bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2024–11–10
thirty papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. How 'miracle' weight-loss drugs will change the world.
  2. CLSTN3B promotes lipid droplet maturation and lipid storage in mouse adipocytes.
  3. Recognition of BACH1 quaternary structure degrons by two F-box proteins under oxidative stress.
  4. Alcohol's necessary accessory.
  5. Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
  6. Diabetes, IL-10 and the brain's microvascular crisis.
  7. Cytosolic N6AMT1-dependent translation supports mitochondrial RNA processing.
  8. Plasma protein-based organ-specific aging and mortality models unveil diseases as accelerated aging of organismal systems.
  9. CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner.
  10. A new kind of mitochondrion.
  11. Dietary nucleic acids promote oral tolerance through innate sensing pathways in mice.
  12. Decoding the epigenetics and chromatin loop dynamics of androgen receptor-mediated transcription.
  13. COQ6 defies immune and metabolic expectations.
  14. Fat keeps metabolism in tune and on time using an inflammatory immune protein.
  15. Chromatin structure and 3D architecture define the differential functions of PU.1 regulatory elements in blood cell lineages.
  16. KLF13 promotes SLE pathogenesis by modifying chromatin accessibility of key proinflammatory cytokine genes.
  17. Science communication will benefit from research integrity standards.
  18. Learning-associated astrocyte ensembles regulate memory recall.
  19. AS160 is a lipid-responsive regulator of cardiac Ca2+ homeostasis by controlling lysophosphatidylinositol metabolism and signaling.
  20. How I hunt down fake degrees and zombie universities.
  21. Prostaglandin E2-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells.
  22. Resolvin D2/GPR 18 axis ameliorates pressure overload-induced heart failure by inhibiting pro-inflammatory macrophage polarization.
  23. Phenotypic and genetic characteristics of retinal vascular parameters and their association with diseases.
  24. Inborn errors of immunity caused by dominant negative interference by a BCL11B variant.
  25. A pathogenic role for IL-10 signalling in capillary stalling and cognitive impairment in type 1 diabetes.
  26. Cat brains age like ours - and could help scientists to understand cognitive decline.
  27. Genetic variants explain ancestry-related differences in type 2 diabetes risk.
  28. Blood markers for type-1,-2, and -3 inflammation are associated with severity of acutely decompensated cirrhosis.
  29. PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity.
  30. HIV-1 remission following stem cell transplant without CCR5Δ32 mutation.
  1. Nature. 2024 Nov;635(8037): 22-24
    How 'miracle' weight-loss drugs will change the world.
    Sara Reardon.
      
    Keywords:  Drug discovery; Economics; Obesity; Society
    DOI:  https://doi.org/10.1038/d41586-024-03589-7
  2. Nat Commun. 2024 Nov 02. 15(1): 9475
    CLSTN3B promotes lipid droplet maturation and lipid storage in mouse adipocytes.
    Chuanhai Zhang, Mengchen Ye, Kamran Melikov, Dengbao Yang, Goncalo Dias do Vale, Jeffrey McDonald, Kaitlyn Eckert, Mei-Jung Lin, Xing Zeng.
      Interorganelle contacts facilitate material exchanges and sustain the structural and functional integrity of organelles. Lipid droplets (LDs) of adipocytes are responsible for energy storage and mobilization responding to body needs. LD biogenesis defects compromise the lipid-storing capacity of adipocytes, resulting in ectopic lipid deposition and metabolic disorders, yet how the uniquely large LDs in adipocytes attain structural and functional maturation is incompletely understood. Here we show that the mammalian adipocyte-specific protein CLSTN3B is crucial for adipocyte LD maturation. CLSTN3B employs an arginine-rich segment to promote extensive contact and hemifusion-like structure formation between the endoplasmic reticulum (ER) and LD, allowing ER-to-LD phospholipid diffusion during LD expansion. CLSTN3B ablation results in reduced LD surface phospholipid density, increased turnover of LD-surface proteins, and impaired LD functions. Our results establish the central role of CLSTN3B in the adipocyte-specific LD maturation pathway that enhances lipid storage and maintenance of metabolic health under caloric overload in mice of both sexes.
    DOI:  https://doi.org/10.1038/s41467-024-53750-z
  3. Cell. 2024 Oct 30. pii: S0092-8674(24)01188-7. [Epub ahead of print]
    Recognition of BACH1 quaternary structure degrons by two F-box proteins under oxidative stress.
    Shiyun Cao, Sheena Faye Garcia, Huigang Shi, Ellie I James, Yuki Kito, Hui Shi, Haibin Mao, Sharon Kaisari, Gergely Rona, Sophia Deng, Hailey V Goldberg, Jackeline Ponce, Beatrix Ueberheide, Luca Lignitto, Miklos Guttman, Michele Pagano, Ning Zheng.
      Ubiquitin-dependent proteolysis regulates diverse cellular functions with high substrate specificity, which hinges on the ability of ubiquitin E3 ligases to decode the targets' degradation signals, i.e., degrons. Here, we show that BACH1, a transcription repressor of antioxidant response genes, features two distinct unconventional degrons encrypted in the quaternary structure of its homodimeric BTB domain. These two degrons are both functionalized by oxidative stress and are deciphered by two complementary E3s. FBXO22 recognizes a degron constructed by the BACH1 BTB domain dimer interface, which is unmasked from transcriptional co-repressors after oxidative stress releases BACH1 from chromatin. When this degron is impaired by oxidation, a second BACH1 degron manifested by its destabilized BTB dimer is probed by a pair of FBXL17 proteins that remodels the substrate into E3-bound monomers for ubiquitination. Our findings highlight the multidimensionality of protein degradation signals and the functional complementarity of different ubiquitin ligases targeting the same substrate.
    Keywords:  BACH1; BTB; FBXL17; FBXO22; SCF; cullin-RING ligases; degron; dimer; heme; nitric oxide; oxidative stress; protein degradation; quaternary structure; transcription factor; ubiquitin ligase
    DOI:  https://doi.org/10.1016/j.cell.2024.10.012
  4. Nat Neurosci. 2024 Nov;27(11): 2053
    Alcohol's necessary accessory.
    Shari Wiseman.
      
    DOI:  https://doi.org/10.1038/s41593-024-01802-4
  5. Nature. 2024 Nov 06.
    Cellular ATP demand creates metabolically distinct subpopulations of mitochondria.
    Keun Woo Ryu, Tak Shun Fung, Daphne C Baker, Michelle Saoi, Jinsung Park, Christopher A Febres-Aldana, Rania G Aly, Ruobing Cui, Anurag Sharma, Yi Fu, Olivia L Jones, Xin Cai, H Amalia Pasolli, Justin R Cross, Charles M Rudin, Craig B Thompson.
      Mitochondria serve a crucial role in cell growth and proliferation by supporting both ATP synthesis and the production of macromolecular precursors. Whereas oxidative phosphorylation (OXPHOS) depends mainly on the oxidation of intermediates from the tricarboxylic acid cycle, the mitochondrial production of proline and ornithine relies on reductive synthesis1. How these competing metabolic pathways take place in the same organelle is not clear. Here we show that when cellular dependence on OXPHOS increases, pyrroline-5-carboxylate synthase (P5CS)-the rate-limiting enzyme in the reductive synthesis of proline and ornithine-becomes sequestered in a subset of mitochondria that lack cristae and ATP synthase. This sequestration is driven by both the intrinsic ability of P5CS to form filaments and the mitochondrial fusion and fission cycle. Disruption of mitochondrial dynamics, by impeding mitofusin-mediated fusion or dynamin-like-protein-1-mediated fission, impairs the separation of P5CS-containing mitochondria from mitochondria that are enriched in cristae and ATP synthase. Failure to segregate these metabolic pathways through mitochondrial fusion and fission results in cells either sacrificing the capacity for OXPHOS while sustaining the reductive synthesis of proline, or foregoing proline synthesis while preserving adaptive OXPHOS. These findings provide evidence of the key role of mitochondrial fission and fusion in maintaining both oxidative and reductive biosyntheses in response to changing nutrient availability and bioenergetic demand.
    DOI:  https://doi.org/10.1038/s41586-024-08146-w
  6. Nat Metab. 2024 Nov 04.
    Diabetes, IL-10 and the brain's microvascular crisis.
    Celine E Riera.
      
    DOI:  https://doi.org/10.1038/s42255-024-01161-1
  7. Proc Natl Acad Sci U S A. 2024 Nov 19. 121(47): e2414187121
    Cytosolic N6AMT1-dependent translation supports mitochondrial RNA processing.
    Mads M Foged, Emeline Recazens, Sylvain Chollet, Miriam Lisci, George E Allen, Boris Zinshteyn, Doha Boutguetait, Christian Münch, Vamsi K Mootha, Alexis A Jourdain.
      Mitochondrial biogenesis relies on both the nuclear and mitochondrial genomes, and imbalance in their expression can lead to inborn errors of metabolism, inflammation, and aging. Here, we investigate N6AMT1, a nucleo-cytosolic methyltransferase that exhibits genetic codependency with mitochondria. We determine transcriptional and translational profiles of N6AMT1 and report that it is required for the cytosolic translation of TRMT10C (MRPP1) and PRORP (MRPP3), two subunits of the mitochondrial RNAse P enzyme. In the absence of N6AMT1, or when its catalytic activity is abolished, RNA processing within mitochondria is impaired, leading to the accumulation of unprocessed and double-stranded RNA, thus preventing mitochondrial protein synthesis and oxidative phosphorylation, and leading to an immune response. Our work sheds light on the function of N6AMT1 in protein synthesis and highlights a cytosolic program required for proper mitochondrial biogenesis.
    Keywords:  OXPHOS; RNA processing; mitochondria; mitochondrial RNA granules; translation
    DOI:  https://doi.org/10.1073/pnas.2414187121
  8. Cell Metab. 2024 Oct 29. pii: S1550-4131(24)00401-7. [Epub ahead of print]
    Plasma protein-based organ-specific aging and mortality models unveil diseases as accelerated aging of organismal systems.
    Ludger J E Goeminne, Anastasiya Vladimirova, Alec Eames, Alexander Tyshkovskiy, M Austin Argentieri, Kejun Ying, Mahdi Moqri, Vadim N Gladyshev.
      Aging is a complex process manifesting at molecular, cellular, organ, and organismal levels. It leads to functional decline, disease, and ultimately death, but the relationship between these fundamental biomedical features remains elusive. By applying elastic net regularization to plasma proteome data of over 50,000 human subjects in the UK Biobank and other cohorts, we report interpretable organ-specific and conventional aging models trained on chronological age, mortality, and longitudinal proteome data. These models predict organ/system-specific disease and indicate that men age faster than women in most organs. Accelerated organ aging leads to diseases in these organs, and specific diets, lifestyles, professions, and medications influence organ aging rates. We then identify proteins driving these associations with organ-specific aging. Our analyses reveal that age-related chronic diseases epitomize accelerated organ- and system-specific aging, modifiable through environmental factors, advocating for both universal whole-organism and personalized organ/system-specific anti-aging interventions.
    Keywords:  aging models; blood plasma; diet; disease; elastic net; lifestyle; longevity interventions; mortality; organ-specific aging; proteomic clocks
    DOI:  https://doi.org/10.1016/j.cmet.2024.10.005
  9. Nat Commun. 2024 Nov 04. 15(1): 9520
    CTLA-4 expressing innate lymphoid cells modulate mucosal homeostasis in a microbiota dependent manner.
    Jonathan W Lo, Jan-Hendrik Schroeder, Luke B Roberts, Rami Mohamed, Domenico Cozzetto, Gordon Beattie, Omer S Omer, Ellen M Ross, Frank Heuts, Geraldine M Jowett, Emily Read, Matthew Madgwick, Joana F Neves, Tamas Korcsmaros, Richard G Jenner, Lucy S K Walker, Nick Powell, Graham M Lord.
      The maintenance of intestinal homeostasis is a fundamental process critical for organismal integrity. Sitting at the interface of the gut microbiome and mucosal immunity, adaptive and innate lymphoid populations regulate the balance between commensal micro-organisms and pathogens. Checkpoint inhibitors, particularly those targeting the CTLA-4 pathway, disrupt this fine balance and can lead to inflammatory bowel disease and immune checkpoint colitis. Here, we show that CTLA-4 is expressed by innate lymphoid cells and that its expression is regulated by ILC subset-specific cytokine cues in a microbiota-dependent manner. Genetic deletion or antibody blockade of CTLA-4 in multiple in vivo models of colitis demonstrates that this pathway plays a key role in intestinal homeostasis. Lastly, we have found that this observation is conserved in human IBD. We propose that this population of CTLA-4-positive ILC may serve as an important target for the treatment of idiopathic and iatrogenic intestinal inflammation.
    DOI:  https://doi.org/10.1038/s41467-024-51719-6
  10. Nature. 2024 Nov 06.
    A new kind of mitochondrion.
    Nick Petrić Howe.
      
    Keywords:  Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-024-03636-3
  11. Nat Commun. 2024 Nov 01. 15(1): 9461
    Dietary nucleic acids promote oral tolerance through innate sensing pathways in mice.
    Tao Yang, Tian Li, Yingying Xing, Mengtao Cao, Mingxiang Zhang, Qibin Leng, Ju Qiu, Xinyang Song, Jianfeng Chen, Guohong Hu, Youcun Qian.
      Oral tolerance is essential for intestinal homeostasis and systemic immune function. However, our understanding of how oral tolerance is maintained is inadequate. Here we report that food-derived nucleic acids promote oral tolerance through innate sensing pathways. We find that dietary nucleic acids, but not microbiota, expand the natural intraepithelial lymphocyte (IEL) pool, specifically in the small intestine. TGF-β1, produced by natural IELs, then promotes activation of gut CD103+ dendritic cells to support the induction of antigen-specific Treg cells in a mouse model of OVA-induced oral tolerance. Mechanistically, MAVS and STING are redundantly required for sensing dietary RNAs and DNAs to activate downstream TBK1 signalling to induce IL-15 production, which results in the accumulation of natural IELs. Thus, our study demonstrates a key role of food-triggered innate sensing pathways in the maintenance of natural IELs and oral tolerance.
    DOI:  https://doi.org/10.1038/s41467-024-53814-0
  12. Nat Commun. 2024 Nov 03. 15(1): 9494
    Decoding the epigenetics and chromatin loop dynamics of androgen receptor-mediated transcription.
    Umut Berkay Altıntaş, Ji-Heui Seo, Claudia Giambartolomei, Dogancan Ozturan, Brad J Fortunato, Geoffrey M Nelson, Seth R Goldman, Karen Adelman, Faraz Hach, Matthew L Freedman, Nathan A Lack.
      Androgen receptor (AR)-mediated transcription plays a critical role in development and prostate cancer growth. AR drives gene expression by binding to thousands of cis-regulatory elements (CRE) that loop to hundreds of target promoters. With multiple CREs interacting with a single promoter, it remains unclear how individual AR bound CREs contribute to gene expression. To characterize the involvement of these CREs, we investigate the AR-driven epigenetic and chromosomal chromatin looping changes by generating a kinetic multi-omic dataset comprised of steady-state mRNA, chromatin accessibility, transcription factor binding, histone modifications, chromatin looping, and nascent RNA. Using an integrated regulatory network, we find that AR binding induces sequential changes in the epigenetic features at CREs, independent of gene expression. Further, we show that binding of AR does not result in a substantial rewiring of chromatin loops, but instead increases the contact frequency of pre-existing loops to target promoters. Our results show that gene expression strongly correlates to the changes in contact frequency. We then propose and experimentally validate an unbalanced multi-enhancer model where the impact on gene expression of AR-bound enhancers is heterogeneous, and is proportional to their contact frequency with target gene promoters. Overall, these findings provide insights into AR-mediated gene expression upon acute androgen simulation and develop a mechanistic framework to investigate nuclear receptor mediated perturbations.
    DOI:  https://doi.org/10.1038/s41467-024-53758-5
  13. Nat Immunol. 2024 Nov 04.
    COQ6 defies immune and metabolic expectations.
    Samuel E Weinberg, Navdeep S Chandel.
      
    DOI:  https://doi.org/10.1038/s41590-024-02005-6
  14. Nature. 2024 Nov 06.
    Fat keeps metabolism in tune and on time using an inflammatory immune protein.
      
    Keywords:  Immunology; Metabolism; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-024-03602-z
  15. Epigenetics Chromatin. 2024 Nov 01. 17(1): 33
    Chromatin structure and 3D architecture define the differential functions of PU.1 regulatory elements in blood cell lineages.
    Kevin Qiu, Duc C Vu, Leran Wang, Nicholas N Nguyen, Anna K Bookstaver, Katia Sol-Church, Hui Li, Thang N Dinh, Adam N Goldfarb, Daniel G Tenen, Bon Q Trinh.
      The precise spatiotemporal expression of the hematopoietic ETS transcription factor PU.1, a key determinant of hematopoietic cell fates, is tightly regulated at the chromatin level. However, how chromatin signatures are linked to this dynamic expression pattern across different blood cell lineages remains uncharacterized. Here, we performed an in-depth analysis of the relationships between gene expression, chromatin structure, 3D architecture, and trans-acting factors at PU.1 cis-regulatory elements (PCREs). By identifying phylogenetically conserved DNA elements within chromatin-accessible regions in primary human blood lineages, we discovered multiple novel candidate PCREs within the upstream region of the human PU.1 locus. A subset of these elements localizes within an 8-kb-wide cluster exhibiting enhancer features, including open chromatin, demethylated DNA, enriched enhancer histone marks, present enhancer RNAs, and PU.1 occupation, presumably mediating PU.1 autoregulation. Importantly, we revealed the presence of a common 35-kb-wide CTCF-flanked insulated neighborhood that contains the PCRE cluster (PCREC), forming a chromatin territory for lineage-specific and PCRE-mediated chromatin interactions. These include functional PCRE-promoter interactions in myeloid and B cells that are absent in erythroid and T cells. By correlating chromatin structure and 3D architecture with PU.1 expression in various lineages, we were able to attribute enhancer versus silencer functions to individual elements. Our findings provide mechanistic insights into the interplay between dynamic chromatin structure and 3D architecture in the chromatin regulation of PU.1 expression. This study lays crucial groundwork for additional experimental studies that validate and dissect the role of PCREs in epigenetic regulation of normal and malignant hematopoiesis.
    Keywords:  Architecture; Cell lineages; Cell type-specific gene induction; Chromatin structure; Configuration; Enhancer; Multimomic analyses; Promoter; Signature; Single-cell sequencing
    DOI:  https://doi.org/10.1186/s13072-024-00556-4
  16. Commun Biol. 2024 Nov 06. 7(1): 1446
    KLF13 promotes SLE pathogenesis by modifying chromatin accessibility of key proinflammatory cytokine genes.
    Andrew Wang, Anna-Marie Fairhurst, Kui Liu, Benjamin Wakeland, Spencer Barnes, Venkat S Malladi, Kasthuribai Viswanathan, Carlos Arana, Igor Dozmorov, Amrita Singhar, Yong Du, Marjaan Imam, Angela Moses, Christian Chen, Ashwini Sunkavalli, Jose Casco, Dinesh Rakheja, Quan-Zhen Li, Chandra Mohan, Carol Clayberger, Edward K Wakeland, Shaheen Khan.
      Although significant progress has been achieved in elucidating the genetic architecture of systemic lupus erythematosus (SLE), identifying genes underlying the pathogenesis has been challenging. The NZM2410-derived lupus susceptibility Sle3 locus is associated with T cell hyperactivity and activated myeloid cells. However, candidate genes associated with these phenotypes have not been identified. Here, we narrow the Sle3 locus to a smaller genomic segment (Sle3k) and show that mice carrying Sle3k and Sle1 loci developed lupus nephritis. We identify Klf13 as the primary candidate gene that is associated with genome-wide transcription changes resulting in higher levels of proinflammatory cytokines, enhanced T cell activation, and hyperresponsiveness of myeloid cells. Correspondingly, Klf13 -/- mice display repression of genes involved in mediating immune activation, including key proinflammatory cytokines/chemokines in T cells and dysregulation in cytokine signaling pathways in myeloid cells in response to toll receptor ligands. Klf13 upregulation is associated with increased production of RANTES, a key chemokine in lupus nephritis, in activated T cells and the kidneys of lupus-prone mice. In sum, our findings reveal Klf13 as a key gene in the Sle3 interval in mediating lupus pathogenesis that may have implications in the rational design of new therapies for SLE.
    DOI:  https://doi.org/10.1038/s42003-024-07099-0
  17. Nature. 2024 Nov;635(8037): 8
    Science communication will benefit from research integrity standards.
      
    Keywords:  Careers; Research management; Scientific community; Society
    DOI:  https://doi.org/10.1038/d41586-024-03586-w
  18. Nature. 2024 Nov 06.
    Learning-associated astrocyte ensembles regulate memory recall.
    Michael R Williamson, Wookbong Kwon, Junsung Woo, Yeunjung Ko, Ehson Maleki, Kwanha Yu, Sanjana Murali, Debosmita Sardar, Benjamin Deneen.
      The physical manifestations of memory formation and recall are fundamental questions that remain unresolved1. At the cellular level, ensembles of neurons called engrams are activated by learning events and control memory recall1-5. Astrocytes are found in close proximity to neurons and engage in a range of activities that support neurotransmission and circuit plasticity6-10. Moreover, astrocytes exhibit experience-dependent plasticity11-13, although whether specific ensembles of astrocytes participate in memory recall remains obscure. Here we show that learning events induce c-Fos expression in a subset of hippocampal astrocytes, and that this subsequently regulates the function of the hippocampal circuit in mice. Intersectional labelling of astrocyte ensembles with c-Fos after learning events shows that they are closely affiliated with engram neurons, and reactivation of these astrocyte ensembles stimulates memory recall. At the molecular level, learning-associated astrocyte (LAA) ensembles exhibit elevated expression of nuclear factor I-A, and its selective deletion from this population suppresses memory recall. Taken together, our data identify LAA ensembles as a form of plasticity that is sufficient to provoke memory recall and indicate that astrocytes are an active component of the engram.
    DOI:  https://doi.org/10.1038/s41586-024-08170-w
  19. Nat Commun. 2024 Nov 06. 15(1): 9602
    AS160 is a lipid-responsive regulator of cardiac Ca2+ homeostasis by controlling lysophosphatidylinositol metabolism and signaling.
    Shu Su, Chao Quan, Qiaoli Chen, Ruizhen Wang, Qian Du, Sangsang Zhu, Min Li, Xinyu Yang, Ping Rong, Jiang Chen, Yingyu Bai, Wen Zheng, Weikuan Feng, Minjun Liu, Bingxian Xie, Kunfu Ouyang, Yun Stone Shi, Feng Lan, Xiuqin Zhang, Ruiping Xiao, Xiongwen Chen, Hong-Yu Wang, Shuai Chen.
      The obese heart undergoes metabolic remodeling and exhibits impaired calcium (Ca2+) homeostasis, which are two critical assaults leading to cardiac dysfunction. The molecular mechanisms underlying these alterations in obese heart are not well understood. Here, we show that the Rab-GTPase activating protein AS160 is a lipid-responsive regulator of Ca2+ homeostasis through governing lysophosphatidylinositol metabolism and signaling. Palmitic acid/high fat diet inhibits AS160 activity through phosphorylation by NEK6, which consequently activates its downstream target Rab8a. Inactivation of AS160 in cardiomyocytes elevates cytosolic Ca2+ that subsequently impairs cardiac contractility. Mechanistically, Rab8a downstream of AS160 interacts with DDHD1 to increase lysophosphatidylinositol metabolism and signaling that leads to Ca2+ release from sarcoplasmic reticulum. Inactivation of NEK6 prevents inhibition of AS160 by palmitic acid/high fat diet, and alleviates cardiac dysfunction in high fat diet-fed mice. Together, our findings reveal a regulatory mechanism governing metabolic remodeling and Ca2+ homeostasis in obese heart, and have therapeutic implications to combat obesity cardiomyopathy.
    DOI:  https://doi.org/10.1038/s41467-024-54031-5
  20. Nature. 2024 Nov 04.
    How I hunt down fake degrees and zombie universities.
    Christine Ro.
      
    Keywords:  Careers; Education; Institutions; Law
    DOI:  https://doi.org/10.1038/d41586-024-03419-w
  21. Nat Commun. 2024 Nov 01. 15(1): 9464
    Prostaglandin E2-EP2/EP4 signaling induces immunosuppression in human cancer by impairing bioenergetics and ribosome biogenesis in immune cells.
    Siwakorn Punyawatthananukool, Ryuma Matsuura, Thamrong Wongchang, Nao Katsurada, Tatsuaki Tsuruyama, Masaki Tajima, Yutaka Enomoto, Toshio Kitamura, Masahiro Kawashima, Masakazu Toi, Koji Yamanoi, Junzo Hamanishi, Shigeo Hisamori, Kazutaka Obama, Varodom Charoensawan, Dean Thumkeo, Shuh Narumiya.
      While prostaglandin E2 (PGE2) is produced in human tumor microenvironment (TME), its role therein remains poorly understood. Here, we examine this issue by comparative single-cell RNA sequencing of immune cells infiltrating human cancers and syngeneic tumors in female mice. PGE receptors EP4 and EP2 are expressed in lymphocytes and myeloid cells, and their expression is associated with the downregulation of oxidative phosphorylation (OXPHOS) and MYC targets, glycolysis and ribosomal proteins (RPs). Mechanistically, CD8+ T cells express EP4 and EP2 upon TCR activation, and PGE2 blocks IL-2-STAT5 signaling by downregulating Il2ra, which downregulates c-Myc and PGC-1 to decrease OXPHOS, glycolysis, and RPs, impairing migration, expansion, survival, and antitumor activity. Similarly, EP4 and EP2 are induced upon macrophage activation, and PGE2 downregulates c-Myc and OXPHOS in M1-like macrophages. These results suggest that PGE2-EP4/EP2 signaling impairs both adaptive and innate immunity in TME by hampering bioenergetics and ribosome biogenesis of tumor-infiltrating immune cells.
    DOI:  https://doi.org/10.1038/s41467-024-53706-3
  22. J Lipid Res. 2024 Oct 25. pii: S0022-2275(24)00184-6. [Epub ahead of print] 100679
    Resolvin D2/GPR 18 axis ameliorates pressure overload-induced heart failure by inhibiting pro-inflammatory macrophage polarization.
    Zihui Zheng, Mengmeng Zhao, Yao Xu, Jishou Zhang, Shanshan Peng, Jianfang Liu, Wei Pan, Zheng Yin, Cheng Wei, Juan-Juan Qin, Jun Wan, Menglong Wang.
      Accumulating evidence has revealed that chronic unresolved inflammation can cause significant tissue damage and can be a key mediator of advanced heart failure (HF). Resolvin (Rv) D2, a member of specialized pro-resolving lipid mediators (SPMs), plays a protective role in various diseases by facilitating resolution. However, whether RvD2 participates in the pathogenesis of HF is still unclear. Our study demonstrated that RvD2 treatment mitigated cardiac remodeling and improved cardiac function in HF mice induced by pressure overload. The absence of G protein-coupled receptor 18 (GPR18), an endogenous receptor for RvD2, abolished the beneficial effects of RvD2 on HF. Additionally, RvD2 inhibited inflammatory responses and Ly6Chigh macrophage polarization during both early and late inflammatory stages involved in HF. Further investigation revealed that bone marrow transplantation from GPR18 deficient mice into WT mice blocked the protective effects of RvD2 in HF mice. Moreover, GPR18 deficiency impeded RvD2's capacity to downregulate inflammatory responses and Ly6Chigh macrophage polarization. Consistent with experiments in vivo, RvD2 treatment in bone marrow-derived macrophages (BMDMs) reduced inflammatory responses through its receptor GPR18. Mechanistically, RvD2 suppressed the phosphorylation of STAT1 and NF-κB p65, and the effects of RvD2 were reversed by the application of STAT1 or NF-κB p65 agonists in BMDMs. In conclusion, RvD2/GPR18 axis improved cardiac remodeling and function in pressure overload-induced HF mice by modulating macrophages phenotype via STAT1 and NF-κB p65 pathways. Our findings underscore the anti-inflammatory potential of RvD2/GPR18 axis, which may be a promising strategy for reducing the burden of HF.
    Keywords:  GPR18; Heart failure; Macrophage polarization; Pressure overload; Resolvin D2
    DOI:  https://doi.org/10.1016/j.jlr.2024.100679
  23. Nat Commun. 2024 Nov 06. 15(1): 9593
    Phenotypic and genetic characteristics of retinal vascular parameters and their association with diseases.
    Sofía Ortín Vela, Michael J Beyeler, Olga Trofimova, Ilaria Iuliani, Jose D Vargas Quiros, Victor A de Vries, Ilenia Meloni, Adham Elwakil, Florence Hoogewoud, Bart Liefers, David Presby, Wishal D Ramdas, Mattia Tomasoni, Reinier Schlingemann, Caroline C W Klaver, Sven Bergmann.
      Fundus images allow for non-invasive assessment of the retinal vasculature whose features provide important information on health. Using a fully automated image processing pipeline, we extract 17 different morphological vascular phenotypes, including median vessels diameter, diameter variability, main temporal angles, vascular density, central retinal equivalents, the number of bifurcations, and tortuosity, from over 130,000 fundus images of close to 72,000 UK Biobank subjects. We perform genome-wide association studies of these phenotypes. From this, we estimate their heritabilities, ranging between 5 and 25%, and genetic cross-phenotype correlations, which mostly mirror the corresponding phenotypic correlations, but tend to be slightly larger. Projecting our genetic association signals onto genes and pathways reveals remarkably low overlap suggesting largely decoupled mechanisms modulating the different phenotypes. We find that diameter variability, especially for the veins, associates with diseases including heart attack, pulmonary embolism, and age of death. Mendelian Randomization analysis suggests a causal influence of blood pressure and body mass index on retinal vessel morphology, among other results. We validate key findings in two independent smaller cohorts. Our analyses provide evidence that large-scale analysis of image-derived vascular phenotypes has sufficient power for obtaining functional and causal insights into the processes modulating the retinal vasculature.
    DOI:  https://doi.org/10.1038/s41467-024-52334-1
  24. Nat Immunol. 2024 Nov 06.
    Inborn errors of immunity caused by dominant negative interference by a BCL11B variant.
      
    DOI:  https://doi.org/10.1038/s41590-024-02003-8
  25. Nat Metab. 2024 Nov 04.
    A pathogenic role for IL-10 signalling in capillary stalling and cognitive impairment in type 1 diabetes.
    Sorabh Sharma, Manjinder Cheema, Patrick L Reeson, Kamal Narayana, Roobina Boghozian, Ana Paula Cota, Tara P Brosschot, Rachael D FitzPatrick, Jakob Körbelin, Lisa A Reynolds, Craig E Brown.
      Vascular pathology is associated with cognitive impairment in diseases such as type 1 diabetes; however, how capillary flow is affected and the underlying mechanisms remain elusive. Here we show that capillaries in the diabetic mouse brain in both sexes are prone to stalling, with blocks consisting primarily of erythrocytes in branches off ascending venules. Screening for circulating inflammatory cytokines revealed persistently high levels of interleukin-10 (IL-10) in diabetic mice. Contrary to expectation, stimulating IL-10 signalling increased capillary obstruction, whereas inhibiting IL-10 receptors with neutralizing antibodies or endothelial specific knockdown in diabetic mice reversed these impairments. Chronic treatment of diabetic mice with IL-10 receptor neutralizing antibodies improved cerebral blood flow, increased capillary flux and diameter, downregulated haemostasis and cell adhesion-related gene expression, and reversed cognitive deficits. These data suggest that IL-10 signalling has an unexpected pathogenic role in cerebral microcirculatory defects and cognitive impairment associated with type 1 diabetes.
    DOI:  https://doi.org/10.1038/s42255-024-01159-9
  26. Nature. 2024 Nov 05.
    Cat brains age like ours - and could help scientists to understand cognitive decline.
    Heidi Ledford.
      
    Keywords:  Ageing; Developmental biology; Zoology
    DOI:  https://doi.org/10.1038/d41586-024-03492-1
  27. Clin Transl Med. 2024 Nov;14(11): e70076
    Genetic variants explain ancestry-related differences in type 2 diabetes risk.
    Aaron J Deutsch, Kirk Smith, Miriam S Udler.
      
    DOI:  https://doi.org/10.1002/ctm2.70076
  28. J Hepatol. 2024 Oct 25. pii: S0168-8278(24)02649-7. [Epub ahead of print]
    Blood markers for type-1,-2, and -3 inflammation are associated with severity of acutely decompensated cirrhosis.
    Zhujun Cao, Yujing Yao, Minghao Cai, Chenxi Zhang, Yuhan Liu, Haiguang Xin, Baoyan An, Hui Wang, Yide Lu, Ziqiang Li, Yaoxing Chen, Yan Huang, Min Xin, Ruokun Li, Zhuping Qian, Yi Zhou, Xiaogang Xiang, Richard Moreau, Qing Xie.
       BACKGROUND AND AIMS: In patients with acutely decompensated cirrhosis (ADC) who present with clinically apparent precipitants (i.e., infections, acute liver injury), alterations in blood markers of inflammation associate with progression toward severe phenotypes (e.g., acute-on-chronic liver failure, ACLF). It is unclear whether alterations in blood inflammatory markers may associate with progression of ADC independently of precipitants.
    METHODS: We prospectively enrolled 394 patients admitted for ADC who were classified into four phenotypes of increasing severity: no organ dysfunction (n=168), organ dysfunction alone (n=72), organ failure without ACLF (n=91), and ACLF (n=63). Clinical blood cell counts and serum levels of inflammatory markers (including soluble markers related to type-1, type-2, and type-3 inflammation) were obtained at enrollment. Ordinal regression with adjacent categories logit model adjusted for confounders (including precipitants) was used to analyze associations between changes in each blood inflammatory marker and the worsening of ADC.
    RESULTS: Inflammatory markers that were associated with higher risk of progressing to the next more severe stage were as follows: increasing neutrophil counts (adjusted common odds ratio [cOR] 1.17, 95%CI 1.06-1.28); increasing levels of the type-2 cytokine interleukin (IL)-25 (cOR 1.21, 95%CI 1.06-1.39), type-3 cytokines IL-6 (cOR 1.15, 95%CI 1.02-1.28) and IL-22 (cOR 1.16, 95%CI 1.03-1.30), or anti-inflammatory soluble CD163 (cOR 1.94, 95%CI 1.58-2.38); decreasing lymphocyte counts (cOR 0.77, 95%CI 0.68-0.87), or decreasing levels of the type-1 cytokine IFN-γ (cOR 0.85, 95%CI 0.75-0.95).
    CONCLUSIONS: Among patients with ADC, alterations in blood levels of cytokines related to type-1, type-2 and type-3 inflammation, together with neutrophilia, lymphopenia and elevated anti-inflammatory signals were individually associated with an increased risk of progressing toward ACLF, independently of the presence of clinically apparent precipitants.
    Keywords:  Acute-on-chronic liver failure; barrier tissue; epithelial cell; immune response; infection; intestinal; lymphopenia; neutrophilia; systemic inflammation; tuft cell
    DOI:  https://doi.org/10.1016/j.jhep.2024.10.028
  29. Nat Commun. 2024 Nov 04. 15(1): 9522
    PTPRK regulates glycolysis and de novo lipogenesis to promote hepatocyte metabolic reprogramming in obesity.
    Eduardo H Gilglioni, Ao Li, Wadsen St-Pierre-Wijckmans, Tzu-Keng Shen, Israel Pérez-Chávez, Garnik Hovhannisyan, Michela Lisjak, Javier Negueruela, Valerie Vandenbempt, Julia Bauzá-Martinez, Jose M Herranz, Daria Ezeriņa, Stéphane Demine, Zheng Feng, Thibaut Vignane, Lukas Otero Sanchez, Flavia Lambertucci, Alena Prašnická, Jacques Devière, David C Hay, Jose A Encinar, Sumeet Pal Singh, Joris Messens, Milos R Filipovic, Hayley J Sharpe, Eric Trépo, Wei Wu, Esteban N Gurzov.
      Fat accumulation, de novo lipogenesis, and glycolysis are key drivers of hepatocyte reprogramming and the consequent metabolic dysfunction-associated steatotic liver disease (MASLD). Here we report that obesity leads to dysregulated expression of hepatic protein-tyrosine phosphatases (PTPs). PTPRK was found to be increased in steatotic hepatocytes in both humans and mice, and correlates positively with PPARγ-induced lipogenic signaling. High-fat-fed PTPRK knockout male and female mice have lower weight gain and reduced hepatic fat accumulation. Phosphoproteomic analysis in primary hepatocytes and hepatic metabolomics identified fructose-1,6-bisphosphatase 1 and glycolysis as PTPRK targets in metabolic reprogramming. Mechanistically, PTPRK-induced glycolysis enhances PPARγ and lipogenesis in hepatocytes. Silencing PTPRK in liver cancer cell lines reduces colony-forming capacity and high-fat-fed PTPRK knockout mice exposed to a hepatic carcinogen develop smaller tumours. Our study defines the role of PTPRK in the regulation of hepatic glycolysis, lipid metabolism, and tumour development in obesity.
    DOI:  https://doi.org/10.1038/s41467-024-53733-0
  30. Nat Med. 2024 Nov 06.
    HIV-1 remission following stem cell transplant without CCR5Δ32 mutation.
      
    DOI:  https://doi.org/10.1038/s41591-024-03365-0
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