9 results on '"Lee, Hong-Gyun"'
Search Results
2. Author Correction: Disease-associated astrocyte epigenetic memory promotes CNS pathology.
- Author
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Lee HG, Rone JM, Li Z, Akl CF, Shin SW, Lee JH, Flausino LE, Pernin F, Chao CC, Kleemann KL, Srun L, Illouz T, Giovannoni F, Charabati M, Sanmarco LM, Kenison JE, Piester G, Zandee SEJ, Antel JP, Rothhammer V, Wheeler MA, Prat A, Clark IC, and Quintana FJ
- Published
- 2024
- Full Text
- View/download PDF
3. Disease-associated astrocyte epigenetic memory promotes CNS pathology.
- Author
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Lee HG, Rone JM, Li Z, Akl CF, Shin SW, Lee JH, Flausino LE, Pernin F, Chao CC, Kleemann KL, Srun L, Illouz T, Giovannoni F, Charabati M, Sanmarco LM, Kenison JE, Piester G, Zandee SEJ, Antel JP, Rothhammer V, Wheeler MA, Prat A, Clark IC, and Quintana FJ
- Subjects
- Animals, Female, Humans, Male, Mice, Acetyl Coenzyme A metabolism, ATP Citrate (pro-S)-Lyase metabolism, Chromatin genetics, Chromatin metabolism, Chromatin Assembly and Disassembly, Chromatin Immunoprecipitation Sequencing, CRISPR-Cas Systems, Inflammation enzymology, Inflammation genetics, Inflammation metabolism, Inflammation pathology, Single-Cell Gene Expression Analysis, Transposases metabolism, Astrocytes enzymology, Astrocytes metabolism, Astrocytes pathology, Encephalomyelitis, Autoimmune, Experimental enzymology, Encephalomyelitis, Autoimmune, Experimental genetics, Encephalomyelitis, Autoimmune, Experimental metabolism, Encephalomyelitis, Autoimmune, Experimental pathology, Epigenetic Memory, Multiple Sclerosis enzymology, Multiple Sclerosis genetics, Multiple Sclerosis metabolism, Multiple Sclerosis pathology
- Abstract
Disease-associated astrocyte subsets contribute to the pathology of neurologic diseases, including multiple sclerosis and experimental autoimmune encephalomyelitis
1-8 (EAE), an experimental model for multiple sclerosis. However, little is known about the stability of these astrocyte subsets and their ability to integrate past stimulation events. Here we report the identification of an epigenetically controlled memory astrocyte subset that exhibits exacerbated pro-inflammatory responses upon rechallenge. Specifically, using a combination of single-cell RNA sequencing, assay for transposase-accessible chromatin with sequencing, chromatin immunoprecipitation with sequencing, focused interrogation of cells by nucleic acid detection and sequencing, and cell-specific in vivo CRISPR-Cas9-based genetic perturbation studies we established that astrocyte memory is controlled by the metabolic enzyme ATP-citrate lyase (ACLY), which produces acetyl coenzyme A (acetyl-CoA) that is used by histone acetyltransferase p300 to control chromatin accessibility. The number of ACLY+ p300+ memory astrocytes is increased in acute and chronic EAE models, and their genetic inactivation ameliorated EAE. We also detected the pro-inflammatory memory phenotype in human astrocytes in vitro; single-cell RNA sequencing and immunohistochemistry studies detected increased numbers of ACLY+ p300+ astrocytes in chronic multiple sclerosis lesions. In summary, these studies define an epigenetically controlled memory astrocyte subset that promotes CNS pathology in EAE and, potentially, multiple sclerosis. These findings may guide novel therapeutic approaches for multiple sclerosis and other neurologic diseases., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2024
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4. Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells.
- Author
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Sanmarco LM, Rone JM, Polonio CM, Fernandez Lahore G, Giovannoni F, Ferrara K, Gutierrez-Vazquez C, Li N, Sokolovska A, Plasencia A, Faust Akl C, Nanda P, Heck ES, Li Z, Lee HG, Chao CC, Rejano-Gordillo CM, Fonseca-Castro PH, Illouz T, Linnerbauer M, Kenison JE, Barilla RM, Farrenkopf D, Stevens NA, Piester G, Chung EN, Dailey L, Kuchroo VK, Hava D, Wheeler MA, Clish C, Nowarski R, Balsa E, Lora JM, and Quintana FJ
- Subjects
- Humans, Autoimmunity, Probiotics therapeutic use, Reactive Oxygen Species metabolism, T-Lymphocytes immunology, Feedback, Physiological, Lactase genetics, Lactase metabolism, Single-Cell Analysis, Autoimmune Diseases immunology, Autoimmune Diseases metabolism, Autoimmune Diseases prevention & control, Central Nervous System cytology, Central Nervous System immunology, Central Nervous System pathology, Dendritic Cells immunology, Dendritic Cells metabolism, Hypoxia-Inducible Factor 1, alpha Subunit chemistry, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Lactic Acid metabolism
- Abstract
Dendritic cells (DCs) have a role in the development and activation of self-reactive pathogenic T cells
1,2 . Genetic variants that are associated with the function of DCs have been linked to autoimmune disorders3,4 , and DCs are therefore attractive therapeutic targets for such diseases. However, developing DC-targeted therapies for autoimmunity requires identification of the mechanisms that regulate DC function. Here, using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies, we identify a regulatory loop of negative feedback that operates in DCs to limit immunopathology. Specifically, we find that lactate, produced by activated DCs and other immune cells, boosts the expression of NDUFA4L2 through a mechanism mediated by hypoxia-inducible factor 1α (HIF-1α). NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs that are involved in the control of pathogenic autoimmune T cells. We also engineer a probiotic that produces lactate and suppresses T cell autoimmunity through the activation of HIF-1α-NDUFA4L2 signalling in DCs. In summary, we identify an immunometabolic pathway that regulates DC function, and develop a synthetic probiotic for its therapeutic activation., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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5. Author Correction: Bystander CD4 + T cells: crossroads between innate and adaptive immunity.
- Author
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Lee HG, Cho MJ, and Choi JM
- Published
- 2023
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6. Steady-state memory-phenotype conventional CD4 + T cells exacerbate autoimmune neuroinflammation in a bystander manner via the Bhlhe40/GM-CSF axis.
- Author
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Cho MJ, Lee HG, Yoon JW, Kim GR, Koo JH, Taneja R, Edelson BT, Lee YJ, and Choi JM
- Subjects
- Mice, Animals, Immunity, Innate, Neuroinflammatory Diseases, Th17 Cells, Interleukin-23, Phenotype, Receptors, Antigen, T-Cell metabolism, CD4-Positive T-Lymphocytes, Mice, Inbred C57BL, Homeodomain Proteins genetics, Basic Helix-Loop-Helix Transcription Factors genetics, Granulocyte-Macrophage Colony-Stimulating Factor genetics, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Encephalomyelitis, Autoimmune, Experimental metabolism
- Abstract
Memory-phenotype (MP) CD4
+ T cells are a substantial population of conventional T cells that exist in steady-state mice, yet their immunological roles in autoimmune disease remain unclear. In this work, we unveil a unique phenotype of MP CD4+ T cells determined by analyzing single-cell transcriptomic data and T cell receptor (TCR) repertoires. We found that steady-state MP CD4+ T cells in the spleen were composed of heterogeneous effector subpopulations and existed regardless of germ and food antigen exposure. Distinct subpopulations of MP CD4+ T cells were specifically activated by IL-1 family cytokines and STAT activators, revealing that the cells exerted TCR-independent bystander effector functions similar to innate lymphoid cells. In particular, CCR6high subpopulation of MP CD4+ T cells were major responders to IL-23 and IL-1β without MOG35-55 antigen reactivity, which gave them pathogenic Th17 characteristics and allowed them to contribute to autoimmune encephalomyelitis. We identified that Bhlhe40 in CCR6high MP CD4+ T cells as a key regulator of GM-CSF expression through IL-23 and IL-1β signaling, contributing to central nervous system (CNS) pathology in experimental autoimmune encephalomyelitis. Collectively, our findings reveal the clearly distinct effector-like heterogeneity of MP CD4+ T cells in the steady state and indicate that CCR6high MP CD4+ T cells exacerbate autoimmune neuroinflammation via the Bhlhe40/GM-CSF axis in a bystander manner., (© 2023. The Author(s).)- Published
- 2023
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7. Identification of astrocyte regulators by nucleic acid cytometry.
- Author
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Clark IC, Wheeler MA, Lee HG, Li Z, Sanmarco LM, Thaploo S, Polonio CM, Shin SW, Scalisi G, Henry AR, Rone JM, Giovannoni F, Charabati M, Akl CF, Aleman DM, Zandee SEJ, Prat A, Douek DC, Boritz EA, Quintana FJ, and Abate AR
- Subjects
- Animals, Humans, Mice, Gene Expression Regulation, Mice, Knockout, Gene Editing, Astrocytes metabolism, Astrocytes pathology, Encephalomyelitis, Autoimmune, Experimental, Multiple Sclerosis pathology, Microfluidics methods, Single-Cell Gene Expression Analysis methods, Nucleic Acids analysis
- Abstract
Multiple sclerosis is a chronic inflammatory disease of the central nervous system
1 . Astrocytes are heterogeneous glial cells that are resident in the central nervous system and participate in the pathogenesis of multiple sclerosis and its model experimental autoimmune encephalomyelitis2,3 . However, few unique surface markers are available for the isolation of astrocyte subsets, preventing their analysis and the identification of candidate therapeutic targets; these limitations are further amplified by the rarity of pathogenic astrocytes. Here, to address these challenges, we developed focused interrogation of cells by nucleic acid detection and sequencing (FIND-seq), a high-throughput microfluidic cytometry method that combines encapsulation of cells in droplets, PCR-based detection of target nucleic acids and droplet sorting to enable in-depth transcriptomic analyses of cells of interest at single-cell resolution. We applied FIND-seq to study the regulation of astrocytes characterized by the splicing-driven activation of the transcription factor XBP1, which promotes disease pathology in multiple sclerosis and experimental autoimmune encephalomyelitis4 . Using FIND-seq in combination with conditional-knockout mice, in vivo CRISPR-Cas9-driven genetic perturbation studies and bulk and single-cell RNA sequencing analyses of samples from mouse experimental autoimmune encephalomyelitis and humans with multiple sclerosis, we identified a new role for the nuclear receptor NR3C2 and its corepressor NCOR2 in limiting XBP1-driven pathogenic astrocyte responses. In summary, we used FIND-seq to identify a therapeutically targetable mechanism that limits XBP1-driven pathogenic astrocyte responses. FIND-seq enables the investigation of previously inaccessible cells, including rare cell subsets defined by unique gene expression signatures or other nucleic acid markers., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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8. Identification of environmental factors that promote intestinal inflammation.
- Author
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Sanmarco LM, Chao CC, Wang YC, Kenison JE, Li Z, Rone JM, Rejano-Gordillo CM, Polonio CM, Gutierrez-Vazquez C, Piester G, Plasencia A, Li L, Giovannoni F, Lee HG, Faust Akl C, Wheeler MA, Mascanfroni I, Jaronen M, Alsuwailm M, Hewson P, Yeste A, Andersen BM, Franks DG, Huang CJ, Ekwudo M, Tjon EC, Rothhammer V, Takenaka M, de Lima KA, Linnerbauer M, Guo L, Covacu R, Queva H, Fonseca-Castro PH, Bladi MA, Cox LM, Hodgetts KJ, Hahn ME, Mildner A, Korzenik J, Hauser R, Snapper SB, and Quintana FJ
- Subjects
- Animals, Mice, Zebrafish, Machine Learning, Databases, Factual, Disease Models, Animal, NF-kappa B, CCAAT-Enhancer-Binding Protein-beta, Receptors, Aryl Hydrocarbon, T-Lymphocytes drug effects, T-Lymphocytes immunology, T-Lymphocytes metabolism, Dendritic Cells drug effects, Dendritic Cells immunology, Dendritic Cells metabolism, Inflammation chemically induced, Inflammation etiology, Inflammation immunology, Inflammation pathology, Inflammatory Bowel Diseases chemically induced, Inflammatory Bowel Diseases etiology, Inflammatory Bowel Diseases immunology, Inflammatory Bowel Diseases pathology, Intestines drug effects, Intestines immunology, Intestines metabolism, Intestines pathology, Herbicides adverse effects, Environment
- Abstract
Genome-wide association studies have identified risk loci linked to inflammatory bowel disease (IBD)
1 -a complex chronic inflammatory disorder of the gastrointestinal tract. The increasing prevalence of IBD in industrialized countries and the augmented disease risk observed in migrants who move into areas of higher disease prevalence suggest that environmental factors are also important determinants of IBD susceptibility and severity2 . However, the identification of environmental factors relevant to IBD and the mechanisms by which they influence disease has been hampered by the lack of platforms for their systematic investigation. Here we describe an integrated systems approach, combining publicly available databases, zebrafish chemical screens, machine learning and mouse preclinical models to identify environmental factors that control intestinal inflammation. This approach established that the herbicide propyzamide increases inflammation in the small and large intestine. Moreover, we show that an AHR-NF-κB-C/EBPβ signalling axis operates in T cells and dendritic cells to promote intestinal inflammation, and is targeted by propyzamide. In conclusion, we developed a pipeline for the identification of environmental factors and mechanisms of pathogenesis in IBD and, potentially, other inflammatory diseases., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2022
- Full Text
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9. Bystander CD4 + T cells: crossroads between innate and adaptive immunity.
- Author
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Lee HG, Cho MJ, and Choi JM
- Subjects
- Animals, Cytokines metabolism, Humans, Lymphocyte Activation immunology, Adaptive Immunity, Bystander Effect immunology, CD4-Positive T-Lymphocytes immunology, Immunity, Innate
- Abstract
T cells are the central mediators of both humoral and cellular adaptive immune responses. Highly specific receptor-mediated clonal selection and expansion of T cells assure antigen-specific immunity. In addition, encounters with cognate antigens generate immunological memory, the capacity for long-term, antigen-specific immunity against previously encountered pathogens. However, T-cell receptor (TCR)-independent activation, termed "bystander activation", has also been found. Bystander-activated T cells can respond rapidly and secrete effector cytokines even in the absence of antigen stimulation. Recent studies have rehighlighted the importance of antigen-independent bystander activation of CD4
+ T cells in infection clearance and autoimmune pathogenesis, suggesting the existence of a distinct innate-like immunological function performed by conventional T cells. In this review, we discuss the inflammatory mediators that activate bystander CD4+ T cells and the potential physiological roles of these cells during infection, autoimmunity, and cancer.- Published
- 2020
- Full Text
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