bims-nimamd Biomed News
on Neuroimmunity and neuroinflammation in ageing and metabolic disease
Issue of 2022–05–01
sixty-one papers selected by
Fawaz Alzaïd, Sorbonne Université
  1. T cell receptor and IL-2 signaling strength control memory CD8+ T cell functional fitness via chromatin remodeling.
  2. Inflammasome activation in infected macrophages drives COVID-19 pathology.
  3. The ImmGen consortium OpenSource T cell project.
  4. T follicular helper and B cell crosstalk in tertiary lymphoid structures and cancer immunotherapy.
  5. C-terminal deletion-induced condensation sequesters AID from IgH targets in immunodeficiency.
  6. Inheritance of repressed chromatin domains during S phase requires the histone chaperone NPM1.
  7. Lineage tracing clarifies the cellular origin of tissue-resident macrophages in the developing heart.
  8. Kronos scRT: a uniform framework for single-cell replication timing analysis.
  9. The timing of differentiation and potency of CD8 effector function is set by RNA binding proteins.
  10. Reference-free cell type deconvolution of multi-cellular pixel-resolution spatially resolved transcriptomics data.
  11. piRNA-guided intron removal from pre-mRNAs regulates density-dependent reproductive strategy.
  12. Reduced chromatin accessibility correlates with resistance to Notch activation.
  13. β-Cell Succinate Dehydrogenase Deficiency Triggers Metabolic Dysfunction and Insulinopenic Diabetes.
  14. Ebola virus VP35 hijacks the PKA-CREB1 pathway for replication and pathogenesis by AKIP1 association.
  15. Subthalamic nucleus stabilizes movements by reducing neural spike variability in monkey basal ganglia.
  16. Knockdown of GABAA alpha3 subunits on thalamic reticular neurons enhances deep sleep in mice.
  17. Transcription factors AP-2α and AP-2β regulate distinct segments of the distal nephron in the mammalian kidney.
  18. Lay A TRAP for myeloid cell response in diabetic kidney disease.
  19. Breakage of cytoplasmic chromosomes by pathological DNA base excision repair.
  20. ERK1/2 is an ancestral organising signal in spiral cleavage.
  21. Single-stranded nucleic acid binding and coacervation by linker histone H1.
  22. GSK3β mediates the spatiotemporal dynamics of NLRP3 inflammasome activation.
  23. Caspase-11 interaction with NLRP3 potentiates the noncanonical activation of the NLRP3 inflammasome.
  24. IFN-γ+ cytotoxic CD4+ T lymphocytes are involved in the pathogenesis of colitis induced by IL-23 and the food colorant Red 40.
  25. Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA.
  26. Deficiency in coatomer complex I causes aberrant activation of STING signalling.
  27. Tissue remodeling by an opportunistic pathogen triggers allergic inflammation.
  28. CD4+c-Met+Itgα4+ T cell subset promotes murine neuroinflammation.
  29. Structure of human chromatin-remodelling PBAF complex bound to a nucleosome.
  30. Enhancement of anaerobic glycolysis - a role of PGC-1α4 in resistance exercise.
  31. β-Hydroxybutyrate suppresses colorectal cancer.
  32. Lipid metabolism in T cell signaling and function.
  33. In vivo labeling reveals continuous trafficking of TCF-1+ T cells between tumor and lymphoid tissue.
  34. Identification of a retinoic acid-dependent haemogenic endothelial progenitor from human pluripotent stem cells.
  35. CD39 and CD326 Are Bona Fide Markers of Murine and Human Plasma Cells and Identify a Bone Marrow Specific Plasma Cell Subpopulation in Lupus.
  36. Epithelial-immune crosstalk in health and disease.
  37. ETS1 acts as a regulator of human healthy aging via decreasing ribosomal activity.
  38. Promoter Binding and Nuclear Retention Features of Zebrafish IRF Family Members in IFN Response.
  39. MicroRNA-200c coordinates HNF1 homeobox B and Apolipoprotein O functions to modulate lipid homeostasis in alcoholic fatty liver disease.
  40. Sparse imaging and reconstruction tomography for high-speed high-resolution whole-brain imaging.
  41. The immune checkpoint B7-H3 (CD276) regulates adipocyte progenitor metabolism and obesity development.
  42. An increase in spontaneous activity mediates visual habituation.
  43. TNFAIP3 Reduction-of-Function Drives Female Infertility and CNS Inflammation.
  44. CD36-Mediated Fatty Acid Oxidation in Hematopoietic Stem Cells Is a Novel Mechanism of Emergency Hematopoiesis in Response to Infection.
  45. Discussion: Genetic Influence on Neurodevelopment in Nonsyndromic Craniosynostosis.
  46. Endogenous Lipid-GPR120 Signaling Modulates Pancreatic Islet Homeostasis to Different Extents.
  47. Yeast Display for the Identification of Peptide-MHC Ligands of Immune Receptors.
  48. Atossa: a royal link between OXPHOS metabolism and macrophage migration.
  49. HOXB13 suppresses de novo lipogenesis through HDAC3-mediated epigenetic reprogramming in prostate cancer.
  50. Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities.
  51. Hepatitis C Virus Alters Macrophage Cholesterol Metabolism Through Interaction with Scavenger Receptors.
  52. Epitranscriptomic dynamics in brain development and disease.
  53. Interferons limit autoantigen-specific CD8+ T-cell expansion in the non-obese diabetic mouse.
  54. Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance.
  55. Contact-Dependent Granzyme B-Mediated Cytotoxicity of Th17-Polarized Cells Toward Human Oligodendrocytes.
  56. A theory of cortical map formation in the visual brain.
  57. TCF-1: a maverick in T cell development and function.
  58. Enhanced safety and efficacy of protease-regulated CAR-T cell receptors.
  59. Natural Killer Cells in Multiple Sclerosis: Entering the Stage.
  60. Postmitotic G1 phase survivin drives mitogen-independent cell division of B lymphocytes.
  61. A genetic bottleneck of mitochondrial DNA during human lymphocyte development.
  1. Nat Commun. 2022 Apr 26. 13(1): 2240
    T cell receptor and IL-2 signaling strength control memory CD8+ T cell functional fitness via chromatin remodeling.
    Shu Shien Chin, Erik Guillen, Laurent Chorro, Sooraj Achar, Karina Ng, Susanne Oberle, Francesca Alfei, Dietmar Zehn, Grégoire Altan-Bonnet, Fabien Delahaye, Grégoire Lauvau.
      Cognate antigen signal controls CD8+ T cell priming, expansion size and effector versus memory cell fates, but it is not known if and how it modulates the functional features of memory CD8+ T cells. Here we show that the strength of T cell receptor (TCR) signaling controls the requirement for interleukin-2 (IL-2) signals to form a pool of memory CD8+ T cells that competitively re-expand upon secondary antigen encounter. Combining strong TCR and intact IL-2 signaling during priming synergistically induces genome-wide chromatin accessibility in regions targeting a wide breadth of biological processes, consistent with greater T cell functional fitness. Chromatin accessibility in promoters of genes encoding for stem cell, cell cycle and calcium-related proteins correlates with faster intracellular calcium accumulation, initiation of cell cycle and more robust expansion. High-dimensional flow-cytometry analysis of these T cells also highlights higher diversity of T cell subsets and phenotypes with T cells primed with stronger TCR and IL-2 stimulation than those primed with weaker strengths of TCR and/or IL-2 signals. These results formally show that epitope selection in vaccine design impacts memory CD8+ T cell epigenetic programming and function.
    DOI:  https://doi.org/10.1038/s41467-022-29718-2
  2. Nature. 2022 Apr 28.
    Inflammasome activation in infected macrophages drives COVID-19 pathology.
    Esen Sefik, Rihao Qu, Caroline Junqueira, Eleanna Kaffe, Haris Mirza, Jun Zhao, J Richard Brewer, Ailin Han, Holly R Steach, Benjamin Israelow, Holly N Blackburn, Sofia Velazquez, Y Grace Chen, Stephanie Halene, Akiko Iwasaki, Eric Meffre, Michel Nussenzweig, Judy Lieberman, Craig B Wilen, Yuval Kluger, Richard A Flavell.
      Severe COVID-19 is characterized by persistent lung inflammation, inflammatory cytokine production, viral RNA, and sustained interferon (IFN) response all of which are recapitulated and required for pathology in the SARS-CoV-2 infected MISTRG6-hACE2 humanized mouse model of COVID-19 with a human immune system1-20. Blocking either viral replication with Remdesivir21-23 or the downstream IFN stimulated cascade with anti-IFNAR2 in vivo in the chronic stages of disease attenuated the overactive immune-inflammatory response, especially inflammatory macrophages. Here, we show SARS-CoV-2 infection and replication in lung-resident human macrophages is a critical driver of disease. In response to infection mediated by CD16 and ACE2 receptors, human macrophages activate inflammasomes, release IL-1 and IL-18 and undergo pyroptosis thereby contributing to the hyperinflammatory state of the lungs. Inflammasome activation and its accompanying inflammatory response is necessary for lung inflammation, as inhibition of the NLRP3 inflammasome pathway reverses chronic lung pathology. Remarkably, this same blockade of inflammasome activation leads to the release of infectious virus by the infected macrophages. Thus, inflammasomes oppose host infection by SARS-CoV-2 by production of inflammatory cytokines and suicide by pyroptosis to prevent a productive viral cycle.
    DOI:  https://doi.org/10.1038/s41586-022-04802-1
  3. Nat Immunol. 2022 Apr 25.
    The ImmGen consortium OpenSource T cell project.
    David Zemmour, Ananda Goldrath, Mitchell Kronenberg, Joonsoo Kang, Christophe Benoist.
      
    DOI:  https://doi.org/10.1038/s41590-022-01197-z
  4. Nat Commun. 2022 Apr 26. 13(1): 2259
    T follicular helper and B cell crosstalk in tertiary lymphoid structures and cancer immunotherapy.
    Soizic Garaud, Marie-Caroline Dieu-Nosjean, Karen Willard-Gallo.
      
    DOI:  https://doi.org/10.1038/s41467-022-29753-z
  5. EMBO J. 2022 Apr 26. e109324
    C-terminal deletion-induced condensation sequesters AID from IgH targets in immunodeficiency.
    Xia Xie, Tingting Gan, Bing Rao, Weiwei Zhang, Rohit A Panchakshari, Dingpeng Yang, Xiong Ji, Yu Cao, Frederick W Alt, Fei-Long Meng, Jiazhi Hu.
      In activated B cells, activation-induced cytidine deaminase (AID) generates programmed DNA lesions required for antibody class switch recombination (CSR), which may also threaten genome integrity. AID dynamically shuttles between cytoplasm and nucleus, and the majority stays in the cytoplasm due to active nuclear export mediated by its C-terminal peptide. In immunodeficient-patient cells expressing mutant AID lacking its C-terminus, a catalytically active AID-delC protein accumulates in the nucleus but nevertheless fails to support CSR. To resolve this apparent paradox, we dissected the function of AID-delC proteins in the CSR process and found that they cannot efficiently target antibody genes. We demonstrate that AID-delC proteins form condensates both in vivo and in vitro, dependent on its N-terminus and on a surface arginine-rich patch. Co-expression of AID-delC and wild-type AID leads to an unbalanced nuclear AID-delC/AID ratio, with AID-delC proteins able to trap wild-type AID in condensates, resulting in a dominant-negative phenotype that could contribute to immunodeficiency. The co-condensation model of mutant and wild-type proteins could be an alternative explanation for the dominant-negative effect in genetic disorders.
    Keywords:  activation-induced cytidine deaminase; class switch recombination; dominant-negative; immunodeficiency; protein condensation
    DOI:  https://doi.org/10.15252/embj.2021109324
  6. Sci Adv. 2022 Apr 29. 8(17): eabm3945
    Inheritance of repressed chromatin domains during S phase requires the histone chaperone NPM1.
    Thelma M Escobar, Jia-Ray Yu, Sanxiong Liu, Kimberly Lucero, Nikita Vasilyev, Evgeny Nudler, Danny Reinberg.
      The epigenetic process safeguards cell identity during cell division through the inheritance of appropriate gene expression profiles. We demonstrated previously that parental nucleosomes are inherited by the same chromatin domains during DNA replication only in the case of repressed chromatin. We now show that this specificity is conveyed by NPM1, a histone H3/H4 chaperone. Proteomic analyses of late S-phase chromatin revealed NPM1 in association with both H3K27me3, an integral component of facultative heterochromatin, and MCM2, an integral component of the DNA replication machinery; moreover, NPM1 interacts directly with PRC2 and with MCM2. Given that NPM1 is essential, the inheritance of repressed chromatin domains was examined anew using mESCs expressing an auxin-degradable version of endogenous NPM1. Upon NPM1 degradation, cells accumulated in the G1-S phase of the cell cycle and parental nucleosome inheritance from repressed chromatin domains was markedly compromised. NPM1 chaperone activity may contribute to the integrity of this process as appropriate inheritance required the NPM1 acidic patches.
    DOI:  https://doi.org/10.1126/sciadv.abm3945
  7. J Cell Biol. 2022 Jun 06. pii: e202108093. [Epub ahead of print]221(6):
    Lineage tracing clarifies the cellular origin of tissue-resident macrophages in the developing heart.
    Kuo Liu, Hengwei Jin, Muxue Tang, Shaohua Zhang, Xueying Tian, Mingjun Zhang, Ximeng Han, Xiuxiu Liu, Juan Tang, Wenjuan Pu, Yan Li, Lingjuan He, Zhongzhou Yang, Kathy O Lui, Bin Zhou.
      Tissue-resident macrophages play essential functions in the maintenance of tissue homeostasis and repair. Recently, the endocardium has been reported as a de novo hemogenic site for the contribution of hematopoietic cells, including cardiac macrophages, during embryogenesis. These observations challenge the current consensus that hematopoiesis originates from the hemogenic endothelium within the yolk sac and dorsal aorta. Whether the developing endocardium has such a hemogenic potential requires further investigation. Here, we generated new genetic tools to trace endocardial cells and reassessed their potential contribution to hematopoietic cells in the developing heart. Fate-mapping analyses revealed that the endocardium contributed minimally to cardiac macrophages and circulating blood cells. Instead, cardiac macrophages were mainly derived from the endothelium during primitive/transient definitive (yolk sac) and definitive (dorsal aorta) hematopoiesis. Our findings refute the concept of endocardial hematopoiesis, suggesting that the developing endocardium gives rise minimally to hematopoietic cells, including cardiac macrophages.
    DOI:  https://doi.org/10.1083/jcb.202108093
  8. Nat Commun. 2022 Apr 28. 13(1): 2329
    Kronos scRT: a uniform framework for single-cell replication timing analysis.
    Stefano Gnan, Joseph M Josephides, Xia Wu, Manuela Spagnuolo, Dalila Saulebekova, Mylène Bohec, Marie Dumont, Laura G Baudrin, Daniele Fachinetti, Sylvain Baulande, Chun-Long Chen.
      Mammalian genomes are replicated in a cell type-specific order and in coordination with transcription and chromatin organization. Currently, single-cell replication studies require individual processing of sorted cells, yielding a limited number (<100) of cells. Here, we develop Kronos scRT, a software for single-cell Replication Timing (scRT) analysis. Kronos scRT does not require a specific platform or cell sorting, which allows investigating large datasets obtained from asynchronous cells. By applying our tool to published data as well as droplet-based single-cell whole-genome sequencing data generated in this study, we exploit scRT from thousands of cells for different mouse and human cell lines. Our results demonstrate that although genomic regions are frequently replicated around their population average RT, replication can occur stochastically throughout S phase. Altogether, Kronos scRT allows fast and comprehensive investigations of the RT programme at the single-cell resolution for both homogeneous and heterogeneous cell populations.
    DOI:  https://doi.org/10.1038/s41467-022-30043-x
  9. Nat Commun. 2022 Apr 27. 13(1): 2274
    The timing of differentiation and potency of CD8 effector function is set by RNA binding proteins.
    Georg Petkau, Twm J Mitchell, Krishnendu Chakraborty, Sarah E Bell, Vanessa D Angeli, Louise Matheson, David J Turner, Alexander Saveliev, Ozge Gizlenci, Fiamma Salerno, Peter D Katsikis, Martin Turner.
      CD8+ T cell differentiation into effector cells is initiated early after antigen encounter by signals from the T cell antigen receptor and costimulatory molecules. The molecular mechanisms that establish the timing and rate of differentiation however are not defined. Here we show that the RNA binding proteins (RBP) ZFP36 and ZFP36L1 limit the rate of differentiation of activated naïve CD8+ T cells and the potency of the resulting cytotoxic lymphocytes. The RBP function in an early and short temporal window to enforce dependency on costimulation via CD28 for full T cell activation and effector differentiation by directly binding mRNA of NF-κB, Irf8 and Notch1 transcription factors and cytokines, including Il2. Their absence in T cells, or the adoptive transfer of small numbers of CD8+ T cells lacking the RBP, promotes resilience to influenza A virus infection without immunopathology. These findings highlight ZFP36 and ZFP36L1 as nodes for the integration of the early T cell activation signals controlling the speed and quality of the CD8+ T cell response.
    DOI:  https://doi.org/10.1038/s41467-022-29979-x
  10. Nat Commun. 2022 Apr 29. 13(1): 2339
    Reference-free cell type deconvolution of multi-cellular pixel-resolution spatially resolved transcriptomics data.
    Brendan F Miller, Feiyang Huang, Lyla Atta, Arpan Sahoo, Jean Fan.
      Recent technological advancements have enabled spatially resolved transcriptomic profiling but at multi-cellular pixel resolution, thereby hindering the identification of cell-type-specific spatial patterns and gene expression variation. To address this challenge, we develop STdeconvolve as a reference-free approach to deconvolve underlying cell types comprising such multi-cellular pixel resolution spatial transcriptomics (ST) datasets. Using simulated as well as real ST datasets from diverse spatial transcriptomics technologies comprising a variety of spatial resolutions such as Spatial Transcriptomics, 10X Visium, DBiT-seq, and Slide-seq, we show that STdeconvolve can effectively recover cell-type transcriptional profiles and their proportional representation within pixels without reliance on external single-cell transcriptomics references. STdeconvolve provides comparable performance to existing reference-based methods when suitable single-cell references are available, as well as potentially superior performance when suitable single-cell references are not available. STdeconvolve is available as an open-source R software package with the source code available at https://github.com/JEFworks-Lab/STdeconvolve .
    DOI:  https://doi.org/10.1038/s41467-022-30033-z
  11. Cell Rep. 2022 Apr 26. pii: S2211-1247(22)00341-2. [Epub ahead of print]39(4): 110593
    piRNA-guided intron removal from pre-mRNAs regulates density-dependent reproductive strategy.
    Jing He, Ya Nan Zhu, Bingcai Wang, Pengcheng Yang, Wei Guo, Bo Liang, Feng Jiang, Huimin Wang, Yuanyuan Wei, Le Kang.
      Animal density-dependent experiences have profound effects on reproductive strategies with marked fecundity differences. Migratory locust adopts distinct population density-dependent reproductive strategies to cope with their respective life cycles, but the mechanisms remain poorly understood. Here, we report that Piwi-interacting RNAs (piRNAs) in the locust germline play key roles in this process. We find that the locust Piwi protein Liwi1 and piRNAs are highly expressed in early developing egg chambers in solitarious locusts, which have higher fecundity than gregarious locusts. Approximately 40% of solitarious locust-associated piRNAs map to protein-coding genes. We find that Liwi1/piRNAs facilitate pre-mRNA splicing of oocyte development-related genes, such as oo18 RNA-binding protein (Orb), in the germline by recruiting the splicing factor U2AF35 to piRNA-targeted introns, thereby increasing fecundity. Such piRNA-guided pre-mRNA splicing is also functional in Drosophila and mouse germ cells. We uncover a piRNA-guided splicing mechanism for processing reproduction-related mRNAs and determining animal reproductive strategies.
    Keywords:  CP: Molecular Biology; Orb; Piwi-interacting RNAs; fecundity plasticity; spliceosomes
    DOI:  https://doi.org/10.1016/j.celrep.2022.110593
  12. Nat Commun. 2022 Apr 25. 13(1): 2210
    Reduced chromatin accessibility correlates with resistance to Notch activation.
    Jelle van den Ameele, Robert Krautz, Seth W Cheetham, Alex P A Donovan, Oriol Llorà-Batlle, Rebecca Yakob, Andrea H Brand.
      The Notch signalling pathway is a master regulator of cell fate transitions in development and disease. In the brain, Notch promotes neural stem cell (NSC) proliferation, regulates neuronal migration and maturation and can act as an oncogene or tumour suppressor. How NOTCH and its transcription factor RBPJ activate distinct gene regulatory networks in closely related cell types in vivo remains to be determined. Here we use Targeted DamID (TaDa), requiring only thousands of cells, to identify NOTCH and RBPJ binding in NSCs and their progeny in the mouse embryonic cerebral cortex in vivo. We find that NOTCH and RBPJ associate with a broad network of NSC genes. Repression of NSC-specific Notch target genes in intermediate progenitors and neurons correlates with decreased chromatin accessibility, suggesting that chromatin compaction may contribute to restricting NOTCH-mediated transactivation.
    DOI:  https://doi.org/10.1038/s41467-022-29834-z
  13. Diabetes. 2022 Apr 26. pii: db210834. [Epub ahead of print]
    β-Cell Succinate Dehydrogenase Deficiency Triggers Metabolic Dysfunction and Insulinopenic Diabetes.
    Sooyeon Lee, Haixia Xu, Aidan Van Vleck, Alex M Mawla, Albert Mao Li, Jiangbin Ye, Mark O Huising, Justin P Annes.
      Mitochondrial dysfunction plays a central role in Type 2 Diabetes (T2D); however, the pathogenic mechanisms in pancreatic β-cells are incompletely elucidated. Succinate dehydrogenase (SDH) is a key mitochondrial enzyme with dual functions in the TCA cycle and electron transport chain (ETC). Using human diabetic samples and a mouse model of β-cell-specific SDH ablation (SDHBβKO), we define SDH deficiency as a driver of mitochondrial dysfunction in β-cell failure and insulinopenic diabetes. β-Cell SDH deficiency impairs glucose-induced respiratory oxidative phosphorylation and mitochondrial membrane potential (ΔΨm) collapse, thereby compromising glucose-stimulated ATP production, insulin secretion and β-cell growth. Mechanistically, metabolomic and transcriptomic studies reveal that the loss of SDH causes excess succinate accumulation, which inappropriately activates mTORC1-regulated metabolic anabolism, including increased SREBP-regulated lipid synthesis. These alterations, which mirror diabetes-associated human β-cell dysfunction, are partially reversed by acute mTOR inhibition with rapamycin. We propose SDH deficiency as a contributing mechanism to the progressive β-cell failure of diabetes and identify mTORC1 inhibition as a potential mitigation strategy.
    DOI:  https://doi.org/10.2337/db21-0834
  14. Nat Commun. 2022 Apr 26. 13(1): 2256
    Ebola virus VP35 hijacks the PKA-CREB1 pathway for replication and pathogenesis by AKIP1 association.
    Lin Zhu, Ting Gao, Yi Huang, Jing Jin, Di Wang, Leike Zhang, Yanwen Jin, Ping Li, Yong Hu, Yan Wu, Hainan Liu, Qincai Dong, Guangfei Wang, Tong Zheng, Caiwei Song, Yu Bai, Xun Zhang, Yaoning Liu, Weihong Yang, Ke Xu, Gang Zou, Lei Zhao, Ruiyuan Cao, Wu Zhong, Xianzhu Xia, Gengfu Xiao, Xuan Liu, Cheng Cao.
      Ebola virus (EBOV), one of the deadliest viruses, is the cause of fatal Ebola virus disease (EVD). The underlying mechanism of viral replication and EBOV-related hemorrhage is not fully understood. Here, we show that EBOV VP35, a cofactor of viral RNA-dependent RNA polymerase, binds human A kinase interacting protein (AKIP1), which consequently activates protein kinase A (PKA) and the PKA-downstream transcription factor CREB1. During EBOV infection, CREB1 is recruited into EBOV ribonucleoprotein complexes in viral inclusion bodies (VIBs) and employed for viral replication. AKIP1 depletion or PKA-CREB1 inhibition dramatically impairs EBOV replication. Meanwhile, the transcription of several coagulation-related genes, including THBD and SERPINB2, is substantially upregulated by VP35-dependent CREB1 activation, which may contribute to EBOV-related hemorrhage. The finding that EBOV VP35 hijacks the host PKA-CREB1 signal axis for viral replication and pathogenesis provides novel potential therapeutic approaches against EVD.
    DOI:  https://doi.org/10.1038/s41467-022-29948-4
  15. Nat Commun. 2022 Apr 25. 13(1): 2233
    Subthalamic nucleus stabilizes movements by reducing neural spike variability in monkey basal ganglia.
    Taku Hasegawa, Satomi Chiken, Kenta Kobayashi, Atsushi Nambu.
      The subthalamic nucleus projects to the external and internal pallidum, the modulatory and output nuclei of the basal ganglia, respectively, and plays an indispensable role in controlling voluntary movements. However, the precise mechanism by which the subthalamic nucleus controls pallidal activity and movements remains elusive. Here, we utilize chemogenetics to reversibly reduce neural activity of the motor subregion of the subthalamic nucleus in three macaque monkeys (Macaca fuscata, both sexes) during a reaching task. Systemic administration of chemogenetic ligands prolongs movement time and increases spike train variability in the pallidum, but only slightly affects firing rate modulations. Across-trial analyses reveal that the irregular discharges in the pallidum coincides with prolonged movement time. Reduction of subthalamic activity also induces excessive abnormal movements in the contralateral forelimb, which are preceded by subthalamic and pallidal phasic activity changes. Our results suggest that the subthalamic nucleus stabilizes pallidal spike trains and achieves stable movements.
    DOI:  https://doi.org/10.1038/s41467-022-29750-2
  16. Nat Commun. 2022 Apr 26. 13(1): 2246
    Knockdown of GABAA alpha3 subunits on thalamic reticular neurons enhances deep sleep in mice.
    David S Uygun, Chun Yang, Elena R Tilli, Fumi Katsuki, Erik L Hodges, James T McKenna, James M McNally, Ritchie E Brown, Radhika Basheer.
      Identification of mechanisms which increase deep sleep could lead to novel treatments which promote the restorative effects of sleep. Here, we show that knockdown of the α3 GABAA-receptor subunit from parvalbumin neurons in the thalamic reticular nucleus using CRISPR-Cas9 gene editing increased the thalamocortical delta (1.5-4 Hz) oscillations which are implicated in many health-promoting effects of sleep. Inhibitory synaptic currents in thalamic reticular parvalbumin neurons were strongly reduced in vitro. Further analysis revealed that delta power in long NREM bouts prior to NREM-REM transitions was preferentially affected by deletion of α3 subunits. Our results identify a role for GABAA receptors on thalamic reticular nucleus neurons and suggest antagonism of α3 subunits as a strategy to enhance delta activity during sleep.
    DOI:  https://doi.org/10.1038/s41467-022-29852-x
  17. Nat Commun. 2022 Apr 25. 13(1): 2226
    Transcription factors AP-2α and AP-2β regulate distinct segments of the distal nephron in the mammalian kidney.
    Joseph O Lamontagne, Hui Zhang, Alia M Zeid, Karin Strittmatter, Alicia D Rocha, Trevor Williams, Sheryl Zhang, Alexander G Marneros.
      Transcription factors AP-2α and AP-2β have been suggested to regulate the differentiation of nephron precursor populations towards distal nephron segments. Here, we show that in the adult mammalian kidney AP-2α is found in medullary collecting ducts, whereas AP-2β is found in distal nephron segments except for medullary collecting ducts. Inactivation of AP-2α in nephron progenitor cells does not affect mammalian nephrogenesis, whereas its inactivation in collecting ducts leads to defects in medullary collecting ducts in the adult. Heterozygosity for AP-2β in nephron progenitor cells leads to progressive distal convoluted tubule abnormalities and β-catenin/mTOR hyperactivation that is associated with renal fibrosis and cysts. Complete loss of AP-2β in nephron progenitor cells caused an absence of distal convoluted tubules, renal cysts, and fibrosis with β-catenin/mTOR hyperactivation, and early postnatal death. Thus, AP-2α and AP-2β have non-redundant distinct spatiotemporal functions in separate segments of the distal nephron in the mammalian kidney.
    DOI:  https://doi.org/10.1038/s41467-022-29644-3
  18. Kidney Int. 2022 May;pii: S0085-2538(22)00098-9. [Epub ahead of print]101(5): 872-874
    Lay A TRAP for myeloid cell response in diabetic kidney disease.
    Hiroshi Nishi.
      The functions of the renin-angiotensin system are crucial in the progression of diabetic kidney disease. ATRAP is a type 1 angiotensin II receptor-associated protein that negatively regulates intracellular angiotensin II signaling. In this issue, Haruhara et al. revealed that ATRAP deficiency of diabetic mice decreases anti-inflammatory macrophage infiltration and exacerbates albuminuria. The adoptive transfer and tubule-specific depletion of ATRAP highlight the crosstalk between glomerular injury and tubulointerstitial angiotensin II signaling and innate immunity.
    DOI:  https://doi.org/10.1016/j.kint.2022.02.001
  19. Nature. 2022 Apr 27.
    Breakage of cytoplasmic chromosomes by pathological DNA base excision repair.
    Shangming Tang, Ema Stokasimov, Yuxiang Cui, David Pellman.
      Chromothripsis is a catastrophic mutational process that promotes tumorigenesis and causes congenital disease1-4. Chromothripsis originates from aberrations of nuclei called micronuclei or chromosome bridge5-8. These structures have fragile nuclear envelopes (NEs) that spontaneously rupture9,10, leading to DNA damage when chromatin is exposed to the interphase cytoplasm. Here, we identify a mechanism explaining a major fraction of this DNA damage. Micronuclei accumulate large amounts of RNA-DNA hybrids, which are edited by ADAR enzymes (adenine deaminases acting on RNA) to generate deoxyinosine (dI). dI is then converted into abasic sites by a DNA base excision repair (BER) glycosylase, MPG (N-methyl-purine DNA glycosylase)11,12. These abasic sites are cleaved by the BER endonuclease, APE1 (apurinic/apyrimidinic endonuclease)12, creating single-strand DNA nicks that can be converted to DNA double strand breaks by DNA replication or when closely spaced nicks occur on opposite strands13,14. This model predicts that MPG should be able to remove the dI base from the DNA strand of RNA-DNA hybrids, which we demonstrate using pure proteins and oligonucleotide substrates. These findings identify a mechanism for fragmentation of micronuclear chromosomes, an important step in generating chromothripsis. Rather than breaking any normal chromosome, we propose that the eukaryotic cytoplasm only damages chromosomes with preexisting defects such as the DNA base abnormality described here.
    DOI:  https://doi.org/10.1038/s41586-022-04767-1
  20. Nat Commun. 2022 Apr 28. 13(1): 2286
    ERK1/2 is an ancestral organising signal in spiral cleavage.
    Océane Seudre, Allan M Carrillo-Baltodano, Yan Liang, José M Martín-Durán.
      Animal development is classified as conditional or autonomous based on whether cell fates are specified through inductive signals or maternal determinants, respectively. Yet how these two major developmental modes evolved remains unclear. During spiral cleavage-a stereotypic embryogenesis ancestral to 15 invertebrate groups, including molluscs and annelids-most lineages specify cell fates conditionally, while some define the primary axial fates autonomously. To identify the mechanisms driving this change, we study Owenia fusiformis, an early-branching, conditional annelid. In Owenia, ERK1/2-mediated FGF receptor signalling specifies the endomesodermal progenitor. This cell likely acts as an organiser, inducing mesodermal and posterodorsal fates in neighbouring cells and repressing anteriorising signals. The organising role of ERK1/2 in Owenia is shared with molluscs, but not with autonomous annelids. Together, these findings suggest that conditional specification of an ERK1/2+ embryonic organiser is ancestral in spiral cleavage and was repeatedly lost in annelid lineages with autonomous development.
    DOI:  https://doi.org/10.1038/s41467-022-30004-4
  21. Nat Struct Mol Biol. 2022 Apr 28.
    Single-stranded nucleic acid binding and coacervation by linker histone H1.
    Rachel Leicher, Adewola Osunsade, Gabriella N L Chua, Sarah C Faulkner, Andrew P Latham, John W Watters, Tuan Nguyen, Emily C Beckwitt, Sophia Christodoulou-Rubalcava, Paul G Young, Bin Zhang, Yael David, Shixin Liu.
      The H1 linker histone family is the most abundant group of eukaryotic chromatin-binding proteins. However, their contribution to chromosome structure and function remains incompletely understood. Here we use single-molecule fluorescence and force microscopy to directly visualize the behavior of H1 on various nucleic acid and nucleosome substrates. We observe that H1 coalesces around single-stranded DNA generated from tension-induced DNA duplex melting. Using a droplet fusion assay controlled by optical tweezers, we find that single-stranded nucleic acids mediate the formation of gel-like H1 droplets, whereas H1-double-stranded DNA and H1-nucleosome droplets are more liquid-like. Molecular dynamics simulations reveal that multivalent and transient engagement of H1 with unpaired DNA strands drives their enhanced phase separation. Using eGFP-tagged H1, we demonstrate that inducing single-stranded DNA accumulation in cells causes an increase in H1 puncta that are able to fuse. We further show that H1 and Replication Protein A occupy separate nuclear regions, but that H1 colocalizes with the replication factor Proliferating Cell Nuclear Antigen, particularly after DNA damage. Overall, our results provide a refined perspective on the diverse roles of H1 in genome organization and maintenance, and indicate its involvement at stalled replication forks.
    DOI:  https://doi.org/10.1038/s41594-022-00760-4
  22. Cell Death Differ. 2022 Apr 27.
    GSK3β mediates the spatiotemporal dynamics of NLRP3 inflammasome activation.
    Suyavaran Arumugam, Yanqin Qin, Ziwen Liang, Sheng-Na Han, S L Tejaswi Boodapati, Junzi Li, Qiuxia Lu, Richard A Flavell, Wajahat Z Mehal, Xinshou Ouyang.
      Subcellular machinery of NLRP3 is essential for inflammasome assembly and activation. However, the stepwise process and mechanistic basis of NLRP3 engagement with organelles remain unclear. Herein, we demonstrated glycogen synthase kinase 3β (GSK3β) as a molecular determinant for the spatiotemporal dynamics of NLRP3 inflammasome activation. Using live cell multispectral time-lapse tracking acquisition, we observed that upon stimuli NLRP3 was transiently associated with mitochondria and subsequently recruited to the Golgi network (TGN) where it was retained for inflammasome assembly. This occurred in relation to the temporal contact of mitochondria to Golgi apparatus. NLRP3 stimuli initiate GSK3β activation with subsequent binding to NLRP3, facilitating NLRP3 recruitment to mitochondria and transition to TGN. GSK3β activation also phosphorylates phosphatidylinositol 4-kinase 2 Α (PI4k2A) in TGN to promote sustained NLRP3 oligomerization. Our study has identified the interplay between GSK3β signaling and the organelles dynamics of NLRP3 required for inflammasome activation and opens new avenues for therapeutic intervention.
    DOI:  https://doi.org/10.1038/s41418-022-00997-y
  23. Nat Immunol. 2022 Apr 29.
    Caspase-11 interaction with NLRP3 potentiates the noncanonical activation of the NLRP3 inflammasome.
    Julien Moretti, Baosen Jia, Zachary Hutchins, Soumit Roy, Hilary Yip, Jiahui Wu, Meimei Shan, Samie R Jaffrey, Jörn Coers, J Magarian Blander.
      Caspase-11 detection of intracellular lipopolysaccharide (LPS) from invasive Gram-negative bacteria mediates noncanonical activation of the NLRP3 inflammasome. While avirulent bacteria do not invade the cytosol, their presence in tissues necessitates clearance and immune system mobilization. Despite sharing LPS, only live avirulent Gram-negative bacteria activate the NLRP3 inflammasome. Here, we found that bacterial mRNA, which signals bacterial viability, was required alongside LPS for noncanonical activation of the NLRP3 inflammasome in macrophages. Concurrent detection of bacterial RNA by NLRP3 and binding of LPS by pro-caspase-11 mediated a pro-caspase-11-NLRP3 interaction before caspase-11 activation and inflammasome assembly. LPS binding to pro-caspase-11 augmented bacterial mRNA-dependent assembly of the NLRP3 inflammasome, while bacterial viability and an assembled NLRP3 inflammasome were necessary for activation of LPS-bound pro-caspase-11. Thus, the pro-caspase-11-NLRP3 interaction nucleated a scaffold for their interdependent activation explaining their functional reciprocal exclusivity. Our findings inform new vaccine adjuvant combinations and sepsis therapy.
    DOI:  https://doi.org/10.1038/s41590-022-01192-4
  24. Cell Mol Immunol. 2022 Apr 25.
    IFN-γ+ cytotoxic CD4+ T lymphocytes are involved in the pathogenesis of colitis induced by IL-23 and the food colorant Red 40.
    Lili Chen, Zhengxiang He, Bernardo S Reis, Jesse D Gelles, Jerry Edward Chipuk, Adrian T Ting, Julie A Spicer, Joseph A Trapani, Glaucia C Furtado, Sergio A Lira.
      The food colorant Red 40 is an environmental risk factor for colitis development in mice with increased expression of interleukin (IL)-23. This immune response is mediated by CD4+ T cells, but mechanistic insights into how these CD4+ T cells trigger and perpetuate colitis have remained elusive. Here, using single-cell transcriptomic analysis, we found that several CD4+ T-cell subsets are present in the intestines of colitic mice, including an interferon (IFN)-γ-producing subset. In vivo challenge of primed mice with Red 40 promoted rapid activation of CD4+ T cells and caused marked intestinal epithelial cell (IEC) apoptosis that was attenuated by depletion of CD4+ cells and blockade of IFN-γ. Ex vivo experiments showed that intestinal CD4+ T cells from colitic mice directly promoted apoptosis of IECs and intestinal enteroids. CD4+ T cell-mediated cytotoxicity was contact-dependent and required FasL, which promoted caspase-dependent cell death in target IECs. Genetic ablation of IFN-γ constrained IL-23- and Red 40-induced colitis development, and blockade of IFN-γ inhibited epithelial cell death in vivo. These results advance the understanding of the mechanisms regulating colitis development caused by IL-23 and food colorants and identify IFN-γ+ cytotoxic CD4+ T cells as a new potential therapeutic target for colitis.
    Keywords:  Allura Red; IL23; Cytotoxic CD4+ T cells; CD4+ CTL; Inflammation; Epithelium damage; Colitis
    DOI:  https://doi.org/10.1038/s41423-022-00864-3
  25. Nat Med. 2022 Apr 28.
    Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA.
    Smita S Chandran, Jiaqi Ma, Martin G Klatt, Friederike Dündar, Chaitanya Bandlamudi, Pedram Razavi, Hannah Y Wen, Britta Weigelt, Paul Zumbo, Si Ning Fu, Lauren B Banks, Fei Yi, Enric Vercher, Inaki Etxeberria, Watchain D Bestman, Arnaud Da Cruz Paula, Ilinca S Aricescu, Alexander Drilon, Doron Betel, David A Scheinberg, Brian M Baker, Christopher A Klebanoff.
      Public neoantigens (NeoAgs) represent an elite class of shared cancer-specific epitopes derived from recurrently mutated driver genes. Here we describe a high-throughput platform combining single-cell transcriptomic and T cell receptor (TCR) sequencing to establish whether mutant PIK3CA, among the most frequently genomically altered driver oncogenes, generates an immunogenic public NeoAg. Using this strategy, we developed a panel of TCRs that recognize an endogenously processed neopeptide encompassing a common PIK3CA hotspot mutation restricted by the prevalent human leukocyte antigen (HLA)-A*03:01 allele. Mechanistically, immunogenicity to this public NeoAg arises from enhanced neopeptide/HLA complex stability caused by a preferred HLA anchor substitution. Structural studies indicated that the HLA-bound neopeptide presents a comparatively 'featureless' surface dominated by the peptide's backbone. To bind this epitope with high specificity and affinity, we discovered that a lead TCR clinical candidate engages the neopeptide through an extended interface facilitated by an unusually long CDR3β loop. In patients with diverse malignancies, we observed NeoAg clonal conservation and spontaneous immunogenicity to the neoepitope. Finally, adoptive transfer of TCR-engineered T cells led to tumor regression in vivo in mice bearing PIK3CA-mutant tumors but not wild-type PIK3CA tumors. Together, these findings establish the immunogenicity and therapeutic potential of a mutant PIK3CA-derived public NeoAg.
    DOI:  https://doi.org/10.1038/s41591-022-01786-3
  26. Nat Commun. 2022 Apr 28. 13(1): 2321
    Deficiency in coatomer complex I causes aberrant activation of STING signalling.
    Annemarie Steiner, Katja Hrovat-Schaale, Ignazia Prigione, Chien-Hsiung Yu, Pawat Laohamonthonkul, Cassandra R Harapas, Ronnie Ren Jie Low, Dominic De Nardo, Laura F Dagley, Michael J Mlodzianoski, Kelly L Rogers, Thomas Zillinger, Gunther Hartmann, Michael P Gantier, Marco Gattorno, Matthias Geyer, Stefano Volpi, Sophia Davidson, Seth L Masters.
      Coatomer complex I (COPI) mediates retrograde vesicular trafficking from Golgi to the endoplasmic reticulum (ER) and within Golgi compartments. Deficiency in subunit alpha causes COPA syndrome and is associated with type I IFN signalling, although the upstream innate immune sensor involved was unknown. Using in vitro models we find aberrant activation of the STING pathway due to deficient retrograde but probably not intra-Golgi transport. Further we find the upstream cytosolic DNA sensor cGAS as essentially required to drive type I IFN signalling. Genetic deletion of COPI subunits COPG1 or COPD similarly induces type I IFN activation in vitro, which suggests that inflammatory diseases associated with mutations in other COPI subunit genes may exist. Finally, we demonstrate that inflammation in COPA syndrome patient peripheral blood mononuclear cells and COPI-deficient cell lines is ameliorated by treatment with the small molecule STING inhibitor H-151, suggesting targeted inhibition of the cGAS/STING pathway as a promising therapeutic approach.
    DOI:  https://doi.org/10.1038/s41467-022-29946-6
  27. Immunity. 2022 Apr 20. pii: S1074-7613(22)00172-8. [Epub ahead of print]
    Tissue remodeling by an opportunistic pathogen triggers allergic inflammation.
    Karen Agaronyan, Lokesh Sharma, Bharat Vaidyanathan, Keith Glenn, Shuang Yu, Charles Annicelli, Talia D Wiggen, Mitchell R Penningroth, Ryan C Hunter, Charles S Dela Cruz, Ruslan Medzhitov.
      Different effector arms of the immune system are optimized to protect from different classes of pathogens. In some cases, pathogens manipulate the host immune system to promote the wrong type of effector response-a phenomenon known as immune deviation. Typically, immune deviation helps pathogens to avoid destructive immune responses. Here, we report on a type of immune deviation whereby an opportunistic pathogen, Pseudomonas aeruginosa (P. aeruginosa), induces the type 2 immune response resulting in mucin production that is used as an energy source by the pathogen. Specifically, P. aeruginosa-secreted toxin, LasB, processed and activated epithelial amphiregulin to induce type 2 inflammation and mucin production. This "niche remodeling" by P. aeruginosa promoted colonization and, as a by-product, allergic sensitization. Our study thus reveals a type of bacterial immune deviation by increasing nutrient supply. It also uncovers a mechanism of allergic sensitization by a bacterial virulence factor.
    Keywords:  LasB; P. aeruginosa; allergic inflammation; amphiregulin; immune deviation; lung; mucin; opportunistic pathogen; type 2 immunity
    DOI:  https://doi.org/10.1016/j.immuni.2022.04.001
  28. J Neuroinflammation. 2022 Apr 29. 19(1): 103
    CD4+c-Met+Itgα4+ T cell subset promotes murine neuroinflammation.
    Mahdia Benkhoucha, Ngoc Lan Tran, Gautier Breville, Isis Senoner, Paul F Bradfield, Thalia Papayannopoulou, Doron Merkler, Thomas Korn, Patrice H Lalive.
       OBJECTIVE: c-Met, a tyrosine kinase receptor, is the unique receptor for hepatocyte growth factor (HGF). The HGF/c-Met axis is reported to modulate cell migration, maturation, cytokine production, and antigen presentation. Here, we report that CD4+c-Met+ T cells are detected at increased levels in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS).
    METHODS: c-Met expression by CD4+ T cells was analyzed mostly by flow cytometry and by immunohistochemistry from mice and human PBMCs. The in vivo role of CD4+c-Met+ T cells was assessed in EAE.
    RESULTS: CD4+c-Met+ T cells found in the CNS during EAE peak disease are characterized by a pro-inflammatory phenotype skewed towards a Th1 and Th17 polarization, with enhanced adhesion and transmigration capacities correlating with increased expression of integrin α4 (Itgα4). The adoptive transfer of Itgα4-expressing CD4+Vα3.2+c-Met+ T cells induces increased disease severity compared to CD4+Vα3.2+c-Met- T cells. Finally, CD4+c-Met+ T cells are detected in the brain of MS patients, as well as in the blood with a higher level of Itgα4. These results highlight c-Met as an immune marker of highly pathogenic pro-inflammatory and pro-migratory CD4+ T lymphocytes associated with neuroinflammation.
    Keywords:  EAE; HGF; Integrin; MS; Neuroinflammation; T lymphocytes; Transmigration; c-Met
    DOI:  https://doi.org/10.1186/s12974-022-02461-7
  29. Nature. 2022 Apr 27.
    Structure of human chromatin-remodelling PBAF complex bound to a nucleosome.
    Junjie Yuan, Kangjing Chen, Wenbo Zhang, Zhucheng Chen.
      DNA wraps around the histone octamer to form nucleosomes1, the repeating unit of chromatin, which create barriers for accessing genetic information. Snf2-like chromatin remodellers couple the energy of ATP binding and hydrolysis to reposition and recompose the nucleosome, and have vital roles in various chromatin-based transactions2,3. Here we report the cryo-electron microscopy structure of the 12-subunit human chromatin-remodelling polybromo-associated BRG1-associated factor (PBAF) complex bound to the nucleosome. The motor subunit SMARCA4 engages the nucleosome in the active conformation, which reveals clustering of multiple disease-associated mutations at the interfaces that are essential for chromatin-remodelling activity. SMARCA4 recognizes the H2A-H2B acidic pocket of the nucleosome through three arginine anchors of the Snf2 ATP coupling (SnAc) domain. PBAF shows notable functional modularity, and most of the auxiliary subunits are interwoven into three lobe-like submodules for nucleosome recognition. The PBAF-specific auxiliary subunit ARID2 acts as the structural core for assembly of the DNA-binding lobe, whereas PBRM1, PHF10 and BRD7 are collectively incorporated into the lobe for histone tail binding. Together, our findings provide mechanistic insights into nucleosome recognition by PBAF and a structural basis for understanding SMARCA4-related human diseases.
    DOI:  https://doi.org/10.1038/s41586-022-04658-5
  30. Nat Commun. 2022 Apr 28. 13(1): 2324
    Enhancement of anaerobic glycolysis - a role of PGC-1α4 in resistance exercise.
    Jin-Ho Koh, Mark W Pataky, Surendra Dasari, Katherine A Klaus, Ivan Vuckovic, Gregory N Ruegsegger, Arathi Prabha Kumar, Matthew M Robinson, K Sreekumaran Nair.
      Resistance exercise training (RET) is an effective countermeasure to sarcopenia, related frailty and metabolic disorders. Here, we show that an RET-induced increase in PGC-1α4 (an isoform of the transcriptional co-activator PGC-1α) expression not only promotes muscle hypertrophy but also enhances glycolysis, providing a rapid supply of ATP for muscle contractions. In human skeletal muscle, PGC-1α4 binds to the nuclear receptor PPARβ following RET, resulting in downstream effects on the expressions of key glycolytic genes. In myotubes, we show that PGC-1α4 overexpression increases anaerobic glycolysis in a PPARβ-dependent manner and promotes muscle glucose uptake and fat oxidation. In contrast, we found that an acute resistance exercise bout activates glycolysis in an AMPK-dependent manner. These results provide a mechanistic link between RET and improved glucose metabolism, offering an important therapeutic target to counteract aging and inactivity-induced metabolic diseases benefitting those who cannot exercise due to many reasons.
    DOI:  https://doi.org/10.1038/s41467-022-30056-6
  31. Nature. 2022 Apr 27.
    β-Hydroxybutyrate suppresses colorectal cancer.
    Oxana Dmitrieva-Posocco, Andrea C Wong, Patrick Lundgren, Aleksandra M Golos, Hélène C Descamps, Lenka Dohnalová, Zvi Cramer, Yuhua Tian, Brian Yueh, Onur Eskiocak, Gabor Egervari, Yemin Lan, Jinping Liu, Jiaxin Fan, Jihee Kim, Bhoomi Madhu, Kai Markus Schneider, Svetlana Khoziainova, Natalia Andreeva, Qiaohong Wang, Ning Li, Emma E Furth, Will Bailis, Judith R Kelsen, Kathryn E Hamilton, Klaus H Kaestner, Shelley L Berger, Jonathan A Epstein, Rajan Jain, Mingyao Li, Semir Beyaz, Christopher J Lengner, Bryson W Katona, Sergei I Grivennikov, Christoph A Thaiss, Maayan Levy.
      Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed1. Here we identify a metabolite signalling pathway that provides actionable insights towards this goal. We perform a dietary screen in autochthonous animal models of CRC and find that ketogenic diets exhibit a strong tumour-inhibitory effect. These properties of ketogenic diets are recapitulated by the ketone body β-hydroxybutyrate (BHB), which reduces the proliferation of colonic crypt cells and potently suppresses intestinal tumour growth. We find that BHB acts through the surface receptor Hcar2 and induces the transcriptional regulator Hopx, thereby altering gene expression and inhibiting cell proliferation. Cancer organoid assays and single-cell RNA sequencing of biopsies from patients with CRC provide evidence that elevated BHB levels and active HOPX are associated with reduced intestinal epithelial proliferation in humans. This study thus identifies a BHB-triggered pathway regulating intestinal tumorigenesis and indicates that oral or systemic interventions with a single metabolite may complement current prevention and treatment strategies for CRC.
    DOI:  https://doi.org/10.1038/s41586-022-04649-6
  32. Nat Chem Biol. 2022 May;18(5): 470-481
    Lipid metabolism in T cell signaling and function.
    Seon Ah Lim, Wei Su, Nicole M Chapman, Hongbo Chi.
      T cells orchestrate adaptive immunity against pathogens and other immune challenges, but their dysfunction can also mediate the pathogenesis of cancer and autoimmunity. Metabolic adaptation in response to immunological and microenvironmental signals contributes to T cell function and fate decision. Lipid metabolism has emerged as a key regulator of T cell responses, with selective lipid metabolites serving as metabolic rheostats to integrate environmental cues and interplay with intracellular signaling processes. Here, we discuss how extracellular, de novo synthesized and membrane lipids orchestrate T cell biology. We also describe the roles of lipids as regulators of intracellular signaling at the levels of transcriptional, epigenetic and post-translational regulation in T cells. Finally, we summarize therapeutic targeting of lipid metabolism and signaling, and conclude with a discussion of important future directions. Understanding the molecular and functional interplay between lipid metabolism and T cell biology will ultimately inform therapeutic intervention for human disease.
    DOI:  https://doi.org/10.1038/s41589-022-01017-3
  33. J Exp Med. 2022 Jun 06. pii: e20210749. [Epub ahead of print]219(6):
    In vivo labeling reveals continuous trafficking of TCF-1+ T cells between tumor and lymphoid tissue.
    Zhi Li, Zewen K Tuong, Isaac Dean, Claire Willis, Fabrina Gaspal, Rémi Fiancette, Suaad Idris, Bethany Kennedy, John R Ferdinand, Ana Peñalver, Mia Cabantous, Syed Murtuza Baker, Jeremy W Fry, Gianluca Carlesso, Scott A Hammond, Simon J Dovedi, Matthew R Hepworth, Menna R Clatworthy, David R Withers.
      Improving the efficacy of immune checkpoint therapies will require a better understanding of how immune cells are recruited and sustained in tumors. Here, we used the photoconversion of the tumor immune cell compartment to identify newly entering lymphocytes, determine how they change over time, and investigate their egress from the tumor. Combining single-cell transcriptomics and flow cytometry, we found that while a diverse mix of CD8 T cell subsets enter the tumor, all CD8 T cells retained within this environment for more than 72 h developed an exhausted phenotype, revealing the rapid establishment of this program. Rather than forming tumor-resident populations, non-effector subsets, which express TCF-1 and include memory and stem-like cells, were continuously recruited into the tumor, but this recruitment was balanced by concurrent egress to the tumor-draining lymph node. Thus, the TCF-1+ CD8 T cell niche in tumors is highly dynamic, with the circulation of cells between the tumor and peripheral lymphoid tissue to bridge systemic and intratumoral responses.
    DOI:  https://doi.org/10.1084/jem.20210749
  34. Nat Cell Biol. 2022 Apr 28.
    Identification of a retinoic acid-dependent haemogenic endothelial progenitor from human pluripotent stem cells.
    Stephanie A Luff, J Philip Creamer, Sara Valsoni, Carissa Dege, Rebecca Scarfò, Analisa Dacunto, Sara Cascione, Lauren N Randolph, Eleonora Cavalca, Ivan Merelli, Samantha A Morris, Andrea Ditadi, Christopher M Sturgeon.
      The generation of haematopoietic stem cells (HSCs) from human pluripotent stem cells (hPSCs) is a major goal for regenerative medicine. During embryonic development, HSCs derive from haemogenic endothelium (HE) in a NOTCH- and retinoic acid (RA)-dependent manner. Although a WNT-dependent (WNTd) patterning of nascent hPSC mesoderm specifies clonally multipotent intra-embryonic-like HOXA+ definitive HE, this HE is functionally unresponsive to RA. Here we show that WNTd mesoderm, before HE specification, is actually composed of two distinct KDR+ CD34neg populations. CXCR4negCYP26A1+ mesoderm gives rise to HOXA+ multilineage definitive HE in an RA-independent manner, whereas CXCR4+ ALDH1A2+ mesoderm gives rise to HOXA+ multilineage definitive HE in a stage-specific, RA-dependent manner. Furthermore, both RA-independent (RAi) and RA-dependent (RAd) HE harbour transcriptional similarity to distinct populations found in the early human embryo, including HSC-competent HE. This revised model of human haematopoietic development provides essential resolution to the regulation and origins of the multiple waves of haematopoiesis. These insights provide the basis for the generation of specific haematopoietic populations, including the de novo specification of HSCs.
    DOI:  https://doi.org/10.1038/s41556-022-00898-9
  35. Front Immunol. 2022 ;13 873217
    CD39 and CD326 Are Bona Fide Markers of Murine and Human Plasma Cells and Identify a Bone Marrow Specific Plasma Cell Subpopulation in Lupus.
    Van Duc Dang, Elodie Mohr, Franziska Szelinski, Tuan Anh Le, Jacob Ritter, Timo Hinnenthal, Ana-Luisa Stefanski, Eva Schrezenmeier, Soeren Ocvirk, Christian Hipfl, Sebastian Hardt, Qingyu Cheng, Falk Hiepe, Max Löhning, Thomas Dörner, Andreia C Lino.
      Antibody-secreting cells (ASCs) contribute to immunity through production of antibodies and cytokines. Identification of specific markers of ASC would allow selective targeting of these cells in several disease contexts. Here, we performed an unbiased, large-scale protein screening, and identified twelve new molecules that are specifically expressed by murine ASCs. Expression of these markers, particularly CD39, CD81, CD130, and CD326, is stable and offers an improved resolution for ASC identification. We accessed their expression in germ-free conditions and in T cell deficient mice, showing that at least in part their expression is controlled by microbial- and T cell-derived signals. Further analysis of lupus mice revealed the presence of a subpopulation of LAG-3- plasma cells, co-expressing high amounts of CD39 and CD326 in the bone marrow. This population was IgM+ and correlated with IgM anti-dsDNA autoantibodies in sera. Importantly, we found that CD39, CD81, CD130, and CD326 are also expressed by human peripheral blood and bone marrow ASCs. Our data provide innovative insights into ASC biology and function in mice and human, and identify an intriguing BM specific CD39++CD326++ ASC subpopulation in autoimmunity.
    Keywords:  CD130; CD326; CD39; CD81; LAG-3; SLE; plasma cell markers; plasma cells
    DOI:  https://doi.org/10.3389/fimmu.2022.873217
  36. Curr Opin Genet Dev. 2022 Apr 20. pii: S0959-437X(22)00019-3. [Epub ahead of print]74 101910
    Epithelial-immune crosstalk in health and disease.
    Daniel Rosenblum, Shruti Naik.
      Far from inert structures, our body's epithelial boundaries engage in a dynamic crosstalk with immune cells that is vital for immune surveillance and barrier function. Using the skin and gut epithelium, two structurally distinct but critical environmental interfaces, here we review the context-dependent interactions between myriad immune cells and epithelial subsets. We discuss immune communique reserved for epithelial progenitors and the enduring consequences for tissue fitness. Then, we delve into the cellular and molecular exchanges between differentiated epithelial subsets and adjacent immune cells. Therapeutically targeting stage-specific immune-epithelial interaction could boost regeneration and mitigate inflammatory pathologies.
    DOI:  https://doi.org/10.1016/j.gde.2022.101910
  37. Sci Adv. 2022 Apr 29. 8(17): eabf2017
    ETS1 acts as a regulator of human healthy aging via decreasing ribosomal activity.
    Fu-Hui Xiao, Qin Yu, Zhi-Li Deng, Ke Yang, Yunshuang Ye, Ming-Xia Ge, Dongjing Yan, Hao-Tian Wang, Xiao-Qiong Chen, Li-Qin Yang, Bin-Yu Yang, Rong Lin, Wen Zhang, Xing-Li Yang, Lei Dong, Yonghan He, Jumin Zhou, Wang-Wei Cai, Ji Li, Qing-Peng Kong.
      Adaptation to reduced energy production during aging is a fundamental issue for maintaining healthspan or prolonging life span. Currently, however, the underlying mechanism in long-lived people remains poorly understood. Here, we analyzed transcriptomes of 193 long-lived individuals (LLIs) and 86 spouses of their children from two independent Chinese longevity cohorts and found that the ribosome pathway was significantly down-regulated in LLIs. We found that the down-regulation is likely controlled by ETS1 (ETS proto-oncogene 1), a transcription factor down-regulated in LLIs and positively coexpressed with most ribosomal protein genes (RPGs). Functional assays showed that ETS1 can bind to RPG promoters, while ETS1 knockdown reduces RPG expression and alleviates cellular senescence in human dermal fibroblast (HDF) and embryonic lung fibroblast (IMR-90) cells. As protein synthesis/turnover in ribosomes is an energy-intensive cellular process, the decline in ribosomal biogenesis governed by ETS1 in certain female LLIs may serve as an alternative mechanism to achieve energy-saving and healthy aging.
    DOI:  https://doi.org/10.1126/sciadv.abf2017
  38. Front Immunol. 2022 ;13 861262
    Promoter Binding and Nuclear Retention Features of Zebrafish IRF Family Members in IFN Response.
    Li-Li An, Xiang Zhao, Xiu-Ying Gong, Yi-Lin Li, Zi-Ling Qu, Hao-Yu Sun, Wen-Hao Guo, Cheng Dan, Jian-Fang Gui, Yi-Bing Zhang.
      Interferon regulatory factors (IRFs) constitute a family of transcription factors that synchronize interferon (IFN) antiviral response through translocating to nucleus and binding to the promoters of IFN and IFN-stimulated genes (ISGs). Fish contain 11 IRF members; however, whether or how fish IRF family genes function in IFN response remains limited. Herein, we determine the regulatory roles of 11 zebrafish IRF family members in IFN response relevant to their subcellular localization and promoter binding. Zebrafish IRF family members display three patterns of constitutive localization, only in nucleus (IRF1/2/9/11), only in cytoplasm (IRF3/5/7), and largely in nucleus with small amounts in cytoplasm (IRF4b/6/8/10). DNA pull-down assays confirm that all zebrafish IRF proteins are capable to bind fish IFN promoters, albeit to various degrees, thus regulating IFN gene transcription as activators (IRF1/3/5/6/7/8/9/11) or repressors (IRF2/4b/10). Further characterization of distinct IFN gene activation reveals that IRF1/3/5/6/7/8/9/11 efficiently stimulate zebrafish IFNφ1 expression, and IRF1/7/11 are responsible for zebrafish IFNφ3 expression. Two conserved basic residues within the helix α3 of DNA binding domains (DBDs) contribute to constitutive or inducible nuclear import for all zebrafish IRF family members and DNA binding for most members, thereby enabling them to function as transcription factors. Our results reveal a conserved and general mechanism that specifies zebrafish IRF family proteins to nuclear import and DNA binding, thereby regulating fish IFN response.
    Keywords:  DNA binding; interferon expression; interferon regulatory factor; nuclear import; nuclear localization signal
    DOI:  https://doi.org/10.3389/fimmu.2022.861262
  39. J Biol Chem. 2022 Apr 20. pii: S0021-9258(22)00406-9. [Epub ahead of print] 101966
    MicroRNA-200c coordinates HNF1 homeobox B and Apolipoprotein O functions to modulate lipid homeostasis in alcoholic fatty liver disease.
    Md Golam Mostofa, Melanie Tran, Shaynian Gilling, Grace Lee, Ondine Fraher, Lei Jin, Hyunju Kang, Young-Ki Park, Ji-Young Lee, Li Wang, Dong-Ju Shin.
      Hepatic steatosis is an initial manifestation of alcoholic liver disease. An imbalance of hepatic lipid processes including fatty acid uptake, esterification, oxidation, and triglyceride (TG) secretion leads to alcoholic fatty liver disease (AFL). However, the precise molecular mechanisms underlying the pathogenesis of AFL remain elusive. Here, we show that mice deficient in microRNAs (miR)-141 and -200c display resistance to the development of AFL. We found that miR-200c directly targets HNF1 homeobox B (Hnf1b), a transcriptional activator for microsomal triglyceride transfer protein (Mttp), as well as apolipoprotein O (ApoO), an integral component of the mitochondrial contact site and cristae organizing system complex (MICOS). We show that expression of these microRNAs is significantly induced by chronic ethanol exposure, which is accompanied by reduced HNF1B and APOO levels. Furthermore, miR-141/200c deficiency normalizes ethanol-mediated impairment of TG secretion, which can be attributed to the restored levels of HNF1B and MTTP, as well as phosphatidylcholine abundance. Moreover, we demonstrate that miR-141/200c deficiency restores ethanol-mediated inhibition of APOO expression and mitochondrial dysfunction, improving mitochondrial antioxidant defense capacity and fatty acid oxidation. Taken together, these results suggest that miR-200c contributes to the modulation of lipid homeostasis in alcoholic fatty liver disease by cooperatively regulating Hnf1b and ApoO functions.
    Keywords:  alcohol; lipid; liver; microRNA; mitochondria
    DOI:  https://doi.org/10.1016/j.jbc.2022.101966
  40. Cell Rep Methods. 2021 Oct 25. 1(6): 100089
    Sparse imaging and reconstruction tomography for high-speed high-resolution whole-brain imaging.
    Han Chen, Tianyi Huang, Yuexin Yang, Xiao Yao, Yan Huo, Yu Wang, Wenyu Zhao, Runan Ji, Hongjiang Yang, Zengcai V Guo.
      Understanding brain functions requires detailed knowledge of long-range connectivity through which different areas communicate. A key step toward illuminating the long-range structures is to image the whole brain at synaptic resolution to trace axonal arbors of individual neurons to their termini. However, high-resolution brain-wide imaging requires continuous imaging for many days to sample over 10 trillion voxels, even in the mouse brain. Here, we have developed a sparse imaging and reconstruction tomography (SMART) system that allows brain-wide imaging of cortical projection neurons at synaptic resolution in about 20 h, an order of magnitude faster than previous methods. Analyses of morphological features reveal that single cortical neurons show remarkable diversity in local and long-range projections, with prefrontal, premotor, and visual neurons having distinct distribution of dendritic and axonal features. The fast imaging system and diverse projection patterns of individual neurons highlight the importance of high-resolution brain-wide imaging in revealing full neuronal morphology.
    Keywords:  motor cortex; prefrontal cortex; single-neuron morphology; sparse imaging; spinning disk confocal; synaptic resolution; visual cortex; whole-brain imaging
    DOI:  https://doi.org/10.1016/j.crmeth.2021.100089
  41. Sci Adv. 2022 Apr 29. 8(17): eabm7012
    The immune checkpoint B7-H3 (CD276) regulates adipocyte progenitor metabolism and obesity development.
    Elodie Picarda, Phillip M Galbo, Haihong Zong, Meenu Rohini Rajan, Ville Wallenius, Deyou Zheng, Emma Börgeson, Rajat Singh, Jeffrey Pessin, Xingxing Zang.
      The immune checkpoint B7-H3 (CD276) is a member of the B7 family that has been studied in the tumor microenvironment and immunotherapy, but its potential role in metabolism remains largely unknown. Here, we show that B7-H3 is highly expressed in mouse and human adipose tissue at steady state, with the highest levels in adipocyte progenitor cells. B7-H3 is rapidly down-regulated upon the initiation of adipocyte differentiation. Combined RNA sequencing and metabolic studies reveal that B7-H3 stimulates glycolytic and mitochondrial activity of adipocyte progenitors. Loss of B7-H3 in progenitors results in impaired oxidative metabolism program and increased lipid accumulation in derived adipocytes. Consistent with these observations, mice knocked out for B7-H3 develop spontaneous obesity, metabolic dysfunction, and adipose tissue inflammation. Our results reveal an unexpected metabolic role for B7-H3 in adipose tissue and open potential new avenues for the treatment of metabolic diseases by targeting the B7-H3 pathway.
    DOI:  https://doi.org/10.1126/sciadv.abm7012
  42. Cell Rep. 2022 Apr 26. pii: S2211-1247(22)00515-0. [Epub ahead of print]39(4): 110751
    An increase in spontaneous activity mediates visual habituation.
    Jae-Eun Kang Miller, Bradley R Miller, Darik A O'Neil, Rafael Yuste.
      The cerebral cortex is spontaneously active, but the function of this ongoing activity remains unclear. To test whether spontaneous activity encodes learned experiences, we measured the response of neuronal populations in mouse primary visual cortex with chronic two-photon calcium imaging during visual habituation to a specific oriented stimulus. We find that, during habituation, spontaneous activity increases in neurons across the full range of orientation selectivity, eventually matching that of evoked levels. This increase in spontaneous activity robustly correlates with the degree of habituation. Moreover, boosting spontaneous activity with two-photon optogenetic stimulation to the levels of visually evoked activity accelerates habituation. Our study shows that cortical spontaneous activity is linked to habituation, and we propose that habituation unfolds by minimizing the difference between spontaneous and stimulus-evoked activity levels. We conclude that baseline spontaneous activity could gate incoming sensory information to the cortex based on the learned experience of the animal.
    Keywords:  CP: Neuroscience; V1; intrinsic activity; mouse; ongoing activity; perceptual learning; visual memory; visual recognition
    DOI:  https://doi.org/10.1016/j.celrep.2022.110751
  43. Front Immunol. 2022 ;13 811525
    TNFAIP3 Reduction-of-Function Drives Female Infertility and CNS Inflammation.
    Nathan W Zammit, Joseph McDowell, Joanna Warren, Walter Muskovic, Joanne Gamble, Yan-Chuan Shi, Dominik Kaczorowski, Chia-Ling Chan, Joseph Powell, Chris Ormandy, David Brown, Samantha R Oakes, Shane T Grey.
      Women with autoimmune and inflammatory aetiologies can exhibit reduced fecundity. TNFAIP3 is a master negative regulator of inflammation, and has been linked to many inflammatory conditions by genome wide associations studies, however its role in fertility remains unknown. Here we show that mice harbouring a mild Tnfaip3 reduction-of-function coding variant (Tnfaip3 I325N) that reduces the threshold for inflammatory NF-κB activation, exhibit reduced fecundity. Sub-fertility in Tnfaip3 I325N mice is associated with irregular estrous cycling, low numbers of ovarian secondary follicles, impaired mammary gland development and insulin resistance. These pathological features are associated with infertility in human subjects. Transplantation of Tnfaip3 I325N ovaries, mammary glands or pancreatic islets into wild-type recipients rescued estrous cycling, mammary branching and hyperinsulinemia respectively, pointing towards a cell-extrinsic hormonal mechanism. Examination of hypothalamic brain sections revealed increased levels of microglial activation with reduced levels of luteinizing hormone. TNFAIP3 coding variants may offer one contributing mechanism for the cause of sub-fertility observed across otherwise healthy populations as well as for the wide variety of auto-inflammatory conditions to which TNFAIP3 is associated. Further, TNFAIP3 represents a molecular mechanism that links heightened immunity with neuronal inflammatory homeostasis. These data also highlight that tuning-up immunity with TNFAIP3 comes with the potentially evolutionary significant trade-off of reduced fertility.
    Keywords:  A20; TNFAIP3; evolutionary medicine; fertility; inflammation; life-history; neuroinflammation; reproduction
    DOI:  https://doi.org/10.3389/fimmu.2022.811525
  44. Immunometabolism. 2022 ;pii: e220008. [Epub ahead of print]4(2):
    CD36-Mediated Fatty Acid Oxidation in Hematopoietic Stem Cells Is a Novel Mechanism of Emergency Hematopoiesis in Response to Infection.
    Maria Maryanovich, Keisuke Ito.
      Hematopoietic homeostasis depends on the close regulation of hematopoietic stem cell (HSC) activity in the bone marrow. Quiescence and activation in response to stress, among other changes in state, are mediated by shifts in HSC metabolic activity. Although HSC steady-state metabolism is well established, the mechanisms driving HSC activation, proliferation, and differentiation in response to stress remain poorly understood. Here we discuss a study by Mistry et al. that describes a novel metabolic mechanism that fuels HSC activation and expansion. The authors show that to meet their metabolic needs in response to infection, hematopoietic stem and progenitor cells uptake free fatty acids from their microenvironment via CD36 to fuel fatty acid oxidation. These exciting findings suggest that in the context of infection, HSCs undergo a metabolic shift toward fatty acid metabolism that drives emergency hematopoiesis and raise questions about the role of the microenvironment in this process.
    Keywords:  CD36; fatty-acid oxidation; hematopoiesis; hematopoietic stem cells; infection; oxidative phosphorylation
    DOI:  https://doi.org/10.20900/immunometab20220008
  45. Plast Reconstr Surg. 2022 May 01. 149(5): 1166-1167
    Discussion: Genetic Influence on Neurodevelopment in Nonsyndromic Craniosynostosis.
    Marie Bargiela, Eric C Liao.
      
    DOI:  https://doi.org/10.1097/PRS.0000000000009007
  46. Diabetes. 2022 Apr 26. pii: db210794. [Epub ahead of print]
    Endogenous Lipid-GPR120 Signaling Modulates Pancreatic Islet Homeostasis to Different Extents.
    Ya-Qin Du, Xue-Ying Sha, Jie Cheng, Jin Wang, Jing-Yu Lin, Wen-Tao An, Wei Pan, Li-Jun Zhang, Xiao-Na Tao, YunFei Xu, Ying-Li Jia, Zhao Yang, Peng Xiao, Ming Liu, Jin-Peng Sun, Xiao Yu.
      Long-chain fatty acids (LCFAs) not only are energy sources but also serve as signaling molecules. GPR120, an LCFA receptor, plays key roles in maintaining metabolic homeostasis. However, whether endogenous ligand-GPR120 circuits exist and how such circuits function in pancreatic islets are unclear. Here, we found that endogenous GPR120 activity in pancreatic δ cells modulated islet functions. At least two unsaturated LCFAs, oleic acid (OA) and linoleic acid (LA), were identified as GPR120 agonists within pancreatic islets. These two LCFAs promoted insulin secretion by inhibiting somatostatin secretion, and showed bias activation of GPR120 in a model system. Compared to OA, LA exerted higher potency in promoting insulin secretion, which is dependent on β-arrestin2 function. Moreover, GPR120 signaling was impaired in the diabetic db/db model, and replenishing OA and LA improved islet function in both the db/db- and STZ-treated diabetic models. Consistently, the administration of LA improved glucose metabolism in db/db mice. Collectively, our results reveal that endogenous LCFA-GPR120 circuits exist and modulate homeostasis in pancreatic islets. The contributions of phenotype differences caused by different LCFA-GPR120 circuits within islets highlight the roles of fine-tuned ligand-receptor signaling networks in maintaining islet homeostasis.
    DOI:  https://doi.org/10.2337/db21-0794
  47. Methods Mol Biol. 2022 ;2491 263-291
    Yeast Display for the Identification of Peptide-MHC Ligands of Immune Receptors.
    Brooke D Huisman, Beth E Grace, Patrick V Holec, Michael E Birnbaum.
      T cells detect peptide antigens presented by major histocompatibility complex (MHC) proteins via their T cell receptor (TCR). The sequence diversity of possible antigens, with trillions of potential peptide-MHC targets, makes it challenging to study, characterize, and manipulate the peptide repertoire of a given TCR. Yeast display has been utilized to study the interactions between peptide-MHCs and T cell receptors to facilitate high-throughput screening of peptide-MHC libraries. Here we present insights on designing and validating a peptide-MHC yeast display construct, designing and constructing peptide libraries, conducting selections, and preparing, processing, and analyzing peptide library sequencing data. Applications for this approach are broad, including characterizing peptide-MHC recognition profiles for a TCR, screening for high-affinity mimotopes of known TCR-binding peptides, and identifying natural ligands of TCRs from expanded T cells.
    Keywords:  Ligand identification; Peptide-MHC; T cell receptor; Yeast display
    DOI:  https://doi.org/10.1007/978-1-0716-2285-8_15
  48. EMBO J. 2022 Apr 25. e111290
    Atossa: a royal link between OXPHOS metabolism and macrophage migration.
    Pedro Latorre-Muro, Pere Puigserver.
      The ability of immune cells to penetrate affected tissues is highly dependent on energy provided by mitochondria, yet their involvement in promoting migration remains unclear. Recent work by Emtenani et al (2022) describes a nuclear Atossa-Porthos axis that adjusts transcription and translation of a small subset of OXPHOS genes to increase mitochondrial bioenergetics and allow macrophage tissue invasion in flies.
    DOI:  https://doi.org/10.15252/embj.2022111290
  49. Nat Genet. 2022 Apr 25.
    HOXB13 suppresses de novo lipogenesis through HDAC3-mediated epigenetic reprogramming in prostate cancer.
    Xiaodong Lu, Ka-Wing Fong, Galina Gritsina, Fang Wang, Sylvan C Baca, Lourdes T Brea, Jacob E Berchuck, Sandor Spisak, Jenny Ross, Colm Morrissey, Eva Corey, Navdeep S Chandel, William J Catalona, Ximing Yang, Matthew L Freedman, Jonathan C Zhao, Jindan Yu.
      HOXB13, a homeodomain transcription factor, critically regulates androgen receptor (AR) activities and androgen-dependent prostate cancer (PCa) growth. However, its functions in AR-independent contexts remain elusive. Here we report HOXB13 interaction with histone deacetylase HDAC3, which is disrupted by the HOXB13 G84E mutation that has been associated with early-onset PCa. Independently of AR, HOXB13 recruits HDAC3 to lipogenic enhancers to catalyze histone deacetylation and suppress lipogenic regulators such as fatty acid synthase. Analysis of human tissues reveals that the HOXB13 gene is hypermethylated and downregulated in approximately 30% of metastatic castration-resistant PCa. HOXB13 loss or G84E mutation leads to lipid accumulation in PCa cells, thereby promoting cell motility and xenograft tumor metastasis, which is mitigated by pharmaceutical inhibition of fatty acid synthase. In summary, we present evidence that HOXB13 recruits HDAC3 to suppress de novo lipogenesis and inhibit tumor metastasis and that lipogenic pathway inhibitors may be useful to treat HOXB13-low PCa.
    DOI:  https://doi.org/10.1038/s41588-022-01045-8
  50. Cell. 2022 Apr 21. pii: S0092-8674(22)00393-2. [Epub ahead of print]
    Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities.
    Xiaofei Li, Hui Wang, Xiang Yu, Gundappa Saha, Lydia Kalafati, Charalampos Ioannidis, Ioannis Mitroulis, Mihai G Netea, Triantafyllos Chavakis, George Hajishengallis.
      Bone marrow (BM)-mediated trained innate immunity (TII) is a state of heightened immune responsiveness of hematopoietic stem and progenitor cells (HSPC) and their myeloid progeny. We show here that maladaptive BM-mediated TII underlies inflammatory comorbidities, as exemplified by the periodontitis-arthritis axis. Experimental-periodontitis-related systemic inflammation in mice induced epigenetic rewiring of HSPC and led to sustained enhancement of production of myeloid cells with increased inflammatory preparedness. The periodontitis-induced trained phenotype was transmissible by BM transplantation to naive recipients, which exhibited increased inflammatory responsiveness and disease severity when subjected to inflammatory arthritis. IL-1 signaling in HSPC was essential for their maladaptive training by periodontitis. Therefore, maladaptive innate immune training of myelopoiesis underlies inflammatory comorbidities and may be pharmacologically targeted to treat them via a holistic approach.
    Keywords:  arthritis; bone marrow transplantation; comorbidities; epigenetic rewiring; hematopoietic stem and progenitor cells; inflammation; myelopoiesis; periodontitis; trained immunity
    DOI:  https://doi.org/10.1016/j.cell.2022.03.043
  51. Viral Immunol. 2022 Apr;35(3): 223-235
    Hepatitis C Virus Alters Macrophage Cholesterol Metabolism Through Interaction with Scavenger Receptors.
    Lucas T Jennelle, Tshifhiwa Magoro, Angelina R Angelucci, Aditya Dandekar, Young S Hahn.
      Lipid accumulation and inflammation act together to induce, sustain, and further development of chronic liver disease. Hepatitis C virus (HCV) infection induces metabolic and immune changes in liver macrophages, promoting lipid accumulation and inflammation that synergize and culminate in the development of steatohepatitis and fibrogenesis. Chronic HCV patients have increased liver macrophages with disruptions in cholesterol metabolism and alterations in inflammatory mediators. While HCV-induced changes in inflammatory mediators are well documented, how HCV triggers metabolic change in macrophages is unknown. In this report, we examined the mechanism of macrophage sensing of HCV to cause metabolic impairment and subsequent immune dysfunction. We demonstrate that HCV protein and RNA kinetics in macrophages are distinct from hepatocytes. In macrophages, HCV RNAs and protein accumulate rapidly after exposure but internalized RNAs quickly decline to a low-level set point. Notably, exposure of macrophages to HCV resulted in increased lipids and cholesterol and activation of cholesterol-sensing, immunomodulatory liver X receptors (LXRs). Furthermore, we provide evidence that HCV RNA accumulation in macrophages occurs through scavenging receptors. These results suggest that HCV released from infected hepatocytes stimulates accumulation of lipids and activation of LXR in macrophages contributing to metabolic changes involved in HCV-induced chronic liver disease. Our results provide novel insight into mechanisms through which impaired lipid metabolism in macrophages associated with HCV infection promotes development of liver steatohepatitis and fibrosis.
    Keywords:  LXR; SR-B1; cholesterol; hepatitis C virus; macrophages; scavenger receptor
    DOI:  https://doi.org/10.1089/vim.2021.0101
  52. Mol Psychiatry. 2022 Apr 26.
    Epitranscriptomic dynamics in brain development and disease.
    Andrew M Shafik, Emily G Allen, Peng Jin.
      Distinct cell types are generated at specific times during brain development and are regulated by epigenetic, transcriptional, and newly emerging epitranscriptomic mechanisms. RNA modifications are known to affect many aspects of RNA metabolism and have been implicated in the regulation of various biological processes and in disease. Recent studies imply that dysregulation of the epitranscriptome may be significantly associated with neuropsychiatric, neurodevelopmental, and neurodegenerative disorders. Here we review the current knowledge surrounding the role of the RNA modifications N6-methyladenosine, 5-methylcytidine, pseudouridine, A-to-I RNA editing, 2'O-methylation, and their associated machinery, in brain development and human diseases. We also highlight the need for the development of new technologies in the pursuit of directly mapping RNA modifications in both genome- and single-molecule-level approach.
    DOI:  https://doi.org/10.1038/s41380-022-01570-2
  53. Cell Rep. 2022 Apr 26. pii: S2211-1247(22)00511-3. [Epub ahead of print]39(4): 110747
    Interferons limit autoantigen-specific CD8+ T-cell expansion in the non-obese diabetic mouse.
    Gaurang Jhala, Balasubramanian Krishnamurthy, Thomas C Brodnicki, Tingting Ge, Satoru Akazawa, Claudia Selck, Prerak M Trivedi, Evan G Pappas, Leanne Mackin, Nicola Principe, Erwan Brémaud, David J De George, Louis Boon, Ian Smyth, Jonathan Chee, Thomas W H Kay, Helen E Thomas.
      Interferon gamma (IFNγ) is a proinflammatory cytokine implicated in autoimmune diseases. However, deficiency or neutralization of IFNγ is ineffective in reducing disease. We characterize islet antigen-specific T cells in non-obese diabetic (NOD) mice lacking all three IFN receptor genes. Diabetes is minimally affected, but at 125 days of age, antigen-specific CD8+ T cells, quantified using major histocompatibility complex class I tetramers, are present in 10-fold greater numbers in Ifngr-mutant NOD mice. T cells from Ifngr-mutant mice have increased proliferative responses to interleukin-2 (IL-2). They also have reduced phosphorylated STAT1 and its target gene, suppressor of cytokine signaling 1 (SOCS-1). IFNγ controls the expansion of antigen-specific CD8+ T cells by mechanisms which include increased SOCS-1 expression that regulates IL-2 signaling. The expanded CD8+ T cells are likely to contribute to normal diabetes progression despite reduced inflammation in Ifngr-mutant mice.
    Keywords:  CP: Immunology; MHC tetramers; autoimmune diabetes; interferons; interleukin-2; suppressor of cytokine singling 1
    DOI:  https://doi.org/10.1016/j.celrep.2022.110747
  54. Nat Metab. 2022 Apr;4(4): 476-494
    Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance.
    V Pellegrinelli, S Rodriguez-Cuenca, C Rouault, E Figueroa-Juarez, H Schilbert, S Virtue, J M Moreno-Navarrete, G Bidault, M C Vázquez-Borrego, A R Dias, B Pucker, M Dale, M Campbell, S Carobbio, Y H Lin, M Vacca, J Aron-Wisnewsky, S Mora, M M Masiero, A Emmanouilidou, S Mukhopadhyay, G Dougan, M den Hoed, R J F Loos, J M Fernández-Real, D Chiarugi, K Clément, A Vidal-Puig.
      Resulting from impaired collagen turnover, fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance (IR). Prolidase, also known as peptidase D (PEPD), plays a vital role in collagen turnover by degrading proline-containing dipeptides but its specific functional relevance in AT is unknown. Here we show that in human and mouse obesity, PEPD expression and activity decrease in AT, and PEPD is released into the systemic circulation, which promotes fibrosis and AT IR. Loss of the enzymatic function of PEPD by genetic ablation or pharmacological inhibition causes AT fibrosis in mice. In addition to its intracellular enzymatic role, secreted extracellular PEPD protein enhances macrophage and adipocyte fibro-inflammatory responses via EGFR signalling, thereby promoting AT fibrosis and IR. We further show that decreased prolidase activity is coupled with increased systemic levels of PEPD that act as a pathogenic trigger of AT fibrosis and IR. Thus, PEPD produced by macrophages might serve as a biomarker of AT fibro-inflammation and could represent a therapeutic target for AT fibrosis and obesity-associated IR and type 2 diabetes.
    DOI:  https://doi.org/10.1038/s42255-022-00561-5
  55. Front Immunol. 2022 ;13 850616
    Contact-Dependent Granzyme B-Mediated Cytotoxicity of Th17-Polarized Cells Toward Human Oligodendrocytes.
    Hélène Jamann, Qiao-Ling Cui, Haritha L Desu, Florian Pernin, Olivier Tastet, Alexandre Halaweh, Negar Farzam-Kia, Victoria Hannah Mamane, Oumarou Ouédraogo, Aurélie Cleret-Buhot, Audrey Daigneault, Renaud Balthazard, Wendy Klement, Florent Lemaître, Nathalie Arbour, Jack Antel, Jo Anne Stratton, Catherine Larochelle.
      Multiple sclerosis (MS) is characterized by the loss of myelin and of myelin-producing oligodendrocytes (OLs) in the central nervous system (CNS). Pro-inflammatory CD4+ Th17 cells are considered pathogenic in MS and are harmful to OLs. We investigated the mechanisms driving human CD4+ T cell-mediated OL cell death. Using fluorescent and brightfield in vitro live imaging, we found that compared to Th2-polarized cells, Th17-polarized cells show greater interactions with primary human OLs and human oligodendrocytic cell line MO3.13, displaying longer duration of contact, lower mean speed, and higher rate of vesicle-like structure formation at the sites of contact. Using single-cell RNA sequencing, we assessed the transcriptomic profile of primary human OLs and Th17-polarized cells in direct contact or separated by an insert. We showed that upon close interaction, OLs upregulate the expression of mRNA coding for chemokines and antioxidant/anti-apoptotic molecules, while Th17-polarized cells upregulate the expression of mRNA coding for chemokines and pro-inflammatory cytokines such as IL-17A, IFN-γ, and granzyme B. We found that secretion of CCL3, CXCL10, IFN-γ, TNFα, and granzyme B is induced upon direct contact in cocultures of human Th17-polarized cells with human OLs. In addition, we validated by flow cytometry and immunofluorescence that granzyme B levels are upregulated in Th17-polarized compared to Th2-polarized cells and are even higher in Th17-polarized cells upon direct contact with OLs or MO3.13 cells compared to Th17-polarized cells separated from OLs by an insert. Moreover, granzyme B is detected in OLs and MO3.13 cells following direct contact with Th17-polarized cells, suggesting the release of granzyme B from Th17-polarized cells into OLs/MO3.13 cells. To confirm granzyme B-mediated cytotoxicity toward OLs, we showed that recombinant human granzyme B can induce OLs and MO3.13 cell death. Furthermore, pretreatment of Th17-polarized cells with a reversible granzyme B blocker (Ac-IEPD-CHO) or a natural granzyme B blocker (serpina3N) improved survival of MO3.13 cells upon coculture with Th17 cells. In conclusion, we showed that human Th17-polarized cells form biologically significant contacts with human OLs and exert direct toxicity by releasing granzyme B.
    Keywords:  CD4 T lymphocytes; Th17 cells; granzyme B; human oligodendrocytes; multiple sclerosis; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2022.850616
  56. Nat Commun. 2022 Apr 28. 13(1): 2303
    A theory of cortical map formation in the visual brain.
    Sohrab Najafian, Erin Koch, Kai Lun Teh, Jianzhong Jin, Hamed Rahimi-Nasrabadi, Qasim Zaidi, Jens Kremkow, Jose-Manuel Alonso.
      The cerebral cortex receives multiple afferents from the thalamus that segregate by stimulus modality forming cortical maps for each sense. In vision, the primary visual cortex maps the multiple dimensions of the visual stimulus in patterns that vary across species for reasons unknown. Here we introduce a general theory of cortical map formation, which proposes that map diversity emerges from species variations in the thalamic afferent density sampling sensory space. In the theory, increasing afferent sampling density enlarges the cortical domains representing the same visual point, allowing the segregation of afferents and cortical targets by multiple stimulus dimensions. We illustrate the theory with an afferent-density model that accurately replicates the maps of different species through afferent segregation followed by thalamocortical convergence pruned by visual experience. Because thalamocortical pathways use similar mechanisms for axon segregation and pruning, the theory may extend to other sensory areas of the mammalian brain.
    DOI:  https://doi.org/10.1038/s41467-022-29433-y
  57. Nat Immunol. 2022 Apr 29.
    TCF-1: a maverick in T cell development and function.
    Fotini Gounari, Khashayarsha Khazaie.
      The T cell-specific DNA-binding protein TCF-1 is a central regulator of T cell development and function along multiple stages and lineages. Because it interacts with β-catenin, TCF-1 has been classically viewed as a downstream effector of canonical Wnt signaling, although there is strong evidence for β-catenin-independent TCF-1 functions. TCF-1 co-binds accessible regulatory regions containing or lacking its conserved motif and cooperates with other nuclear factors to establish context-dependent epigenetic and transcription programs that are essential for T cell development and for regulating immune responses to infection, autoimmunity and cancer. Although it has mostly been associated with positive regulation of chromatin accessibility and gene expression, TCF-1 has the potential to reduce chromatin accessibility and thereby suppress gene expression. In addition, the binding of TCF-1 bends the DNA and affects the chromatin conformation genome wide. This Review discusses the current understanding of the multiple roles of TCF-1 in T cell development and function and their mechanistic underpinnings.
    DOI:  https://doi.org/10.1038/s41590-022-01194-2
  58. Cell. 2022 Apr 20. pii: S0092-8674(22)00391-9. [Epub ahead of print]
    Enhanced safety and efficacy of protease-regulated CAR-T cell receptors.
    Louai Labanieh, Robbie G Majzner, Dorota Klysz, Elena Sotillo, Chris J Fisher, José G Vilches-Moure, Kaithlen Zen B Pacheco, Meena Malipatlolla, Peng Xu, Jessica H Hui, Tara Murty, Johanna Theruvath, Nishant Mehta, Sean A Yamada-Hunter, Evan W Weber, Sabine Heitzeneder, Kevin R Parker, Ansuman T Satpathy, Howard Y Chang, Michael Z Lin, Jennifer R Cochran, Crystal L Mackall.
      Regulatable CAR platforms could circumvent toxicities associated with CAR-T therapy, but existing systems have shortcomings including leakiness and attenuated activity. Here, we present SNIP CARs, a protease-based platform for regulating CAR activity using an FDA-approved small molecule. Design iterations yielded CAR-T cells that manifest full functional capacity with drug and no leaky activity in the absence of drug. In numerous models, SNIP CAR-T cells were more potent than constitutive CAR-T cells and showed diminished T cell exhaustion and greater stemness. In a ROR1-based CAR lethality model, drug cessation following toxicity onset reversed toxicity, thereby credentialing the platform as a safety switch. In the same model, reduced drug dosing opened a therapeutic window that resulted in tumor eradication in the absence of toxicity. SNIP CARs enable remote tuning of CAR activity, which provides solutions to safety and efficacy barriers that are currently limiting progress in using CAR-T cells to treat solid tumors.
    Keywords:  CAR-T therapy; T cell differentiation; T cell exhaustion; brain tumors; cellular immunotherapy; chimeric antigen receptors; immune cell engineering; solid cancers; synthetic biology
    DOI:  https://doi.org/10.1016/j.cell.2022.03.041
  59. Front Immunol. 2022 ;13 869447
    Natural Killer Cells in Multiple Sclerosis: Entering the Stage.
    Jarne Beliën, An Goris, Patrick Matthys.
      Studies investigating the immunopathology of multiple sclerosis (MS) have largely focused on adaptive T and B lymphocytes. However, in recent years there has been an increased interest in the contribution of innate immune cells, amongst which the natural killer (NK) cells. Apart from their canonical role of controlling viral infections, cell stress and malignancies, NK cells are increasingly being recognized for their modulating effect on the adaptive immune system, both in health and autoimmune disease. From different lines of research there is now evidence that NK cells contribute to MS immunopathology. In this review, we provide an overview of studies that have investigated the role of NK cells in the pathogenesis of MS by use of the experimental autoimmune encephalomyelitis (EAE) animal model, MS genetics or through ex vivo and in vitro work into the immunology of MS patients. With the advent of modern hypothesis-free technologies such as single-cell transcriptomics, we are exposing an unexpected NK cell heterogeneity, increasingly blurring the boundaries between adaptive and innate immunity. We conclude that unravelling this heterogeneity, as well as the mechanistic link between innate and adaptive immune cell functions will lay the foundation for the use of NK cells as prognostic tools and therapeutic targets in MS and a myriad of other currently uncurable autoimmune disorders.
    Keywords:  autoimmune disorders; experimental autoimmune encephalomyelitis (EAE); immune cell heterogeneity; multiple sclerosis; multiple sclerosis genetics; natural killer (NK) cells
    DOI:  https://doi.org/10.3389/fimmu.2022.869447
  60. Proc Natl Acad Sci U S A. 2022 May 03. 119(18): e2115567119
    Postmitotic G1 phase survivin drives mitogen-independent cell division of B lymphocytes.
    Amit Singh, Matthew H Spitzer, Jaimy P Joy, Mary Kaileh, Xiang Qiu, Garry P Nolan, Ranjan Sen.
      SignificanceThe prevailing dogma is that renewed mitogenic signaling is essential to traverse G1 phase of the cell cycle after each division. B lymphocytes undergo multiple mitotic divisions, termed clonal expansion, to expand antigen-specific cells that mediate effective immunity. Here we demonstrate that B cells that have undergone one cell division continue to proliferate even in absence of further mitogenic signals. This mitogen-independent proliferation is accompanied by an altered G1 phase marked by transcriptomic and proteomic features of G2/M. Survivin, a G2/M-specific oncogene, is required in G1 to achieve mitogen-independent proliferation.
    Keywords:  B lymphocytes; G1-S; cell cycle regulation; clonal expansion; mitogen-independent proliferation
    DOI:  https://doi.org/10.1073/pnas.2115567119
  61. Mol Biol Evol. 2022 Apr 28. pii: msac090. [Epub ahead of print]
    A genetic bottleneck of mitochondrial DNA during human lymphocyte development.
    Zhongjie Tang, Zhaolian Lu, Baizhen Chen, Weixing Zhang, Howard Y Chang, Zheng Hu, Jin Xu.
      Mitochondria are essential organelles in eukaryotic cells that provide critical support for energetic and metabolic homeostasis. Although the elimination of pathogenic mitochondrial DNA (mtDNA) mutations in somatic cells has been observed, the mechanisms for somatic cells to maintain proper functions despite their mtDNA mutation load are poorly understood. In this study, we analyzed somatic mtDNA mutations in more than 30,000 single human peripheral and bone marrow mononuclear cells. We observed a significant overrepresentation of homoplasmic mtDNA mutations in B, T and NK lymphocytes. Intriguingly, their overall mutational burden was lower than that in hematopoietic progenitors and myeloid cells. This characteristic mtDNA mutational landscape indicates a genetic bottleneck during lymphoid development, as confirmed with single cell datasets from multiple platforms and individuals. We further demonstrated that mtDNA replication lags behind cell proliferation in both pro-B and pre-B progenitor cells, thus likely causing the genetic bottleneck by diluting mtDNA copies per cell. Through computational simulations and approximate Bayesian computation (ABC), we recapitulated this lymphocyte-specific mutational landscape and estimated the minimal mtDNA copies as <30 in T, B, and NK lineages. Our integrative analysis revealed a novel discovery of a lymphoid-specific mtDNA genetic bottleneck, thus illuminating a potential mechanism used by highly metabolically active immune cells to limit their mtDNA mutation load.
    DOI:  https://doi.org/10.1093/molbev/msac090
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