242 results on '"Quintana FJ"'
Search Results
2. Natalizumab treatment is associated with peripheral sequestration of proinflammatory T cells.
- Author
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Kivisäkk P, Healy BC, Viglietta V, Quintana FJ, Hootstein MA, Weiner HL, Khoury SJ, Kivisäkk, P, Healy, B C, Viglietta, V, Quintana, F J, Hootstein, M A, Weiner, H L, and Khoury, S J
- Published
- 2009
- Full Text
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3. Immunopathology of multiple sclerosis
- Author
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Francisco J Quintana, Soledad Pérez-Sánchez, Mauricio F Farez, and [Quintana,FJ] Center for Neurologic Diseases, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA. [Pérez-Sánchez,S] Unidad de Esclerosis Múltiple, Hospital Universitario Virgen Macarena, Sevilla, España. [Farez,MF] Instituto de Investigaciones Neurológicas Dr. Raúl Carrea, FLENI, Buenos Aires, Argentina.
- Subjects
lcsh:Immunologic diseases. Allergy ,Vaina de mielina ,Phenomena and Processes::Immune System Phenomena::Immunity::Adaptive Immunity::Immunity, Cellular [Medical Subject Headings] ,lcsh:R ,lcsh:Medicine ,Pathogenesis ,Anatomy::Nervous System::Neuroglia [Medical Subject Headings] ,Anatomy::Hemic and Immune Systems::Immune System::Antibody-Producing Cells::B-Lymphocytes [Medical Subject Headings] ,Enfermedades neurodegenerativas ,lcsh:Infectious and parasitic diseases ,Multiple sclerosis ,Patogénesis ,Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] ,Anatomy::Nervous System::Neuroglia::Oligodendroglia::Myelin Sheath [Medical Subject Headings] ,Esclerosis múltiple ,Anatomy::Cells::Connective Tissue Cells::Macrophages [Medical Subject Headings] ,Diseases::Nervous System Diseases::Neurodegenerative Diseases [Medical Subject Headings] ,Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Nerve Degeneration [Medical Subject Headings] ,lcsh:RC109-216 ,lcsh:RC581-607 ,Inmunidad celular ,Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation [Medical Subject Headings] ,Diseases::Immune System Diseases::Autoimmune Diseases::Autoimmune Diseases of the Nervous System::Demyelinating Autoimmune Diseases, CNS::Multiple Sclerosis [Medical Subject Headings] ,Anatomy::Cells::Blood Cells::Leukocytes::Leukocytes, Mononuclear::Cytokine-Induced Killer Cells::T-Lymphocytes, Cytotoxic [Medical Subject Headings] - Abstract
English Abstract; Journal Article; Review; Multiple sclerosis is an inflammatory demyelinating disease affecting the central nervous system and considered one of the leading causes of disability in young adults. The precise cause of multiple sclerosis is unknown, although the current evidence points towards a combination of genetic and environmental factors leading to an autoimmune response that promotes neuronal degeneration. In this review, we will describe the association between the immune response and neurodegeneration in multiple sclerosis. Yes La esclerosis múltiple es una enfermedad inflamatoria desmielinizante que afecta el sistema nervioso central y que es considerada una de las principales causas de discapacidad en jóvenes adultos. Las causas de la esclerosis múltiple son aún desconocidas, aunque se cree que una combinación de factores genéticos y ambientales resulta en una respuesta autoinmune que promueve la degeneración neuronal/axonal. En esta revisión se analiza la asociación entre la respuesta inmune y la neurodegeneración en la esclerosis múltiple.
- Published
- 2014
4. Microglia modulate the cerebrovascular reactivity through ectonucleotidase CD39.
- Author
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Fu Z, Ganesana M, Hwang P, Tan X, Kinkaid MM, Sun YY, Bian E, Weybright A, Chen HR, Sol-Church K, Eyo UB, Pridans C, Quintana FJ, Robson SC, Kumar P, Venton BJ, Schaefer A, and Kuan CY
- Subjects
- Animals, Male, Female, Mice, Receptors, Purinergic P2Y12 metabolism, Mice, Inbred C57BL, Vibrissae physiology, Mice, Knockout, Neurovascular Coupling, CX3C Chemokine Receptor 1 metabolism, CX3C Chemokine Receptor 1 genetics, Microglia metabolism, Apyrase metabolism, Antigens, CD metabolism, Antigens, CD genetics, Adenosine Triphosphate metabolism, Cerebrovascular Circulation physiology, Adenosine metabolism
- Abstract
Microglia and the border-associated macrophages contribute to the modulation of cerebral blood flow, but the mechanisms have remained uncertain. Here, we show that microglia regulate the cerebral blood flow baseline and the responses to whisker stimulation or intra-cisternal magna injection of adenosine triphosphate, but not intra-cisternal magna injection of adenosine in mice model. Notably, microglia repopulation corrects these cerebral blood flow anomalies. The microglial-dependent regulation of cerebral blood flow requires the adenosine triphosphate-sensing P2RY12 receptor and ectonucleotidase CD39 that initiates the dephosphorylation of extracellular adenosine triphosphate into adenosine in both male and female mice. Pharmacological inhibition or CX3CR1-CreER-mediated deletion of CD39 mimics the cerebral blood flow anomalies in microglia-deficient mice and reduces the upsurges of extracellular adenosine following whisker stimulation. Together, these results suggest that the microglial CD39-initiated breakdown of extracellular adenosine triphosphate co-transmitter is an important step in neurovascular coupling and the regulation of cerebrovascular reactivity., Competing Interests: Competing interests: S.C.R. is a scientific founder of Purinomia Biotech Inc and has consulted for eGenesis and SynLogic Inc; his interests are reviewed and managed by HMFP, Beth Israel Deaconess Medical Center by the institutional conflict-of-interest policies. The other authors declare no competing interests., (© 2025. The Author(s).)
- Published
- 2025
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5. Intestinal microbiome metabolites control sepsis outcome.
- Author
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Polonio CM and Quintana FJ
- Abstract
Competing Interests: Competing interests: The authors declare no competing interests.
- Published
- 2025
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6. Advancements in Immunity and Dementia Research: Highlights from the 2023 AAIC Advancements: Immunity Conference.
- Author
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Kloske CM, Mahinrad S, Barnum CJ, Batista AF, Bradshaw EM, Butts B, Carrillo MC, Chakrabarty P, Chen X, Craft S, Da Mesquita S, Dabin LC, Devanand D, Duran-Laforet V, Elyaman W, Evans EE, Fitzgerald-Bocarsly P, Foley KE, Harms AS, Heneka MT, Hong S, Huang YA, Jackvony S, Lai L, Guen YL, Lemere CA, Liddelow SA, Martin-Peña A, Orr AG, Quintana FJ, Ramey GD, Rexach JE, Rizzo SJS, Sexton C, Tang AS, Torrellas JG, Tsai AP, van Olst L, Walker KA, Wharton W, Tansey MG, and Wilcock DM
- Subjects
- Humans, Animals, Dementia immunology, Brain immunology, Brain pathology, Congresses as Topic, Biomarkers, Alzheimer Disease immunology
- Abstract
The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell-mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in the brain in the context of AD and related dementias (ADRD) remain unclear. Furthermore, the roles of the peripheral immune system in driving ADRD pathology remain incompletely elucidated. In March of 2023, the Alzheimer's Association convened the Alzheimer's Association International Conference (AAIC), Advancements: Immunity, to discuss the roles of the immune system in ADRD. A wide range of topics were discussed, such as animal models that replicate human pathology, immune-related biomarkers and clinical trials, and lessons from other fields describing immune responses in neurodegeneration. This manuscript presents highlights from the conference and outlines avenues for future research on the roles of immunity in neurodegenerative disorders. HIGHLIGHTS: The immune system plays a central role in the pathogenesis of Alzheimer's disease. The immune system exerts numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The 2023 AAIC, Advancements: Immunity, encouraged discussions and collaborations on understanding the role of the immune system., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)
- Published
- 2025
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7. Immunosuppressive dura-derived macrophages in leptomeningeal metastasis.
- Author
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Kilian M and Quintana FJ
- Abstract
Competing Interests: Competing interests: The authors declare no competing interests.
- Published
- 2024
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8. Implementation and validation of single-cell genomics experiments in neuroscience.
- Author
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Colonna M, Konopka G, Liddelow SA, Nowakowski T, Awatramani R, Bateup HS, Cadwell CR, Caglayan E, Chen JL, Gillis J, Kampmann M, Krienen F, Marsh SE, Monje M, O'Dea MR, Patani R, Pollen AA, Quintana FJ, Scavuzzo M, Schmitz M, Sloan SA, Tesar PJ, Tollkuhn J, Tosches MA, Urbanek ME, Werner JM, Bayraktar OA, Gokce O, and Habib N
- Subjects
- Animals, Humans, Transcriptome, Gene Expression Profiling methods, Single-Cell Analysis methods, Neurosciences methods, Genomics methods
- Abstract
Single-cell or single-nucleus transcriptomics is a powerful tool for identifying cell types and cell states. However, hypotheses derived from these assays, including gene expression information, require validation, and their functional relevance needs to be established. The choice of validation depends on numerous factors. Here, we present types of orthogonal and functional validation experiment to strengthen preliminary findings obtained using single-cell and single-nucleus transcriptomics as well as the challenges and limitations of these approaches., Competing Interests: Competing interests: M.C. is a member of the Scientific Advisory Board of Vigil, NGMBio, Cartesian and Halyardtx. M.C. receives research support from Ono Pharmaceutical, is a consultant for CST and has patents pending on LILRB4 and TREM2. S.A.L. maintains a financial interest in AstronauTx and Synapticure and is on the Scientific Advisory Board of the Global BioAccess Fund. S.A.L. is an inventor on US Patents WO2018081250A1 and WO2022187517A1. M.K. is a co-scientific founder of Montara Therapeutics and serves on the Scientific Advisory Boards of Engine Biosciences, Casma Therapeutics, Cajal Neuroscience, Alector and Montara Therapeutics, and is an advisor to Modulo Bio and Recursion Therapeutics. M.K. is an inventor on US Patent 11,254,933 related to CRISPRi and CRISPRa screening, and on a US Patent Application on in vivo screening methods. All other authors declare no competing interests., (© 2024. Springer Nature America, Inc.)
- Published
- 2024
- Full Text
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9. Microglia modulate cerebral blood flow and neurovascular coupling through ectonucleotidase CD39.
- Author
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Fu Z, Ganesana M, Hwang P, Tan X, Kinkaid MM, Sun YY, Bian E, Weybright A, Sol-Church K, Eyo UB, Pridans C, Quintana FJ, Robson SC, Kumar P, Venton BJ, Schaefer A, and Kuan CY
- Abstract
Microglia and the border-associated macrophages (BAMs) contribute to the modulation of cerebral blood flow (CBF), but the mechanisms have remained ill-defined. Here, we show that microglia regulate the CBF baseline and upsurges after whisker stimulation or intracisternal magna injection of adenosine triphosphate (ATP). Genetic or pharmacological depletion of microglia reduces the activity-dependent hyperemia but not the cerebrovascular responses to adenosine stimulation. Notably, microglia repopulation corrects these CBF reactivity deficits. The microglial-dependent regulation of CBF requires the ATP-sensing P2ry12 receptor and the ectonucleotidase CD39 that initiates the breakdown of extracellular ATP. Pharmacological inhibition or microglia-specific deletion of CD39 simulates the CBF anomalies detected in microglia-deficient mice and reduces the rise of extracellular adenosine after whisker stimulation. Together, these results suggest that the microglial CD39-initiated conversion of extracellular ATP to adenosine is an important step in neurovascular coupling and the regulation of cerebrovascular reactivity.
- Published
- 2024
- Full Text
- View/download PDF
10. FIND-seq: high-throughput nucleic acid cytometry for rare single-cell transcriptomics.
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Shin SW, Mudvari P, Thaploo S, Wheeler MA, Douek DC, Quintana FJ, Boritz EA, Abate AR, and Clark IC
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- Humans, High-Throughput Nucleotide Sequencing methods, Transcriptome, Gene Expression Profiling methods, Flow Cytometry methods, Single-Cell Analysis methods
- Abstract
Rare cells have an important role in development and disease, and methods for isolating and studying cell subsets are therefore an essential part of biology research. Such methods traditionally rely on labeled antibodies targeted to cell surface proteins, but large public databases and sophisticated computational approaches increasingly define cell subsets on the basis of genomic, epigenomic and transcriptomic sequencing data. Methods for isolating cells on the basis of nucleic acid sequences powerfully complement these approaches by providing experimental access to cell subsets discovered in cell atlases, as well as those that cannot be otherwise isolated, including cells infected with pathogens, with specific DNA mutations or with unique transcriptional or splicing signatures. We recently developed a nucleic acid cytometry platform called 'focused interrogation of cells by nucleic acid detection and sequencing' (FIND-seq), capable of isolating rare cells on the basis of RNA or DNA markers, followed by bulk or single-cell transcriptomic analysis. This platform has previously been used to characterize the splicing-dependent activation of the transcription factor XBP1 in astrocytes and HIV persistence in memory CD4 T cells from people on long-term antiretroviral therapy. Here, we outline the molecular and microfluidic steps involved in performing FIND-seq, including protocol updates that allow detection and whole transcriptome sequencing of rare HIV-infected cells that harbor genetically intact virus genomes. FIND-seq requires knowledge of microfluidics, optics and molecular biology. We expect that FIND-seq, and this comprehensive protocol, will enable mechanistic studies of rare HIV
+ cells, as well as other cell subsets that were previously difficult to recover and sequence., (© 2024. Springer Nature Limited.)- Published
- 2024
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11. Deletion of murine astrocytic vesicular nucleotide transporter increases anxiety and depressive-like behavior and attenuates motivation for reward.
- Author
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Huang Q, Lee HH, Volpe B, Zhang Q, Xue C, Liu BC, Abuhasan YR, Li L, Yang JS, Egholm J, Gutierrez-Vazquez C, Li A, Lee A, Tang S, Wong CW, Liu T, Huang Y, Ramos RL, Stout RF, El Ouaamari A, Quintana FJ, Lowell BB, Kahn CR, Pothos EN, and Cai W
- Subjects
- Animals, Mice, Female, Male, Dopamine metabolism, Exocytosis physiology, Mice, Inbred C57BL, Mice, Knockout, Astrocytes metabolism, Depression metabolism, Reward, Anxiety metabolism, Motivation physiology, Adenosine Triphosphate metabolism, Nucleus Accumbens metabolism, Nucleotide Transport Proteins metabolism, Nucleotide Transport Proteins genetics
- Abstract
Astrocytes are multi-functional glial cells in the central nervous system that play critical roles in modulation of metabolism, extracellular ion and neurotransmitter levels, and synaptic plasticity. Astrocyte-derived signaling molecules mediate many of these modulatory functions of astrocytes, including vesicular release of ATP. In the present study, we used a unique genetic mouse model to investigate the functional significance of astrocytic exocytosis of ATP. Using primary cultured astrocytes, we show that loss of vesicular nucleotide transporter (Vnut), a primary transporter responsible for loading cytosolic ATP into the secretory vesicles, dramatically reduces ATP loading into secretory lysosomes and ATP release, without any change in the molecular machinery of exocytosis or total intracellular ATP content. Deletion of astrocytic Vnut in adult mice leads to increased anxiety, depressive-like behaviors, and decreased motivation for reward, especially in females, without significant impact on food intake, systemic glucose metabolism, cognition, or sociability. These behavioral alterations are associated with significant decreases in the basal extracellular dopamine levels in the nucleus accumbens. Likewise, ex vivo brain slices from these mice show a strong trend toward a reduction in evoked dopamine release in the nucleus accumbens. Mechanistically, the reduced dopamine signaling we observed is likely due to an increased expression of monoamine oxidases. Together, these data demonstrate a key modulatory role of astrocytic exocytosis of ATP in anxiety, depressive-like behavior, and motivation for reward, by regulating the mesolimbic dopamine circuitry., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)
- Published
- 2025
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12. Droplet-based functional CRISPR screening of cell-cell interactions by SPEAC-seq.
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Faust Akl C, Linnerbauer M, Li Z, Lee HG, Clark IC, Wheeler MA, and Quintana FJ
- Abstract
Cell-cell interactions are essential for the function and contextual regulation of biological tissues. We present a platform for high-throughput microfluidics-supported genetic screening of functional regulators of cell-cell interactions. Systematic perturbation of encapsulated associated cells followed by sequencing (SPEAC-seq) combines genome-wide CRISPR libraries, cell coculture in droplets and microfluidic droplet sorting based on functional read-outs determined by fluorescent reporter circuits to enable the unbiased discovery of interaction regulators. This technique overcomes limitations of traditional methods for characterization of cell-cell communication, which require a priori knowledge of cellular interactions, are highly engineered and lack functional read-outs. As an example of this technique, we describe the investigation of neuroinflammatory intercellular communication between microglia and astrocytes, using genome-wide CRISPR-Cas9 inactivation libraries and fluorescent reporters of NF-κB activation. This approach enabled the discovery of thousands of microglial regulators of astrocyte NF-κB activation important for the control of central nervous system inflammation. Importantly, SPEAC-seq can be adapted to different cell types, screening modalities, cell functions and physiological contexts, only limited by the ability to fluorescently report cell functions and by droplet cultivation conditions. Performing genome-wide screening takes less than 2 weeks and requires microfluidics capabilities. Thus, SPEAC-seq enables the large-scale investigation of cell-cell interactions., (© 2024. Springer Nature Limited.)
- Published
- 2024
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13. Host-gut microbiota crosstalk predicts neuroinflammation.
- Author
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Polonio CM and Quintana FJ
- Subjects
- Humans, Animals, Brain-Gut Axis physiology, Mice, Inflammation microbiology, Gastrointestinal Microbiome, Neuroinflammatory Diseases microbiology, Neuroinflammatory Diseases metabolism
- Published
- 2024
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14. Astrocytes at the border of repair.
- Author
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Lee HG and Quintana FJ
- Subjects
- Animals, Humans, Nerve Regeneration physiology, Astrocytes physiology
- Published
- 2024
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15. STING: Stay near to STIM(1) neuroprotection.
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Lee HG and Quintana FJ
- Subjects
- Humans, Animals, Stromal Interaction Molecule 1 metabolism, Stromal Interaction Molecule 1 genetics, Glutamic Acid metabolism, Inflammation, Signal Transduction, Membrane Proteins metabolism, Membrane Proteins genetics, Neuroprotection, Multiple Sclerosis genetics, Multiple Sclerosis immunology, Multiple Sclerosis drug therapy, Multiple Sclerosis metabolism, Ferroptosis drug effects, Ferroptosis genetics
- Abstract
In a recent publication in Cell, Woo et al.
1 report that stimulator of interferon genes (STING) links inflammation with glutamate-driven excitotoxicity to induce ferroptosis, identifying a mechanism of inflammation-induced neurodegeneration and also a novel candidate therapeutic target for multiple sclerosis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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16. 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
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17. Tapinarof validates the aryl hydrocarbon receptor as a therapeutic target: A clinical review.
- Author
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Silverberg JI, Boguniewicz M, Quintana FJ, Clark RA, Gross L, Hirano I, Tallman AM, Brown PM, Fredericks D, Rubenstein DS, and McHale KA
- Subjects
- Humans, Animals, Resorcinols, Stilbenes, Receptors, Aryl Hydrocarbon agonists, Receptors, Aryl Hydrocarbon metabolism, Receptors, Aryl Hydrocarbon genetics, Dermatitis, Atopic drug therapy, Dermatitis, Atopic immunology, Dermatitis, Atopic genetics, Psoriasis drug therapy, Psoriasis immunology
- Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that has wide-ranging roles, including regulation of inflammation and homeostasis. AhR is not a cell surface receptor; rather, it exists in a cytoplasmic complex that responds to a wide variety of structurally dissimilar endogenous, microbial, and environmental ligands. The ubiquitous expression of AhR, its ability to be activated by a wide range of ligands, and its capacity to act as a master regulator for gene expression and homeostasis make it a promising new therapeutic target. Clinical trials of tapinarof cream have now validated AhR agonism as a therapeutic approach that can deliver significant efficacy for treating inflammatory skin diseases, including psoriasis and atopic dermatitis. Tapinarof 1% cream is a first-in-class, nonsteroidal, topical, AhR agonist with a pharmacokinetic profile that results in localized exposure at sites of disease, avoiding systemic safety concerns, drug interactions, or off-target effects. Psoriasis and atopic dermatitis both involve epidermal inflammation, cellular immune responses, dysregulation of skin barrier protein expression, and oxidative stress. On the basis of the clinical effectiveness of tapinarof cream for treating inflammatory skin diseases, we review how targeting AhR may offer a significant opportunity in other conditions that share key aspects of pathogenesis, including asthma, inflammatory bowel disease, eosinophilic esophagitis, ophthalmic, and nervous system diseases., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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18. Therapeutic induction of antigen-specific immune tolerance.
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Kenison JE, Stevens NA, and Quintana FJ
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- Humans, Animals, Antigens immunology, Autoimmunity immunology, Organ Transplantation, Autoimmune Diseases immunology, Autoimmune Diseases therapy, Immune Tolerance immunology
- Abstract
The development of therapeutic approaches for the induction of robust, long-lasting and antigen-specific immune tolerance remains an important unmet clinical need for the management of autoimmunity, allergy, organ transplantation and gene therapy. Recent breakthroughs in our understanding of immune tolerance mechanisms have opened new research avenues and therapeutic opportunities in this area. Here, we review mechanisms of immune tolerance and novel methods for its therapeutic induction., (© 2023. Springer Nature Limited.)
- Published
- 2024
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19. Charting the cellular biogeography in colitis reveals fibroblast trajectories and coordinated spatial remodeling.
- Author
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Cadinu P, Sivanathan KN, Misra A, Xu RJ, Mangani D, Yang E, Rone JM, Tooley K, Kye YC, Bod L, Geistlinger L, Lee T, Mertens RT, Ono N, Wang G, Sanmarco L, Quintana FJ, Anderson AC, Kuchroo VK, Moffitt JR, and Nowarski R
- Subjects
- Animals, Humans, Mice, Fibroblasts metabolism, Fibroblasts pathology, In Situ Hybridization, Fluorescence methods, Inflammation metabolism, Inflammation pathology, Cell Communication, Gastrointestinal Tract metabolism, Gastrointestinal Tract pathology, Colitis metabolism, Colitis pathology, Colitis, Ulcerative metabolism, Colitis, Ulcerative pathology
- Abstract
Gut inflammation involves contributions from immune and non-immune cells, whose interactions are shaped by the spatial organization of the healthy gut and its remodeling during inflammation. The crosstalk between fibroblasts and immune cells is an important axis in this process, but our understanding has been challenged by incomplete cell-type definition and biogeography. To address this challenge, we used multiplexed error-robust fluorescence in situ hybridization (MERFISH) to profile the expression of 940 genes in 1.35 million cells imaged across the onset and recovery from a mouse colitis model. We identified diverse cell populations, charted their spatial organization, and revealed their polarization or recruitment in inflammation. We found a staged progression of inflammation-associated tissue neighborhoods defined, in part, by multiple inflammation-associated fibroblasts, with unique expression profiles, spatial localization, cell-cell interactions, and healthy fibroblast origins. Similar signatures in ulcerative colitis suggest conserved human processes. Broadly, we provide a framework for understanding inflammation-induced remodeling in the gut and other tissues., Competing Interests: Declaration of interests J.R.M. is a co-founder of, stakeholder in, and advisor for Vizgen, Inc. J.R.M. is an inventor on patents associated with MERFISH applied for on his behalf by Harvard University and Boston Children’s Hospital. J.R.M.’s interests were reviewed and are managed by Boston Children’s Hospital in accordance with their conflict-of-interest policies. R.N. is a paid consultant for Quris-AI. V.K.K. has an ownership interest in Tizona Therapeutics, Trishula Therapeutics, Celsius Therapeutics, Bicara Therapeutics, Larkspur Therapeutics. V.K.K. has financial interests in Biocon Biologic, Compass, Elpiscience Biopharmaceutical Ltd, Equilium Inc, PerkinElmer, and Syngene Intl. V.K.K. is a member of SABs for Cell Signaling Technology, Elpiscience Biopharmaceutical Ltd, GlaxoSmithKline, Larkspur, Novartis Sabatolimab, Tizona Therapeutics, Tr1X, and Werewolf. A.C.A. is a member of the SAB for Tizona Therapeutics, Trishula Therapeutics, Compass Therapeutics, Zumutor Biologics, ImmuneOncia, and Nekonal Sarl. A.C.A. is also a paid consultant for iTeos Therapeutics, Larkspur Biosciences, and Excepgen. R.N., V.K.K., and A.C.A.’s interests were reviewed and managed by Mass General Brigham in accordance with their conflict-of-interest policies., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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20. Astrocyte control of brain metastasis.
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Rone JM, Faust Akl C, and Quintana FJ
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- Humans, Brain pathology, Neuroglia, Tumor Microenvironment, Astrocytes, Brain Neoplasms pathology
- Abstract
Developing therapeutics to improve metastatic brain cancer prognosis is hampered by limited experimental systems that recapitulate the brain tumor microenvironment. In this issue of Developmental Cell, Ishibashi et al. describe a glial-cancer cell co-culture system that enabled the identification of a targetable, astrocyte-driven mechanism of brain metastasis., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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21. The astrocyte-produced growth factor HB-EGF limits autoimmune CNS pathology.
- Author
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Linnerbauer M, Lößlein L, Vandrey O, Peter A, Han Y, Tsaktanis T, Wogram E, Needhamsen M, Kular L, Nagel L, Zissler J, Andert M, Meszaros L, Hanspach J, Zuber F, Naumann UJ, Diebold M, Wheeler MA, Beyer T, Nirschl L, Cirac A, Laun FB, Günther C, Winkler J, Bäuerle T, Jagodic M, Hemmer B, Prinz M, Quintana FJ, and Rothhammer V
- Subjects
- Animals, Humans, Mice, Anti-Inflammatory Agents, Disease Models, Animal, Epigenesis, Genetic, Heparin-binding EGF-like Growth Factor genetics, Inflammation, Proteomics, Astrocytes, Multiple Sclerosis
- Abstract
Central nervous system (CNS)-resident cells such as microglia, oligodendrocytes and astrocytes are gaining increasing attention in respect to their contribution to CNS pathologies including multiple sclerosis (MS). Several studies have demonstrated the involvement of pro-inflammatory glial subsets in the pathogenesis and propagation of inflammatory events in MS and its animal models. However, it has only recently become clear that the underlying heterogeneity of astrocytes and microglia can not only drive inflammation, but also lead to its resolution through direct and indirect mechanisms. Failure of these tissue-protective mechanisms may potentiate disease and increase the risk of conversion to progressive stages of MS, for which currently available therapies are limited. Using proteomic analyses of cerebrospinal fluid specimens from patients with MS in combination with experimental studies, we here identify Heparin-binding EGF-like growth factor (HB-EGF) as a central mediator of tissue-protective and anti-inflammatory effects important for the recovery from acute inflammatory lesions in CNS autoimmunity. Hypoxic conditions drive the rapid upregulation of HB-EGF by astrocytes during early CNS inflammation, while pro-inflammatory conditions suppress trophic HB-EGF signaling through epigenetic modifications. Finally, we demonstrate both anti-inflammatory and tissue-protective effects of HB-EGF in a broad variety of cell types in vitro and use intranasal administration of HB-EGF in acute and post-acute stages of autoimmune neuroinflammation to attenuate disease in a preclinical mouse model of MS. Altogether, we identify astrocyte-derived HB-EGF and its epigenetic regulation as a modulator of autoimmune CNS inflammation and potential therapeutic target in MS., (© 2024. The Author(s).)
- Published
- 2024
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22. 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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23. Association between altered tryptophan metabolism, plasma aryl hydrocarbon receptor agonists, and inflammatory Chagas disease.
- Author
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Ambrosio LF, Volpini X, Quiroz JN, Brugo MB, Knubel CP, Herrera MR, Fozzatti L, Avila Pacheco J, Clish CB, Takenaka MC, Beloscar J, Theumer MG, Quintana FJ, Perez AR, and Motrán CC
- Subjects
- Animals, Humans, Mice, Cytochrome P-450 CYP1A1 metabolism, Receptors, Aryl Hydrocarbon agonists, Tryptophan metabolism, Chagas Cardiomyopathy, Chagas Disease metabolism
- Abstract
Introduction: Chagas disease causes a cardiac illness characterized by immunoinflammatory reactions leading to myocardial fibrosis and remodeling. The development of Chronic Chagas Cardiomyopathy (CCC) in some patients while others remain asymptomatic is not fully understood, but dysregulated inflammatory responses are implicated. The Aryl hydrocarbon receptor (AhR) plays a crucial role in regulating inflammation. Certain tryptophan (Trp) metabolites have been identified as AhR ligands with regulatory functions., Methods Results and Discussion: We investigated AhR expression, agonist response, ligand production, and AhR-dependent responses, such as IDO activation and regulatory T (Treg) cells induction, in two T. cruzi-infected mouse strains (B6 and Balb/c) showing different polymorphisms in AhR. Furthermore, we assessed the metabolic profile of Trp catabolites and AhR agonistic activity levels in plasma samples from patients with chronic Chagas disease (CCD) and healthy donors (HD) using a luciferase reporter assay and liquid chromatography-mass spectrophotometry (LC-MS) analysis. T. cruzi-infected B6 mice showed impaired AhR-dependent responses compared to Balb/c mice, including reduced IDO activity, kynurenine levels, Treg cell induction, CYP1A1 up-regulation, and AhR expression following agonist activation. Additionally, B6 mice exhibited no detectable AhR agonist activity in plasma and displayed lower CYP1A1 up-regulation and AhR expression upon agonist activation. Similarly, CCC patients had decreased AhR agonistic activity in plasma compared to HD patients and exhibited dysregulation in Trp metabolic pathways, resulting in altered plasma metabolite profiles. Notably, patients with severe CCC specifically showed increased N-acetylserotonin levels in their plasma. The methods and findings presented here contribute to a better understanding of CCC development mechanisms and may identify potential specific biomarkers for T. cruzi infection and the severity of associated heart disease. These insights could be valuable in designing new therapeutic strategies. Ultimately, this research aims to establish the AhR agonistic activity and Trp metabolic profile in plasma as an innovative, non-invasive predictor of prognosis for chronic Chagas disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Ambrosio, Volpini, Quiroz, Brugo, Knubel, Herrera, Fozzatti, Avila Pacheco, Clish, Takenaka, Beloscar, Theumer, Quintana, Perez and Motrán.)
- Published
- 2024
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24. Neuroinflammation: An astrocyte perspective.
- Author
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Lee HG, Lee JH, Flausino LE, and Quintana FJ
- Subjects
- Humans, Central Nervous System, Neuroglia, Inflammation metabolism, Astrocytes metabolism, Neuroinflammatory Diseases
- Abstract
Astrocytes are abundant glial cells in the central nervous system (CNS) that play active roles in health and disease. Recent technologies have uncovered the functional heterogeneity of astrocytes and their extensive interactions with other cell types in the CNS. In this Review, we highlight the intricate interactions between astrocytes, other CNS-resident cells, and CNS-infiltrating cells as well as their potential therapeutic value in the context of inflammation and neurodegeneration.
- Published
- 2023
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25. Astrocytes on steroids binge on synapses to cope with stress.
- Author
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Wheeler MA and Quintana FJ
- Subjects
- Central Nervous System, Steroids, Astrocytes, Synapses
- Abstract
Many mechanisms by which stress mediates its effects within the central nervous system still remain unknown. Byun, Kim, Kim et al. find that early-life stress triggers corticosterone release to drive astrocyte-dependent synapse elimination and altered behavior. Thus, this work defines a steroid-sensitive astrocyte transcriptional circuit controlling behavior, highlighting how the study of CNS immunoregulation may shed light on behavior., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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26. PD-L1 positive astrocytes attenuate inflammatory functions of PD-1 positive microglia in models of autoimmune neuroinflammation.
- Author
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Linnerbauer M, Beyer T, Nirschl L, Farrenkopf D, Lößlein L, Vandrey O, Peter A, Tsaktanis T, Kebir H, Laplaud D, Oellinger R, Engleitner T, Alvarez JI, Rad R, Korn T, Hemmer B, Quintana FJ, and Rothhammer V
- Subjects
- Animals, Mice, Astrocytes, Neuroinflammatory Diseases, Programmed Cell Death 1 Receptor genetics, B7-H1 Antigen genetics, Inflammation, Microglia, Multiple Sclerosis
- Abstract
Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disorder of the central nervous system (CNS). Current therapies mainly target inflammatory processes during acute stages, but effective treatments for progressive MS are limited. In this context, astrocytes have gained increasing attention as they have the capacity to drive, but also suppress tissue-degeneration. Here we show that astrocytes upregulate the immunomodulatory checkpoint molecule PD-L1 during acute autoimmune CNS inflammation in response to aryl hydrocarbon receptor and interferon signaling. Using CRISPR-Cas9 genetic perturbation in combination with small-molecule and antibody-mediated inhibition of PD-L1 and PD-1 both in vivo and in vitro, we demonstrate that astrocytic PD-L1 and its interaction with microglial PD-1 is required for the attenuation of autoimmune CNS inflammation in acute and progressive stages in a mouse model of MS. Our findings suggest the glial PD-L1/PD-1 axis as a potential therapeutic target for both acute and progressive MS stages., (© 2023. Springer Nature Limited.)
- Published
- 2023
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27. 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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28. Regulation of the programmed cell death protein 1/programmed cell death ligand 1 axis in relapsing-remitting multiple sclerosis.
- Author
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Tsaktanis T, Linnerbauer M, Lößlein L, Farrenkopf D, Vandrey O, Peter A, Cirac A, Beyer T, Nirschl L, Grummel V, Mühlau M, Bussas M, Hemmer B, Quintana FJ, and Rothhammer V
- Abstract
The programmed cell death protein 1/programmed cell death ligand 1 axis plays an important role in the adaptive immune system and has influence on neoplastic and inflammatory diseases, while its role in multiple sclerosis is unclear. Here, we aimed to analyse expression patterns of programmed cell death protein 1 and programmed cell death ligand 1 on peripheral blood mononuclear cells and their soluble variants in multiple sclerosis patients and controls, to determine their correlation with clinical disability and disease activity. In a cross-sectional study, we performed in-depth flow cytometric immunophenotyping of peripheral blood mononuclear cells and analysed soluble programmed cell death protein 1 and programmed cell death ligand 1 serum levels in patients with relapsing-remitting multiple sclerosis and controls. In comparison to control subjects, relapsing-remitting multiple sclerosis patients displayed distinct cellular programmed cell death protein 1/programmed cell death ligand 1 expression patterns in immune cell subsets and increased soluble programmed cell death ligand 1 levels, which correlated with clinical measures of disability and MRI activity over time. This study extends our knowledge of how programmed cell death protein 1 and programmed cell death ligand 1 are expressed in the membranes of patients with relapsing-remitting multiple sclerosis and describes for the first time the elevation of soluble programmed cell death ligand 1 in the blood of multiple sclerosis patients. The distinct expression pattern of membrane-bound programmed cell death protein 1 and programmed cell death ligand 1 and the correlation between soluble programmed cell death ligand 1, membrane-bound programmed cell death ligand 1, disease and clinical factors may offer therapeutic potential in the setting of multiple sclerosis and might improve future diagnosis and clinical decision-making., Competing Interests: The other authors report no conflicts of interest related to the contents of the manuscript., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)
- Published
- 2023
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29. B-cell-specific checkpoint molecules that regulate anti-tumour immunity.
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Bod L, Kye YC, Shi J, Torlai Triglia E, Schnell A, Fessler J, Ostrowski SM, Von-Franque MY, Kuchroo JR, Barilla RM, Zaghouani S, Christian E, Delorey TM, Mohib K, Xiao S, Slingerland N, Giuliano CJ, Ashenberg O, Li Z, Rothstein DM, Fisher DE, Rozenblatt-Rosen O, Sharpe AH, Quintana FJ, Apetoh L, Regev A, and Kuchroo VK
- Subjects
- Animals, Mice, Lymphocyte Activation, T-Lymphocytes cytology, T-Lymphocytes immunology, Flow Cytometry, Melanoma, Experimental immunology, Melanoma, Experimental pathology, Lymph Nodes cytology, Lymph Nodes immunology, Antigen Presentation, Receptors, Antigen, B-Cell genetics, Single-Cell Gene Expression Analysis, Tumor Burden, Interferon Type I, B-Lymphocytes cytology, B-Lymphocytes immunology, B-Lymphocytes metabolism, Melanoma immunology, Melanoma pathology, Melanoma prevention & control
- Abstract
The role of B cells in anti-tumour immunity is still debated and, accordingly, immunotherapies have focused on targeting T and natural killer cells to inhibit tumour growth
1,2 . Here, using high-throughput flow cytometry as well as bulk and single-cell RNA-sequencing and B-cell-receptor-sequencing analysis of B cells temporally during B16F10 melanoma growth, we identified a subset of B cells that expands specifically in the draining lymph node over time in tumour-bearing mice. The expanding B cell subset expresses the cell surface molecule T cell immunoglobulin and mucin domain 1 (TIM-1, encoded by Havcr1) and a unique transcriptional signature, including multiple co-inhibitory molecules such as PD-1, TIM-3, TIGIT and LAG-3. Although conditional deletion of these co-inhibitory molecules on B cells had little or no effect on tumour burden, selective deletion of Havcr1 in B cells both substantially inhibited tumour growth and enhanced effector T cell responses. Loss of TIM-1 enhanced the type 1 interferon response in B cells, which augmented B cell activation and increased antigen presentation and co-stimulation, resulting in increased expansion of tumour-specific effector T cells. Our results demonstrate that manipulation of TIM-1-expressing B cells enables engagement of the second arm of adaptive immunity to promote anti-tumour immunity and inhibit tumour growth., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2023
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30. Charting the cellular biogeography in colitis reveals fibroblast trajectories and coordinated spatial remodeling.
- Author
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Cadinu P, Sivanathan KN, Misra A, Xu RJ, Mangani D, Yang E, Rone JM, Tooley K, Kye YC, Bod L, Geistlinger L, Lee T, Ono N, Wang G, Sanmarco L, Quintana FJ, Anderson AC, Kuchroo VK, Moffitt JR, and Nowarski R
- Abstract
Gut inflammation involves contributions from immune and non-immune cells, whose interactions are shaped by the spatial organization of the healthy gut and its remodeling during inflammation. The crosstalk between fibroblasts and immune cells is an important axis in this process, but our understanding has been challenged by incomplete cell-type definition and biogeography. To address this challenge, we used MERFISH to profile the expression of 940 genes in 1.35 million cells imaged across the onset and recovery from a mouse colitis model. We identified diverse cell populations; charted their spatial organization; and revealed their polarization or recruitment in inflammation. We found a staged progression of inflammation-associated tissue neighborhoods defined, in part, by multiple inflammation-associated fibroblasts, with unique expression profiles, spatial localization, cell-cell interactions, and healthy fibroblast origins. Similar signatures in ulcerative colitis suggest conserved human processes. Broadly, we provide a framework for understanding inflammation-induced remodeling in the gut and other tissues., Competing Interests: Declaration of interests J.R.M is a co-founder of, stake-holder in, and advisor for Vizgen, Inc. J.R.M. is an inventor on patents associated with MERFISH applied for on his behalf by Harvard University and Boston Children’s Hospital. J.R.M.’s interests were reviewed and are managed by Boston Children’s Hospital in accordance with their conflict-of-interest policies. A.C.A. is a member of the SAB for Tizona Therapeutics, Trishula Therapeutics, Compass Therapeutics, Zumutor Biologics, ImmuneOncia, and Nekonal Sarl. A.C.A. is also a paid consultant for iTeos Therapeutics, Larkspur Biosciences, and Excepgen. A.C.A.’s interests were reviewed and managed by the Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. Additional authors in this manuscript declare no competing financial interests.
- Published
- 2023
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31. Multiple sclerosis: Neuroimmune crosstalk and therapeutic targeting.
- Author
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Charabati M, Wheeler MA, Weiner HL, and Quintana FJ
- Subjects
- Humans, Central Nervous System, Neuroglia, Cell Physiological Phenomena, Inflammation pathology, Multiple Sclerosis drug therapy
- Abstract
Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of the central nervous system afflicting nearly three million individuals worldwide. Neuroimmune interactions between glial, neural, and immune cells play important roles in MS pathology and offer potential targets for therapeutic intervention. Here, we review underlying risk factors, mechanisms of MS pathogenesis, available disease modifying therapies, and examine the value of emerging technologies, which may address unmet clinical needs and identify novel therapeutic targets., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Inc. All rights reserved.)
- Published
- 2023
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- View/download PDF
32. Engineered probiotics limit CNS autoimmunity by stabilizing HIF-1α in dendritic cells.
- Author
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Sanmarco LM, Rone JM, Polonio CM, Giovannoni F, Lahore GF, Ferrara K, Gutierrez-Vazquez C, Li N, Sokolovska A, Plasencia A, Akl CF, 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, Piester G, Dailey L, Kuchroo VK, Hava D, Wheeler MA, Clish C, Nowarski R, Balsa E, Lora JM, and Quintana FJ
- Abstract
Dendritic cells (DCs) control the generation of self-reactive pathogenic T cells. Thus, DCs are considered attractive therapeutic targets for autoimmune diseases. Using single-cell and bulk transcriptional and metabolic analyses in combination with cell-specific gene perturbation studies we identified a negative feedback regulatory pathway that operates in DCs to limit immunopathology. Specifically, we found that lactate, produced by activated DCs and other immune cells, boosts NDUFA4L2 expression through a mechanism mediated by HIF-1α. NDUFA4L2 limits the production of mitochondrial reactive oxygen species that activate XBP1-driven transcriptional modules in DCs involved in the control of pathogenic autoimmune T cells. Moreover, we engineered a probiotic that produces lactate and suppresses T-cell autoimmunity in the central nervous system via the activation of HIF-1α/NDUFA4L2 signaling in DCs. In summary, we identified an immunometabolic pathway that regulates DC function, and developed a synthetic probiotic for its therapeutic activation.
- Published
- 2023
- Full Text
- View/download PDF
33. Droplet-based forward genetic screening of astrocyte-microglia cross-talk.
- Author
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Wheeler MA, Clark IC, Lee HG, Li Z, Linnerbauer M, Rone JM, Blain M, Akl CF, Piester G, Giovannoni F, Charabati M, Lee JH, Kye YC, Choi J, Sanmarco LM, Srun L, Chung EN, Flausino LE, Andersen BM, Rothhammer V, Yano H, Illouz T, Zandee SEJ, Daniel C, Artis D, Prinz M, Abate AR, Kuchroo VK, Antel JP, Prat A, and Quintana FJ
- Subjects
- High-Throughput Screening Assays, Gene Expression, Humans, Astrocytes physiology, Genetic Testing methods, Microfluidic Analytical Techniques methods, Microglia physiology, Amphiregulin genetics, Autocrine Communication genetics
- Abstract
Cell-cell interactions in the central nervous system play important roles in neurologic diseases. However, little is known about the specific molecular pathways involved, and methods for their systematic identification are limited. Here, we developed a forward genetic screening platform that combines CRISPR-Cas9 perturbations, cell coculture in picoliter droplets, and microfluidic-based fluorescence-activated droplet sorting to identify mechanisms of cell-cell communication. We used SPEAC-seq (systematic perturbation of encapsulated associated cells followed by sequencing), in combination with in vivo genetic perturbations, to identify microglia-produced amphiregulin as a suppressor of disease-promoting astrocyte responses in multiple sclerosis preclinical models and clinical samples. Thus, SPEAC-seq enables the high-throughput systematic identification of cell-cell communication mechanisms.
- Published
- 2023
- Full Text
- View/download PDF
34. HIV silencing and cell survival signatures in infected T cell reservoirs.
- Author
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Clark IC, Mudvari P, Thaploo S, Smith S, Abu-Laban M, Hamouda M, Theberge M, Shah S, Ko SH, Pérez L, Bunis DG, Lee JS, Kilam D, Zakaria S, Choi S, Darko S, Henry AR, Wheeler MA, Hoh R, Butrus S, Deeks SG, Quintana FJ, Douek DC, Abate AR, and Boritz EA
- Subjects
- Humans, Cell Proliferation drug effects, Cell Survival drug effects, DNA, Viral isolation & purification, Immunologic Memory, Microfluidics, Necroptosis drug effects, Signal Transduction drug effects, Transcriptome drug effects, Anti-Retroviral Agents pharmacology, Anti-Retroviral Agents therapeutic use, CD4-Positive T-Lymphocytes cytology, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes virology, Gene Expression Regulation, Viral drug effects, HIV Infections drug therapy, HIV Infections genetics, HIV Infections immunology, HIV Infections virology, HIV-1 drug effects, HIV-1 genetics, HIV-1 isolation & purification, HIV-1 pathogenicity, Virus Latency drug effects
- Abstract
Rare CD4 T cells that contain HIV under antiretroviral therapy represent an important barrier to HIV cure
1-3 , but the infeasibility of isolating and characterizing these cells in their natural state has led to uncertainty about whether they possess distinctive attributes that HIV cure-directed therapies might exploit. Here we address this challenge using a microfluidic technology that isolates the transcriptomes of HIV-infected cells based solely on the detection of HIV DNA. HIV-DNA+ memory CD4 T cells in the blood from people receiving antiretroviral therapy showed inhibition of six transcriptomic pathways, including death receptor signalling, necroptosis signalling and antiproliferative Gα12/13 signalling. Moreover, two groups of genes identified by network co-expression analysis were significantly associated with HIV-DNA+ cells. These genes (n = 145) accounted for just 0.81% of the measured transcriptome and included negative regulators of HIV transcription that were higher in HIV-DNA+ cells, positive regulators of HIV transcription that were lower in HIV-DNA+ cells, and other genes involved in RNA processing, negative regulation of mRNA translation, and regulation of cell state and fate. These findings reveal that HIV-infected memory CD4 T cells under antiretroviral therapy are a distinctive population with host gene expression patterns that favour HIV silencing, cell survival and cell proliferation, with important implications for the development of HIV cure strategies., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)- Published
- 2023
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35. 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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36. 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
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37. Glioblastoma scRNA-seq shows treatment-induced, immune-dependent increase in mesenchymal cancer cells and structural variants in distal neural stem cells.
- Author
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Couturier CP, Nadaf J, Li Z, Baig S, Riva G, Le P, Kloosterman DJ, Monlong J, Nkili Meyong A, Allache R, Degenhard T, Al-Rashid M, Guiot MC, Bourque G, Ragoussis J, Akkari L, Quintana FJ, and Petrecca K
- Subjects
- Humans, Lateral Ventricles pathology, Single-Cell Analysis, Tumor Microenvironment, Brain Neoplasms pathology, Glioblastoma pathology, Neural Stem Cells pathology
- Abstract
Background: Glioblastoma is a treatment-resistant brain cancer. Its hierarchical cellular nature and its tumor microenvironment (TME) before, during, and after treatments remain unresolved., Methods: Here, we used single-cell RNA sequencing to analyze new and recurrent glioblastoma and the nearby subventricular zone (SVZ)., Results: We found 4 glioblastoma neural lineages are present in new and recurrent glioblastoma with an enrichment of the cancer mesenchymal lineage, immune cells, and reactive astrocytes in early recurrences. Cancer lineages were hierarchically organized around cycling oligodendrocytic and astrocytic progenitors that are transcriptomically similar but distinct to SVZ neural stem cells (NSCs). Furthermore, NSCs from the SVZ of patients with glioblastoma harbored glioblastoma chromosomal anomalies. Lastly, mesenchymal cancer cells and TME reactive astrocytes shared similar gene signatures which were induced by radiotherapy in a myeloid-dependent fashion in vivo., Conclusion: These data reveal the dynamic, immune-dependent nature of glioblastoma's response to treatments and identify distant NSCs as likely cells of origin., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
- View/download PDF
38. Glucose promotes regulatory T cell differentiation to maintain intestinal homeostasis.
- Author
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Yu Y, Yang W, Yu T, Zhao X, Zhou Z, Yu Y, Xiong L, Yang H, Bilotta AJ, Yao S, Golovko G, Plasencia A, Quintana FJ, Zhou L, Li Y, and Cong Y
- Abstract
Glucose, the critical energy source in the human body, is considered a potential risk factor in various autoimmune diseases when consumed in high amounts. However, the roles of glucose at moderate doses in the regulation of autoimmune inflammatory diseases and CD4
+ T cell responses are controversial. Here, we show that while glucose at a high concentration (20% w/v) promotes intestinal inflammation, it suppresses colitis at a moderate dose (6% w/v), which increases the proportion of intestinal regulatory T (Treg) cells but does not affect effector CD4+ T cells. Glucose treatment promotes Treg cell differentiation but it does not affect Treg stability. Feeding glucose alters gut microbiota compositions, which are not involved in the glucose induction of Treg cells. Glucose promotes aryl hydrocarbon receptor (AhR) activation to induce Treg polarization. These findings reveal the different effects of glucose at different doses on the intestinal immune response., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)- Published
- 2022
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39. Analysis of chronic kidney disease patients by targeted next-generation sequencing identifies novel variants in kidney-related genes.
- Author
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Alaamery M, Alghamdi J, Massadeh S, Alsawaji M, Aljawini N, Albesher N, Alghamdi B, Almutairi M, Hejaili F, Alfadhel M, Baz B, Almuzzaini B, Almutairi AF, Abdullah M, Quintana FJ, and Sayyari A
- Abstract
Despite the enormous economic and societal burden of chronic kidney disease (CKD), its pathogenesis remains elusive, impeding specific diagnosis and targeted therapy. Herein, we sought to elucidate the genetic causes of end-stage renal disease (ESRD) and identify genetic variants associated with CKD and related traits in Saudi kidney disease patients. We applied a genetic testing approach using a targeted next-generation sequencing gene panel including 102 genes causative or associated with CKD. A total of 1,098 Saudi participants were recruited for the study, including 534 patients with ESRD and 564 healthy controls. The pre-validated NGS panel was utilized to screen for genetic variants, and then, statistical analysis was conducted to test for associations. The NGS panel revealed 7,225 variants in 102 sequenced genes. Cases had a significantly higher number of confirmed pathogenic variants as classified by the ClinVar database than controls (i.e., individuals with at least one allele of a confirmed pathogenic variant that is associated with CKD; 279 (0.52) vs. 258 (0.45); p -value = 0.03). A total of 13 genetic variants were found to be significantly associated with ESRD in PLCE1 , CLCN5 , ATP6V1B1 , LAMB2 , INVS , FRAS1 , C5orf42 , SLC12A3 , COL4A6 , SLC3A1 , RET , WNK1 , and BICC1 , including four novel variants that were not previously reported in any other population. Furthermore, studies are necessary to validate these associations in a larger sample size and among individuals of different ethnic groups., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alaamery, Alghamdi, Massadeh, Alsawaji, Aljawini, Albesher, Alghamdi, Almutairi, Hejaili, Alfadhel, Baz, Almuzzaini, Almutairi, Abdullah, Quintana and Sayyari.)
- Published
- 2022
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40. Serum levels of IgM to phosphatidylcholine predict the response of multiple sclerosis patients to natalizumab or IFN-β.
- Author
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Muñoz Ú, Sebal C, Escudero E, Urcelay E, Arroyo R, García-Martínez MA, Quintana FJ, Álvarez-Lafuente R, and Sádaba MC
- Subjects
- Biomarkers, Humans, Immunoglobulin M, Interferon-beta therapeutic use, Natalizumab therapeutic use, Phosphatidylcholines, Multiple Sclerosis drug therapy
- Abstract
We developed an ELISA assay demonstrating the high prevalence of serum IgM to phosphatidylcholine (IgM-PC) in the first stages of multiple sclerosis (MS). We aimed to analyze the role of serum IgM-PC as a biomarker of response to treatment. Paired serum samples from 95 MS patients were obtained before (b.t) and after (a.t) treatment with disease modifying therapies. Patients were classified as non-responders or responders to treatment, according to classical criteria. Serum IgM-PC concentration was analyzed using our house ELISA assay. The level of serum IgM-PC b.t was higher in patients treated later with natalizumab than in those treated with Copaxone (p = 0.011) or interferon-β (p = 0.009). Responders to natalizumab showed higher concentration of serum IgM-PC b.t than those who did not respond to it (p = 0.019). The 73.3% of patients with the highest level of serum IgM-PC b.t responded to natalizumab. IgM-PC level decreased a.t in both cases, non-responders and responders to natalizumab. IgM-PC levels a.t did not decrease in non-responders to interferon-β, but in responders to it the IgM-PC level decreased (p = 0.007). Serum IgM-PC could be a biomarker of response to natalizumab or interferon-β treatment. Further studies would be necessary to validate these results., (© 2022. The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
41. Neuro-immune crosstalk in drug-resistant epilepsy.
- Author
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Andersen BM and Quintana FJ
- Subjects
- Humans, Neuroimmunomodulation, Drug Resistant Epilepsy
- Published
- 2022
- Full Text
- View/download PDF
42. Astrocytes and Microglia in Stress-Induced Neuroinflammation: The African Perspective.
- Author
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Olude MA, Mouihate A, Mustapha OA, Farina C, Quintana FJ, and Olopade JO
- Subjects
- Adolescent, Adult, Astrocytes, Female, Humans, Infant, Newborn, Inflammation, Inflammation Mediators, Neuroinflammatory Diseases, Malnutrition, Microglia
- Abstract
Background: Africa is laden with a youthful population, vast mineral resources and rich fauna. However, decades of unfortunate historical, sociocultural and leadership challenges make the continent a hotspot for poverty, indoor and outdoor pollutants with attendant stress factors such as violence, malnutrition, infectious outbreaks and psychological perturbations. The burden of these stressors initiate neuroinflammatory responses but the pattern and mechanisms of glial activation in these scenarios are yet to be properly elucidated. Africa is therefore most vulnerable to neurological stressors when placed against a backdrop of demographics that favor explosive childbearing, a vast population of unemployed youths making up a projected 42% of global youth population by 2030, repressive sociocultural policies towards women, poor access to healthcare, malnutrition, rapid urbanization, climate change and pollution. Early life stress, whether physical or psychological, induces neuroinflammatory response in developing nervous system and consequently leads to the emergence of mental health problems during adulthood. Brain inflammatory response is driven largely by inflammatory mediators released by glial cells; namely astrocytes and microglia. These inflammatory mediators alter the developmental trajectory of fetal and neonatal brain and results in long-lasting maladaptive behaviors and cognitive deficits. This review seeks to highlight the patterns and mechanisms of stressors such as poverty, developmental stress, environmental pollutions as well as malnutrition stress on astrocytes and microglia in neuroinflammation within the African context., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Olude, Mouihate, Mustapha, Farina, Quintana and Olopade.)
- Published
- 2022
- Full Text
- View/download PDF
43. Editorial: Nanoparticle-Mediated Signaling Rewiring and Reprogramming of Immune Responses.
- Author
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Quintana FJ and Pozo D
- Subjects
- Immunity, Signal Transduction, Biological Phenomena, Nanoparticles
- Abstract
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
- Published
- 2022
- Full Text
- View/download PDF
44. Function and therapeutic value of astrocytes in neurological diseases.
- Author
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Lee HG, Wheeler MA, and Quintana FJ
- Subjects
- Astrocytes metabolism, Cell Communication, Glutamic Acid metabolism, Humans, Multiple Sclerosis, Nervous System Diseases metabolism, Nervous System Diseases therapy
- Abstract
Astrocytes are abundant glial cells in the central nervous system (CNS) that perform diverse functions in health and disease. Astrocyte dysfunction is found in numerous diseases, including multiple sclerosis, Alzheimer disease, Parkinson disease, Huntington disease and neuropsychiatric disorders. Astrocytes regulate glutamate and ion homeostasis, cholesterol and sphingolipid metabolism and respond to environmental factors, all of which have been implicated in neurological diseases. Astrocytes also exhibit significant heterogeneity, driven by developmental programmes and stimulus-specific cellular responses controlled by CNS location, cell-cell interactions and other mechanisms. In this Review, we highlight general mechanisms of astrocyte regulation and their potential as therapeutic targets, including drugs that alter astrocyte metabolism, and therapies that target transporters and receptors on astrocytes. Emerging ideas, such as engineered probiotics and glia-to-neuron conversion therapies, are also discussed. We further propose a concise nomenclature for astrocyte subsets that we use to highlight the roles of astrocytes and specific subsets in neurological diseases., (© 2022. Springer Nature Limited.)
- Published
- 2022
- Full Text
- View/download PDF
45. Intranasal delivery of a small-molecule ErbB inhibitor promotes recovery from acute and late-stage CNS inflammation.
- Author
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Linnerbauer M, Lößlein L, Vandrey O, Tsaktanis T, Beer A, Naumann UJ, Panier F, Beyer T, Nirschl L, Kuramatsu JB, Winkler J, Quintana FJ, and Rothhammer V
- Subjects
- Afatinib, Animals, Inflammation drug therapy, Inflammation metabolism, Mice, Oligodendroglia metabolism, Astrocytes, Multiple Sclerosis
- Abstract
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the CNS that is characterized by demyelination and axonal degeneration. Although several established treatments reduce relapse burden, effective treatments to halt chronic progression are scarce. Single-cell transcriptomic studies in MS and its animal models have described astrocytes and their spatial and functional heterogeneity as important cellular determinants of chronic disease. We combined CNS single-cell transcriptome data and small-molecule screens in primary mouse and human astrocytes to identify glial interactions, which could be targeted by repurposing FDA-approved small-molecule modulators for the treatment of acute and late-stage CNS inflammation. Using hierarchical in vitro and in vivo validation studies, we demonstrate that among selected pathways, blockade of ErbB by the tyrosine kinase inhibitor afatinib efficiently mitigates proinflammatory astrocyte polarization and promotes tissue-regenerative functions. We found that i.n. delivery of afatinib during acute and late-stage CNS inflammation ameliorates disease severity by reducing monocyte infiltration and axonal degeneration while increasing oligodendrocyte proliferation. We used unbiased screening approaches of astrocyte interactions to identify ErbB signaling and its modulation by afatinib as a potential therapeutic strategy for acute and chronic stages of autoimmune CNS inflammation.
- Published
- 2022
- Full Text
- View/download PDF
46. Protocol for inducing inflammation and acute myelin degeneration in larval zebrafish.
- Author
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Jaronen M, Wheeler MA, and Quintana FJ
- Subjects
- Animals, Inflammation, Larva metabolism, Myelin Sheath, Demyelinating Diseases, Zebrafish genetics
- Abstract
This protocol details the induction of inflammation and acute myelin degeneration in larval zebrafish with a duration of <10 days. We describe the use of this model to screen the effects of candidate compounds on inflammation, followed by RNA isolation, and qPCR-based quantification of gene expression. We then outline the steps for bioinformatic analysis of the mechanisms associated with the compounds. This protocol can be used in combination with drugs and genetic targeting to identify pathways that contribute to neurodegeneration. For complete details on the use and execution of this profile, please refer to Wheeler et al. (2019)., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)
- Published
- 2022
- Full Text
- View/download PDF
47. The Immune Response in Multiple Sclerosis.
- Author
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Rodríguez Murúa S, Farez MF, and Quintana FJ
- Subjects
- Central Nervous System pathology, Humans, Immunity, Inflammation pathology, Multiple Sclerosis genetics, Multiple Sclerosis pathology, Neurodegenerative Diseases pathology
- Abstract
Multiple sclerosis (MS) is a chronic autoimmune, inflammatory, and neurodegenerative disease that affects the central nervous system (CNS). MS is characterized by immune dysregulation, which results in the infiltration of the CNS by immune cells, triggering demyelination, axonal damage, and neurodegeneration. Although the exact causes of MS are not fully understood, genetic and environmental factors are thought to control MS onset and progression. In this article, we review the main immunological mechanisms involved in MS pathogenesis.
- Published
- 2022
- Full Text
- View/download PDF
48. DICAM promotes T H 17 lymphocyte trafficking across the blood-brain barrier during autoimmune neuroinflammation.
- Author
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Charabati M, Grasmuck C, Ghannam S, Bourbonnière L, Fournier AP, Lécuyer MA, Tastet O, Kebir H, Rébillard RM, Hoornaert C, Gowing E, Larouche S, Fortin O, Pittet C, Filali-Mouhim A, Lahav B, Moumdjian R, Bouthillier A, Girard M, Duquette P, Cayrol R, Peelen E, Quintana FJ, Antel JP, Flügel A, Larochelle C, Arbour N, Zandee S, and Prat A
- Subjects
- Animals, Blood-Brain Barrier metabolism, Cell Adhesion Molecules metabolism, Humans, Mice, Natalizumab metabolism, Natalizumab pharmacology, Natalizumab therapeutic use, Neuroinflammatory Diseases, T-Lymphocytes metabolism, Th17 Cells, Multiple Sclerosis drug therapy, Multiple Sclerosis metabolism, Multiple Sclerosis, Relapsing-Remitting
- Abstract
The migration of circulating leukocytes into the central nervous system (CNS) is a key driver of multiple sclerosis (MS) pathogenesis. The monoclonal antibody natalizumab proved that pharmaceutically obstructing this process is an effective therapeutic approach for treating relapsing-remitting MS (RRMS). Unfortunately, the clinical efficacy of natalizumab is somewhat offset by its incapacity to control the progressive forms of MS (PMS) and by life-threatening side effects in RRMS rising from the expression of its molecular target, very late antigen 4 (VLA4), on most immune cells and consequent impairment of CNS immunosurveillance. Here, we identified dual immunoglobulin domain containing cell adhesion molecule (DICAM) as a cell trafficking molecule preferentially expressed by T helper 17 (T
H 17)–polarized CD4+ T lymphocytes. We found that DICAM expression on circulating CD4+ T cells was increased in patients with active RRMS and PMS disease courses, and expression of DICAM ligands was increased on the blood-brain barrier endothelium upon inflammation and in MS lesions. Last, we demonstrated that pharmaceutically neutralizing DICAM reduced murine and human TH 17 cell trafficking across the blood-brain barrier in vitro and in vivo, and alleviated disease symptoms in four distinct murine autoimmune encephalomyelitis models, including relapsing-remitting and progressive disease models. Collectively, our data highlight DICAM as a candidate therapeutic target to impede the migration of disease-inducing leukocytes into the CNS in both RRMS and PMS and suggest that blocking DICAM with a monoclonal antibody may be a promising therapeutic approach.- Published
- 2022
- Full Text
- View/download PDF
49. Protocol for in vitro analysis of pro-inflammatory and metabolic functions of cultured primary murine astrocytes.
- Author
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Gutiérrez-Vázquez C and Quintana FJ
- Subjects
- Animals, Mice, Oxygen Consumption, Astrocytes metabolism, Brain metabolism
- Abstract
Robust protocols are required to investigate in vitro the molecular mechanisms that control astrocyte metabolism and pro-inflammatory activities. In the present protocol, we describe step by step the isolation and culture of primary murine astrocytes from neonatal brains, followed by their genetic manipulation with siRNA. We further describe cytokine activation of the cultured astrocytes for the analysis of their pro-inflammatory responses, and the oxygen consumption analysis to assess their metabolic function. For complete details on the use and execution of this protocol, please refer to Chao et al. (2019), Clark et al. (2021), and Rothhammer et al. (2018)., Competing Interests: The authors declare no competing interests., (© 2021 The Author(s).)
- Published
- 2021
- Full Text
- View/download PDF
50. Glial and myeloid heterogeneity in the brain tumour microenvironment.
- Author
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Andersen BM, Faust Akl C, Wheeler MA, Chiocca EA, Reardon DA, and Quintana FJ
- Subjects
- Brain, Humans, Microglia pathology, Tumor Microenvironment, Brain Neoplasms pathology, Glioma pathology
- Abstract
Brain cancers carry bleak prognoses, with therapeutic advances helping only a minority of patients over the past decade. The brain tumour microenvironment (TME) is highly immunosuppressive and differs from that of other malignancies as a result of the glial, neural and immune cell populations that constitute it. Until recently, the study of the brain TME was limited by the lack of methods to de-convolute this complex system at the single-cell level. However, novel technical approaches have begun to reveal the immunosuppressive and tumour-promoting properties of distinct glial and myeloid cell populations in the TME, identifying new therapeutic opportunities. Here, we discuss the immune modulatory functions of microglia, monocyte-derived macrophages and astrocytes in brain metastases and glioma, highlighting their disease-associated heterogeneity and drawing from the insights gained by studying these malignancies and other neurological disorders. Lastly, we consider potential approaches for the therapeutic modulation of the brain TME., (© 2021. Springer Nature Limited.)
- Published
- 2021
- Full Text
- View/download PDF
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