RUNX1 interacts with lncRNA SMANTIS to regulate monocytic cell functions.
    Lisa M Weiss, Timothy Warwick, Simonida Zehr, Stefan Günther, Sebastian Wolf, Tessa Schmachtel, Judit Izquierdo Ponce, Katalin Pálfi, Tom Teichmann, Alicia Schneider, Julia Stötzel, Stefan Knapp, Andreas Weigert, Rajkumar Savai, Michael A Rieger, Thomas Oellerich, Ilka Wittig, James A Oo, Ralf P Brandes, Matthias S Leisegang.
      Monocytes, the circulating macrophage precursors, contribute to diseases like atherosclerosis and asthma. Long non-coding RNAs (lncRNAs) have been shown to modulate the phenotype and inflammatory capacity of monocytes. We previously discovered the lncRNA SMANTIS, which contributes to cellular phenotype expression by controlling BRG1 in mesenchymal cells. Here, we report that SMANTIS is particularly highly expressed in monocytes and lost during differentiation into macrophages. Moreover, different types of myeloid leukemia presented specific SMANTIS expression patterns. Interaction studies revealed that SMANTIS binds RUNX1, a transcription factor frequently mutated in AML, primarily through its Alu-element on the RUNT domain. RNA-seq after CRISPR/Cas9-mediated deletion of SMANTIS or RUNX1 revealed an association with cell adhesion and both limited the monocyte adhesion to endothelial cells. Mechanistically, SMANTIS KO reduced RUNX1 genomic binding and altered the interaction of RUNX1 with EP300 and CBFB. Collectively, SMANTIS interacts with RUNX1 and attenuates monocyte adhesion, which might limit monocyte vascular egress.
    DOI:  https://doi.org/10.1038/s42003-024-06794-2
  42. Nat Commun. 2024 Sep 10. 15(1): 7909
    Variants in LRRC7 lead to intellectual disability, autism, aggression and abnormal eating behaviors.
    Undiagnosed Diseases Network
      Members of the leucine rich repeat (LRR) and PDZ domain (LAP) protein family are essential for animal development and histogenesis. Densin-180, encoded by LRRC7, is the only LAP protein selectively expressed in neurons. Densin-180 is a postsynaptic scaffold at glutamatergic synapses, linking cytoskeletal elements with signalling proteins such as the α-subunit of Ca2+/calmodulin-dependent protein kinase II. We have previously observed an association between high impact variants in LRRC7 and Intellectual Disability; also three individual cases with variants in LRRC7 had been described. We identify here 33 individuals (one of them previously described) with a dominant neurodevelopmental disorder due to heterozygous missense or loss-of-function variants in LRRC7. The clinical spectrum involves intellectual disability, autism, ADHD, aggression and, in several cases, hyperphagia-associated obesity. A PDZ domain variant interferes with synaptic targeting of Densin-180 in primary cultured neurons. Using in vitro systems (two hybrid, BioID, coimmunoprecipitation of tagged proteins from 293T cells) we identified new candidate interaction partners for the LRR domain, including protein phosphatase 1 (PP1), and observed that variants in the LRR reduced binding to these proteins. We conclude that LRRC7 encodes a major determinant of intellectual development and behaviour.
    DOI:  https://doi.org/10.1038/s41467-024-52095-x
  43. Nat Commun. 2024 Sep 11. 15(1): 7957
    IL-1β promotes adipogenesis by directly targeting adipocyte precursors.
    Kaisa Hofwimmer, Joyce de Paula Souza, Narmadha Subramanian, Milica Vujičić, Leila Rachid, Hélène Méreau, Cheng Zhao, Erez Dror, Emelie Barreby, Niklas K Björkström, Ingrid Wernstedt Asterholm, Marianne Böni-Schnetzler, Daniel T Meier, Marc Y Donath, Jurga Laurencikiene.
      Postprandial IL-1β surges are predominant in the white adipose tissue (WAT), but its consequences are unknown. Here, we investigate the role of IL-1β in WAT energy storage and show that adipocyte-specific deletion of IL-1 receptor 1 (IL1R1) has no metabolic consequences, whereas ubiquitous lack of IL1R1 reduces body weight, WAT mass, and adipocyte formation in mice. Among all major WAT-resident cell types, progenitors express the highest IL1R1 levels. In vitro, IL-1β potently promotes adipogenesis in murine and human adipose-derived stem cells. This effect is exclusive to early-differentiation-stage cells, in which the adipogenic transcription factors C/EBPδ and C/EBPβ are rapidly upregulated by IL-1β and enriched near important adipogenic genes. The pro-adipogenic, but not pro-inflammatory effect of IL-1β is potentiated by acute treatment and blocked by chronic exposure. Thus, we propose that transient postprandial IL-1β surges regulate WAT remodeling by promoting adipogenesis, whereas chronically elevated IL-1β levels in obesity blunts this physiological function.
    DOI:  https://doi.org/10.1038/s41467-024-51938-x
  44. Cell Metab. 2024 Sep 08. pii: S1550-4131(24)00335-8. [Epub ahead of print]
    Endothelial metabolic control of insulin sensitivity through resident macrophages.
    Jing Zhang, Kim Anker Sjøberg, Songlin Gong, Tongtong Wang, Fengqi Li, Andrew Kuo, Stephan Durot, Adam Majcher, Raphaela Ardicoglu, Thibaut Desgeorges, Charlotte Greta Mann, Ines Soro Arnáiz, Gillian Fitzgerald, Paola Gilardoni, E Dale Abel, Shigeyuki Kon, Danyvid Olivares-Villagómez, Nicola Zamboni, Christian Wolfrum, Thorsten Hornemann, Raphael Morscher, Nathalie Tisch, Bart Ghesquière, Manfred Kopf, Erik A Richter, Katrien De Bock.
      Endothelial cells (ECs) not only form passive blood conduits but actively contribute to nutrient transport and organ homeostasis. The role of ECs in glucose homeostasis is, however, poorly understood. Here, we show that, in skeletal muscle, endothelial glucose transporter 1 (Glut1/Slc2a1) controls glucose uptake via vascular metabolic control of muscle-resident macrophages without affecting transendothelial glucose transport. Lowering endothelial Glut1 via genetic depletion (Glut1ΔEC) or upon a short-term high-fat diet increased angiocrine osteopontin (OPN/Spp1) secretion. This promoted resident muscle macrophage activation and proliferation, which impaired muscle insulin sensitivity. Consequently, co-deleting Spp1 from ECs prevented macrophage accumulation and improved insulin sensitivity in Glut1ΔEC mice. Mechanistically, Glut1-dependent endothelial glucose metabolic rewiring increased OPN in a serine metabolism-dependent fashion. Our data illustrate how the glycolytic endothelium creates a microenvironment that controls resident muscle macrophage phenotype and function and directly links resident muscle macrophages to the maintenance of muscle glucose homeostasis.
    Keywords:  GLUT1; endothelial cells; endothelial metabolism; inflammation; insulin sensitivity; osteopontin; resident macrophages; serine; skeletal muscle; vasculature
    DOI:  https://doi.org/10.1016/j.cmet.2024.08.008
  45. Nat Commun. 2024 Sep 10. 15(1): 7914
    A mouse protozoan boosts antigen-specific mucosal IgA responses in a specific lipid metabolism- and signaling-dependent manner.
    Yanbo Kou, Shenghan Zhang, Junru Chen, Yusi Shen, Zhiwei Zhang, Haohan Huang, Yulu Ma, Yaoyao Xiang, Longxiang Liao, Junyang Zhou, Wanpeng Cheng, Yuan Zhou, Huan Yang, Zhuanzhuan Liu, Yanxia Wei, Hui Wang, Yugang Wang.
      IgA antibodies play an important role in mucosal immunity. However, there is still no effective way to consistently boost mucosal IgA responses, and the factors influencing these responses are not fully understood. We observed that colonization with the murine intestinal symbiotic protozoan Tritrichomonas musculis (T.mu) boosted antigen-specific mucosal IgA responses in wild-type C57BL/6 mice. This enhancement was attributed to the accumulation of free arachidonic acid (ARA) in the intestinal lumen, which served as a signal to stimulate the production of antigen-specific mucosal IgA. When ARA was prevented from undergoing its downstream metabolic transformation using the 5-lipoxygenase inhibitor zileuton or by blocking its downstream biological signaling through genetic deletion of the Leukotriene B4 receptor 1 (Blt1), the T.mu-mediated enhancement of antigen-specific mucosal IgA production was suppressed. Moreover, both T.mu transfer and dietary supplementation of ARA augmented the efficacy of an oral vaccine against Salmonella infection, with this effect being dependent on Blt1. Our findings elucidate a tripartite circuit linking nutrients from the diet or intestinal microbiota, host lipid metabolism, and the mucosal humoral immune response.
    DOI:  https://doi.org/10.1038/s41467-024-52336-z
  46. Mol Cell. 2024 Sep 06. pii: S1097-2765(24)00668-3. [Epub ahead of print]
    Targeting APT2 improves MAVS palmitoylation and antiviral innate immunity.
    Lang Bu, Huan Wang, Shuishen Zhang, Yi Zhang, Miaowen Liu, Zhengkun Zhang, Xueji Wu, Qiwei Jiang, Lei Wang, Wei Xie, Miao He, Zhengran Zhou, Chao Cheng, Jianping Guo.
      Innate immunity serves as the primary defense against viral and microbial infections in humans. The precise influence of cellular metabolites, especially fatty acids, on antiviral innate immunity remains largely elusive. Here, through screening a metabolite library, palmitic acid (PA) has been identified as a key modulator of antiviral infections in human cells. Mechanistically, PA induces mitochondrial antiviral signaling protein (MAVS) palmitoylation, aggregation, and subsequent activation, thereby enhancing the innate immune response. The palmitoyl-transferase ZDHHC24 catalyzes MAVS palmitoylation, thereby boosting the TBK1-IRF3-interferon (IFN) pathway, particularly under conditions of PA stimulation or high-fat-diet-fed mouse models, leading to antiviral immune responses. Additionally, APT2 de-palmitoylates MAVS, thus inhibiting antiviral signaling, suggesting that its inhibitors, such as ML349, effectively reverse MAVS activation in response to antiviral infections. These findings underscore the critical role of PA in regulating antiviral innate immunity through MAVS palmitoylation and provide strategies for enhancing PA intake or targeting APT2 for combating viral infections.
    Keywords:  APT2; MAVS; ZDHHC24; innate immunity; palmitoylation
    DOI:  https://doi.org/10.1016/j.molcel.2024.08.014
  47. Nat Commun. 2024 Sep 12. 15(1): 7992
    Structure and mechanism of a phosphotransferase system glucose transporter.
    Patrick Roth, Jean-Marc Jeckelmann, Inken Fender, Zöhre Ucurum, Thomas Lemmin, Dimitrios Fotiadis.
      Glucose is the primary source of energy for many organisms and is efficiently taken up by bacteria through a dedicated transport system that exhibits high specificity. In Escherichia coli, the glucose-specific transporter IICBGlc serves as the major glucose transporter and functions as a component of the phosphoenolpyruvate-dependent phosphotransferase system. Here, we report cryo-electron microscopy (cryo-EM) structures of the glucose-bound IICBGlc protein. The dimeric transporter embedded in lipid nanodiscs was captured in the occluded, inward- and occluded, outward-facing conformations. Together with biochemical and biophysical analyses, and molecular dynamics (MD) simulations, we provide insights into the molecular basis and dynamics for substrate recognition and binding, including the gates regulating the binding sites and their accessibility. By combination of these findings, we present a mechanism for glucose transport across the plasma membrane. Overall, this work provides molecular insights into the structure, dynamics, and mechanism of the IICBGlc transporter in a native-like lipid environment.
    DOI:  https://doi.org/10.1038/s41467-024-52100-3
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