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1. An adapted protocol to derive microglia from stem cells and its application in the study of CSF1R-related disorders

Author

Dorion, Marie-France, Casas, Diana, Shlaifer, Irina, Yaqubi, Moein, Fleming, Peter, Karpilovsky, Nathan, Chen, Carol X.-Q., Nicouleau, Michael, Piscopo, Valerio E. C., MacDougall, Emma J., Alluli, Aeshah, Goldsmith, Taylor M., Schneider, Alexandria, Dorion, Samuel, Aprahamian, Nathalia, MacDonald, Adam, Thomas, Rhalena A., Dudley, Roy W. R., Hall, Jeffrey A., Fon, Edward A., Antel, Jack P., Stratton, Jo Anne, Durcan, Thomas M., La Piana, Roberta, and Healy, Luke M.

Published
2024
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2. Regulation of stress granule formation in human oligodendrocytes

Author

Pernin, Florian, Cui, Qiao-Ling, Mohammadnia, Abdulshakour, Fernandes, Milton G. F., Hall, Jeffery A., Srour, Myriam, Dudley, Roy W. R., Zandee, Stephanie E. J., Klement, Wendy, Prat, Alexandre, Salapa, Hannah E., Levin, Michael C., Moore, G. R. Wayne, Kennedy, Timothy E., Vande Velde, Christine, and Antel, Jack P.

Published
2024
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3. Disease-associated astrocyte epigenetic memory promotes CNS pathology

Author

Lee, Hong-Gyun, Rone, Joseph M., Li, Zhaorong, Akl, Camilo Faust, Shin, Seung Won, Lee, Joon-Hyuk, Flausino, Lucas E., Pernin, Florian, Chao, Chun-Cheih, Kleemann, Kilian L., Srun, Lena, Illouz, Tomer, Giovannoni, Federico, Charabati, Marc, Sanmarco, Liliana M., Kenison, Jessica E., Piester, Gavin, Zandee, Stephanie E. J., Antel, Jack P., Rothhammer, Veit, Wheeler, Michael A., Prat, Alexandre, Clark, Iain C., and Quintana, Francisco J.

Published
2024
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4. Droplet-based forward genetic screening of astrocyte–microglia cross-talk

Author

Wheeler, Michael A, Clark, Iain C, Lee, Hong-Gyun, Li, Zhaorong, Linnerbauer, Mathias, Rone, Joseph M, Blain, Manon, Akl, Camilo Faust, Piester, Gavin, Giovannoni, Federico, Charabati, Marc, Lee, Joon-Hyuk, Kye, Yoon-Chul, Choi, Joshua, Sanmarco, Liliana M, Srun, Lena, Chung, Elizabeth N, Flausino, Lucas E, Andersen, Brian M, Rothhammer, Veit, Yano, Hiroshi, Illouz, Tomer, Zandee, Stephanie EJ, Daniel, Carolin, Artis, David, Prinz, Marco, Abate, Adam R, Kuchroo, Vijay K, Antel, Jack P, Prat, Alexandre, and Quintana, Francisco J

Subjects
Neurosciences, Human Genome, Biotechnology, Genetics, 2.1 Biological and endogenous factors, Aetiology, Astrocytes, Genetic Testing, High-Throughput Screening Assays, Microfluidic Analytical Techniques, Microglia, Amphiregulin, Autocrine Communication, Gene Expression, Humans, General Science & Technology
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

5. Author Correction: Disease-associated astrocyte epigenetic memory promotes CNS pathology

Author

Lee, Hong-Gyun, Rone, Joseph M., Li, Zhaorong, Akl, Camilo Faust, Shin, Seung Won, Lee, Joon-Hyuk, Flausino, Lucas E., Pernin, Florian, Chao, Chun-Cheih, Kleemann, Kilian L., Srun, Lena, Illouz, Tomer, Giovannoni, Federico, Charabati, Marc, Sanmarco, Liliana M., Kenison, Jessica E., Piester, Gavin, Zandee, Stephanie E. J., Antel, Jack P., Rothhammer, Veit, Wheeler, Michael A., Prat, Alexandre, Clark, Iain C., and Quintana, Francisco J.

Published
2024
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6. Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases

Author

Nutma, Erik, Fancy, Nurun, Weinert, Maria, Tsartsalis, Stergios, Marzin, Manuel C., Muirhead, Robert C. J., Falk, Irene, Breur, Marjolein, de Bruin, Joy, Hollaus, David, Pieterman, Robin, Anink, Jasper, Story, David, Chandran, Siddharthan, Tang, Jiabin, Trolese, Maria C., Saito, Takashi, Saido, Takaomi C., Wiltshire, Katharine H., Beltran-Lobo, Paula, Phillips, Alexandra, Antel, Jack, Healy, Luke, Dorion, Marie-France, Galloway, Dylan A., Benoit, Rochelle Y., Amossé, Quentin, Ceyzériat, Kelly, Badina, Aurélien M., Kövari, Enikö, Bendotti, Caterina, Aronica, Eleonora, Radulescu, Carola I., Wong, Jia Hui, Barron, Anna M., Smith, Amy M., Barnes, Samuel J., Hampton, David W., van der Valk, Paul, Jacobson, Steven, Howell, Owain W., Baker, David, Kipp, Markus, Kaddatz, Hannes, Tournier, Benjamin B., Millet, Philippe, Matthews, Paul M., Moore, Craig S., Amor, Sandra, and Owen, David R.

Published
2023
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7. Mechanisms of metabolic stress induced cell death of human oligodendrocytes: relevance for progressive multiple sclerosis

Author

Fernandes, Milton Guilherme Forestieri, Mohammadnia, Abdulshakour, Pernin, Florian, Schmitz-Gielsdorf, Laura Eleonora, Hodgins, Caroline, Cui, Qiao-Ling, Yaqubi, Moein, Blain, Manon, Hall, Jeffery, Dudley, Roy, Srour, Myriam, Zandee, Stephanie E. J., Klement, Wendy, Prat, Alexandre, Stratton, Jo Anne, Rodriguez, Moses, Kuhlmann, Tanja, Moore, Wayne, Kennedy, Timothy E., and Antel, Jack P.

Published
2023
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9. Artificial intelligence extension of the OSCAR‐IB criteria

Author

Petzold, Axel, Albrecht, Philipp, Balcer, Laura, Bekkers, Erik, Brandt, Alexander U, Calabresi, Peter A, Deborah, Orla Galvin, Graves, Jennifer S, Green, Ari, Keane, Pearse A, Bijvank, Jenny A Nij, Sander, Josemir W, Paul, Friedemann, Saidha, Shiv, Villoslada, Pablo, Wagner, Siegfried K, Yeh, E Ann, Aktas, Orhan, Antel, Jack, Asgari, Nasrin, Audo, Isabelle, Avasarala, Jagannadha, Avril, Daly, Bagnato, Francesca R, Banwell, Brenda, Bar‐Or, Amit, Behbehani, Raed, Manterola, Arnaldo Belzunce, Bennett, Jeffrey, Benson, Leslie, Bernard, Jacqueline, Bremond‐Gignac, Dominique, Britze, Josefine, Burton, Jodie, Calkwood, Jonathan, Carroll, William, Chandratheva, Arvind, Cohen, Jeffrey, Comi, Giancarlo, Cordano, Christian, Costa, Silvana, Costello, Fiona, Courtney, Ardith, Cruz‐Herranz, Anes, Cutter, Gary, Crabb, David, Delott, Lindsey, De Seze, Jerome, Diem, Ricarda, Dollfuss, Helene, Ayoubi, Nabil K El, Fasser, Christina, Finke, Carsten, Fischer, Dominik, Fitzgerald, Kathryn, Fonseca, Pedro, Frederiksen, Jette L, Frohman, Elliot, Frohman, Teresa, Fujihara, Kazuo, Cuellar, Iñigo Gabilondo, Galetta, Steven, Garcia‐Martin, Elena, Giovannoni, Gavin, Glebauskiene, Brigita, Suárez, Inés González, Jensen, Gorm Pihl, Hamann, Steffen, Hartung, Hans‐Peter, Havla, Joachim, Hemmer, Bernhard, Huang, Su‐Chun, Imitola, Jaime, Jasinskas, Vytautas, Jiang, Hong, Kafieh, Rahele, Kappos, Ludwig, Kardon, Randy, Keegan, David, Kildebeck, Eric, Kim, Ungsoo Samuel, Klistorner, Sasha, Knier, Benjamin, Kolbe, Scott, Korn, Thomas, Krupp, Lauren, Lagrèze, Wolf, Leocani, Letizia, Levin, Netta, Liskova, Petra, Preiningerova, Jana Lizrova, Lorenz, Birgit, May, Eugene, Miller, David, Mikolajczak, Janine, Saïd, Saddek Mohand, Montalban, Xavier, Morrow, Mark, Mowry, Ellen, and Murta, Joaquim

Subjects
Biomedical and Clinical Sciences, Neurosciences, Bioengineering, Biomedical Imaging, Autoimmune Disease, Neurodegenerative, Aging, Brain Disorders, Neurological, Algorithms, Artificial Intelligence, Big Data, Cohort Studies, Humans, Nervous System Diseases, Retina, Tomography, Optical Coherence, IMSVISUAL, ERN-EYE Consortium, Clinical Sciences, Clinical and health psychology
Abstract

Artificial intelligence (AI)-based diagnostic algorithms have achieved ambitious aims through automated image pattern recognition. For neurological disorders, this includes neurodegeneration and inflammation. Scalable imaging technology for big data in neurology is optical coherence tomography (OCT). We highlight that OCT changes observed in the retina, as a window to the brain, are small, requiring rigorous quality control pipelines. There are existing tools for this purpose. Firstly, there are human-led validated consensus quality control criteria (OSCAR-IB) for OCT. Secondly, these criteria are embedded into OCT reporting guidelines (APOSTEL). The use of the described annotation of failed OCT scans advances machine learning. This is illustrated through the present review of the advantages and disadvantages of AI-based applications to OCT data. The neurological conditions reviewed here for the use of big data include Alzheimer disease, stroke, multiple sclerosis (MS), Parkinson disease, and epilepsy. It is noted that while big data is relevant for AI, ownership is complex. For this reason, we also reached out to involve representatives from patient organizations and the public domain in addition to clinical and research centers. The evidence reviewed can be grouped in a five-point expansion of the OSCAR-IB criteria to embrace AI (OSCAR-AI). The review concludes by specific recommendations on how this can be achieved practically and in compliance with existing guidelines.

Published
2021

10. Barcoded viral tracing of single-cell interactions in central nervous system inflammation

Author

Clark, Iain C, Gutiérrez-Vázquez, Cristina, Wheeler, Michael A, Li, Zhaorong, Rothhammer, Veit, Linnerbauer, Mathias, Sanmarco, Liliana M, Guo, Lydia, Blain, Manon, Zandee, Stephanie EJ, Chao, Chun-Cheih, Batterman, Katelyn V, Schwabenland, Marius, Lotfy, Peter, Tejeda-Velarde, Amalia, Hewson, Patrick, Manganeli Polonio, Carolina, Shultis, Michael W, Salem, Yasmin, Tjon, Emily C, Fonseca-Castro, Pedro H, Borucki, Davis M, Alves de Lima, Kalil, Plasencia, Agustin, Abate, Adam R, Rosene, Douglas L, Hodgetts, Kevin J, Prinz, Marco, Antel, Jack P, Prat, Alexandre, and Quintana, Francisco J

Subjects
Brain Disorders, Autoimmune Disease, Multiple Sclerosis, Neurosciences, Genetics, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological, Good Health and Well Being, Animals, Antigens, CD, Astrocytes, Brain, Cell Communication, Central Nervous System, Encephalomyelitis, Autoimmune, Experimental, Ephrin-B3, Herpesvirus 1, Suid, Humans, Male, Mice, Mice, Inbred C57BL, Microglia, Mitochondria, NF-kappa B, Nerve Tissue Proteins, RNA-Seq, Reactive Oxygen Species, Receptor, EphB3, Receptors, Cell Surface, Semaphorins, Signal Transduction, Single-Cell Analysis, T-Lymphocytes, TOR Serine-Threonine Kinases, General Science & Technology
Abstract

Cell-cell interactions control the physiology and pathology of the central nervous system (CNS). To study astrocyte cell interactions in vivo, we developed rabies barcode interaction detection followed by sequencing (RABID-seq), which combines barcoded viral tracing and single-cell RNA sequencing (scRNA-seq). Using RABID-seq, we identified axon guidance molecules as candidate mediators of microglia-astrocyte interactions that promote CNS pathology in experimental autoimmune encephalomyelitis (EAE) and, potentially, multiple sclerosis (MS). In vivo cell-specific genetic perturbation EAE studies, in vitro systems, and the analysis of MS scRNA-seq datasets and CNS tissue established that Sema4D and Ephrin-B3 expressed in microglia control astrocyte responses via PlexinB2 and EphB3, respectively. Furthermore, a CNS-penetrant EphB3 inhibitor suppressed astrocyte and microglia proinflammatory responses and ameliorated EAE. In summary, RABID-seq identified microglia-astrocyte interactions and candidate therapeutic targets.

Published
2021

12. MAFG-driven astrocytes promote CNS inflammation

Author

Wheeler, Michael A, Clark, Iain C, Tjon, Emily C, Li, Zhaorong, Zandee, Stephanie EJ, Couturier, Charles P, Watson, Brianna R, Scalisi, Giulia, Alkwai, Sarah, Rothhammer, Veit, Rotem, Assaf, Heyman, John A, Thaploo, Shravan, Sanmarco, Liliana M, Ragoussis, Jiannis, Weitz, David A, Petrecca, Kevin, Moffitt, Jeffrey R, Becher, Burkhard, Antel, Jack P, Prat, Alexandre, and Quintana, Francisco J

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Biotechnology, Autoimmune Disease, Neurosciences, Neurodegenerative, Multiple Sclerosis, Brain Disorders, Human Genome, 2.1 Biological and endogenous factors, Aetiology, 1.1 Normal biological development and functioning, Underpinning research, Neurological, Animals, Antioxidants, Astrocytes, Central Nervous System, DNA Methylation, Encephalomyelitis, Autoimmune, Experimental, Female, Granulocyte-Macrophage Colony-Stimulating Factor, Humans, Inflammation, MafG Transcription Factor, Male, Methionine Adenosyltransferase, Mice, NF-E2-Related Factor 2, Repressor Proteins, Sequence Analysis, RNA, Signal Transduction, Transcription, Genetic, General Science & Technology
Abstract

Multiple sclerosis is a chronic inflammatory disease of the CNS1. Astrocytes contribute to the pathogenesis of multiple sclerosis2, but little is known about the heterogeneity of astrocytes and its regulation. Here we report the analysis of astrocytes in multiple sclerosis and its preclinical model experimental autoimmune encephalomyelitis (EAE) by single-cell RNA sequencing in combination with cell-specific Ribotag RNA profiling, assay for transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing (ChIP-seq), genome-wide analysis of DNA methylation and in vivo CRISPR-Cas9-based genetic perturbations. We identified astrocytes in EAE and multiple sclerosis that were characterized by decreased expression of NRF2 and increased expression of MAFG, which cooperates with MAT2α to promote DNA methylation and represses antioxidant and anti-inflammatory transcriptional programs. Granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling in astrocytes drives the expression of MAFG and MAT2α and pro-inflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, multiple sclerosis. Our results identify candidate therapeutic targets in multiple sclerosis.

Published
2020

16. Cover Image, Volume 72, Issue 6

Author

Piscopo, Valerio E. C., primary, Chapleau, Alexandra, additional, Blaszczyk, Gabriela J., additional, Sirois, Julien, additional, You, Zhipeng, additional, Soubannier, Vincent, additional, Chen, Carol X.‐Q., additional, Bernard, Geneviève, additional, Antel, Jack P., additional, and Durcan, Thomas M., additional

Published
2024
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18. The use of a SOX10 reporter toward ameliorating oligodendrocyte lineage differentiation from human induced pluripotent stem cells

Author

Piscopo, Valerio E. C., primary, Chapleau, Alexandra, additional, Blaszczyk, Gabriela J., additional, Sirois, Julien, additional, You, Zhipeng, additional, Soubannier, Vincent, additional, Chen, Carol X.‐Q., additional, Bernard, Geneviève, additional, Antel, Jack P., additional, and Durcan, Thomas M., additional

Published
2024
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19. Seeking neuroprotection in multiple sclerosis: an ongoing challenge

Author

Antel, Jack P., Kennedy, Timothy E., and Kuhlmann, Tanja

Subjects
Neurons -- Analysis, Multiple sclerosis -- Diagnosis -- Complications and side effects, Health care industry
Abstract

Multiple sclerosis (MS) Is an autoimmune disease of the CNS, featuring Inflammation and demyelination with variable recovery. In this issue of the JCI, Kapell, Fazio, and authors address the potential for targeting neuron-oligodendrocyte potassium shuttling at the nodes of Ranvier as a neuroprotective strategy during inflammatory demyelination of the CNS in experimental MS. Their extensive and impressive study could serve as a template for defining the physiologic properties of a putative protective pathway. The authors examined MS features in existent disease models, investigated the impact of pharmacologic intervention, and evaluated its status in tissues from patients with MS. We await future studies that will tackle the challenge of translating these findings into a clinical therapy., Early events in multiple sclerosis drive disability Multiple sclerosis (MS) follows an unpredictable clinical disease course most frequently characterized by initial episodes of neurologic relapses with variable recovery; up to [...]

Published
2023
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20. iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases

Author

Abud, Edsel M, Ramirez, Ricardo N, Martinez, Eric S, Healy, Luke M, Nguyen, Cecilia HH, Newman, Sean A, Yeromin, Andriy V, Scarfone, Vanessa M, Marsh, Samuel E, Fimbres, Cristhian, Caraway, Chad A, Fote, Gianna M, Madany, Abdullah M, Agrawal, Anshu, Kayed, Rakez, Gylys, Karen H, Cahalan, Michael D, Cummings, Brian J, Antel, Jack P, Mortazavi, Ali, Carson, Monica J, Poon, Wayne W, and Blurton-Jones, Mathew

Subjects
Biological Psychology, Biomedical and Clinical Sciences, Neurosciences, Psychology, Stem Cell Research, Alzheimer's Disease, Aging, Stem Cell Research - Induced Pluripotent Stem Cell, Acquired Cognitive Impairment, Neurodegenerative, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Dementia, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Genetics, Brain Disorders, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Alzheimer Disease, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Animals, Brain, Cells, Cultured, Cytokines, Disease Models, Animal, Humans, Induced Pluripotent Stem Cells, Mice, Microglia, Peptide Fragments, 3D organoids, AD-GWAS, Alzheimer’s disease, Beta-amyloid, Tau, cell models of disease, induced pluripotent stem cells, microglia, mouse transplantation, neurodegenerative diseases, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGLs) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer's disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates. iMGLs were used to examine the effects of Aβ fibrils and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning. Furthermore, iMGLs transplanted into transgenic mice and human brain organoids resemble microglia in vivo. Together, these findings demonstrate that iMGLs can be used to study microglial function, providing important new insight into human neurological disease.

Published
2017

22. Extrinsic immune cell-derived, but not intrinsic oligodendroglial factors contribute to oligodendroglial differentiation block in multiple sclerosis

Author

Starost, Laura, Lindner, Maren, Herold, Martin, Xu, Yu Kang T., Drexler, Hannes C. A., Heß, Katharina, Ehrlich, Marc, Ottoboni, Linda, Ruffini, Francesca, Stehling, Martin, Röpke, Albrecht, Thomas, Christian, Schöler, Hans R., Antel, Jack, Winkler, Jürgen, Martino, Gianvito, Klotz, Luisa, and Kuhlmann, Tanja

Published
2020
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25. Naive CD4 T-cell activation identifies MS patients having rapid transition to progressive MS.

Author

Zastepa, Evelyn, Fitz-Gerald, Leslie, Hallett, Michael, Antel, Jack, Bar-Or, Amit, Lapierre, Yves, Haegert, David, and Baranzini, Sergio

Subjects
Adult, CD4-Positive T-Lymphocytes, Disease Progression, Female, Gene Expression, Humans, Immunity, Innate, Lymphocyte Activation, Middle Aged, Multiple Sclerosis, Chronic Progressive, Multiple Sclerosis, Relapsing-Remitting, Receptors, Antigen, T-Cell
Abstract

OBJECTIVE: Our objective was to determine whether altered naive CD4 T-cell biology contributes to development of disease progression in secondary progressive multiple sclerosis (SPMS). METHODS: We compared the naive CD4 T-cell gene expression profiles of 19 patients with SPMS and 14 healthy controls (HCs) using a whole-genome microarray approach. We analyzed surface protein expression of critical genes by flow cytometry after T-cell receptor (TCR) stimulation of naive CD4 T cells isolated from HCs and patients with SPMS. RESULTS: Hierarchical clustering segregated patients with SPMS into 2 subgroups: SP-1, which had a short duration of relapsing-remitting multiple sclerosis (MS), and SP-2, which had a long duration of relapsing-remitting MS. SP-1 patients upregulated numerous immune genes, including genes within TCR and toll-like receptor (TLR) signaling pathways. SP-2 patients showed immune gene downregulation in comparison with HCs. We identified an SP-1-specific transcriptional signature of 3 genes (TLR4, TLR2, and chemokine receptor 1), and these genes had higher surface protein expression in SP-1 than in SP-2. After TCR stimulation for 48 hours, only SP-1 showed a progressive linear increase in TLR2 and TLR4 protein expression. CONCLUSIONS: Differences in naive CD4 T-cell biology, notably of TCR and TLR signaling pathways, identified patients with MS with more rapid conversion to secondary progression, a critical determinant of long-term disability in MS.

Published
2014

26. MerTK is a mediator of alpha-synuclein fibril uptake by human microglia.

Author

Dorion, Marie-France, Yaqubi, Moein, Senkevich, Konstantin, Kieran, Nicholas W, MacDonald, Adam, Chen, Carol X Q, Luo, Wen, Wallis, Amber, Shlaifer, Irina, Hall, Jeffery A, Dudley, Roy W R, Glass, Ian A, Laboratory, Birth Defects Research, Stratton, Jo Anne, Fon, Edward A, Bartels, Tim, Antel, Jack P, Gan-or, Ziv, Durcan, Thomas M, and Healy, Luke M

Subjects
LEWY body dementia, ALPHA-synuclein, MICROGLIA, PARKINSON'S disease, PROTEIN-tyrosine kinases
Abstract

Mer tyrosine kinase (MerTK) is a receptor tyrosine kinase that mediates non-inflammatory, homeostatic phagocytosis of diverse types of cellular debris. Highly expressed on the surface of microglial cells, MerTK is of importance in brain development, homeostasis, plasticity and disease. Yet, involvement of this receptor in the clearance of protein aggregates that accumulate with ageing and in neurodegenerative diseases has yet to be defined. The current study explored the function of MerTK in the microglial uptake of alpha-synuclein fibrils which play a causative role in the pathobiology of synucleinopathies. Using human primary and induced pluripotent stem cell-derived microglia, the MerTK-dependence of alpha-synuclein fibril internalization was investigated in vitro. Relevance of this pathway in synucleinopathies was assessed through burden analysis of MERTK variants and analysis of MerTK expression in patient-derived cells and tissues. Pharmacological inhibition of MerTK and siRNA-mediated MERTK knockdown both caused a decreased rate of alpha-synuclein fibril internalization by human microglia. Consistent with the non-inflammatory nature of MerTK-mediated phagocytosis, alpha-synuclein fibril internalization was not observed to induce secretion of pro-inflammatory cytokines such as IL-6 or TNF, and downmodulated IL-1β secretion from microglia. Burden analysis in two independent patient cohorts revealed a significant association between rare functionally deleterious MERTK variants and Parkinson's disease in one of the cohorts (P = 0.002). Despite a small upregulation in MERTK mRNA expression in nigral microglia from Parkinson's disease/Lewy body dementia patients compared to those from non-neurological control donors in a single-nuclei RNA-sequencing dataset (P = 5.08 × 10−21), no significant upregulation in MerTK protein expression was observed in human cortex and substantia nigra lysates from Lewy body dementia patients compared to controls. Taken together, our findings define a novel role for MerTK in mediating the uptake of alpha-synuclein fibrils by human microglia, with possible involvement in limiting alpha-synuclein spread in synucleinopathies such as Parkinson's disease. Upregulation of this pathway in synucleinopathies could have therapeutic values in enhancing alpha-synuclein fibril clearance in the brain. [ABSTRACT FROM AUTHOR]

Published
2024
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28. T follicular helper cells in human efferent lymph retain lymphoid characteristics

Author

Vella, Laura A., Buggert, Marcus, Manne, Sasikanth, Herati, Ramin S., Sayin, Ismail, Kuri-Cervantes, Leticia, Brody, Irene Bukh, OBoyle, Kaitlin C., Kaprielian, Hagop, Giles, Josephine R., Nguyen, Son, Muselman, Alexander, Antel, Jack P., Bar-Or, Amit, Johnson, Matthew E., Canaday, David H., Naji, Ali, Ganusov, Vitaly V., Laufer, Terri M., Wells, Andrew D., Dori, Yoav, Itkin, Maxim G., Betts, Michael R., and Wherry, E. John

Subjects
B cells, Fingolimod, T cells, Epigenetic inheritance, Health care industry, University of Pennsylvania. Perelman School of Medicine, Children's Hospital of Philadelphia, University of Pennsylvania
Abstract

T follicular helper cells (Tfh), a subset of [CD4.sup.+] T cells, provide requisite help to B cells in the germinal centers (GC) of lymphoid tissue. GC Tfh are identified by high expression of the chemokine receptor CXCR5 and the inhibitory molecule PD-1. Although more accessible, blood contains lower frequencies of [CXCR5.sup.+] and [PD-1.sup.+] cells that have been termed circulating Tfh (cTfh). However, it remains unclear whether GC Tfh exit lymphoid tissues and populate this cTfh pool. To examine exiting cells, we assessed the phenotype of Tfh present within the major conduit of efferent lymph from lymphoid tissues into blood, the human thoracic duct. Unlike what was found in blood, we consistently identified a CXCR5-bright PD-1-bright ([CXCR5.sup.Br][PD-1.sup.Br]) Tfh population in thoracic duct lymph (TDL). These [CXCR5.sup.Br][PD-1.sup.Br] TDL Tfh shared phenotypic and transcriptional similarities with GC Tfh. Moreover, components of the epigenetic profile of GC Tfh could be detected in [CXCR5.sup.Br][PD-1.sup.Br] TDL Tfh and the transcriptional imprint of this epigenetic signature was enriched in an activated cTfh subset known to contain vaccine-responding cells. Together with data showing shared TCR sequences between the [CXCR5.sup.Br][PD-1.sup.Br] TDL Tfh and cTfh, these studies identify a population in TDL as a circulatory intermediate connecting the biology of Tfh in blood to Tfh in lymphoid tissue., Introduction T follicular helper cells (Tfh) are a subset of [CD4.sup.+] T cells that provide B cell help within the follicles of secondary lymphoid tissues. Tfh promote B cell class [...]

Published
2019
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29. Control of tumor-associated macrophages and T cells in glioblastoma via AHR and CD39

Author

Takenaka, Maisa C., Gabriely, Galina, Rothhammer, Veit, Mascanfroni, Ivan D., Wheeler, Michael A., Chao, Chun-Cheih, Gutiérrez-Vázquez, Cristina, Kenison, Jessica, Tjon, Emily C., Barroso, Andreia, Vandeventer, Tyler, de Lima, Kalil Alves, Rothweiler, Sonja, Mayo, Lior, Ghannam, Soufiene, Zandee, Stephanie, Healy, Luke, Sherr, David, Farez, Mauricio F., Prat, Alexandre, Antel, Jack, Reardon, David A., Zhang, Hailei, Robson, Simon C., Getz, Gad, Weiner, Howard L., and Quintana, Francisco J.

Published
2019
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30. Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy

Author

Couturier, Charles P., Ayyadhury, Shamini, Le, Phuong U., Nadaf, Javad, Monlong, Jean, Riva, Gabriele, Allache, Redouane, Baig, Salma, Yan, Xiaohua, Bourgey, Mathieu, Lee, Changseok, Wang, Yu Chang David, Wee Yong, V., Guiot, Marie-Christine, Najafabadi, Hamed, Misic, Bratislav, Antel, Jack, Bourque, Guillaume, Ragoussis, Jiannis, and Petrecca, Kevin

Published
2020
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32. Author Correction: Single-cell RNA-seq reveals that glioblastoma recapitulates a normal neurodevelopmental hierarchy

Author

Couturier, Charles P., Ayyadhury, Shamini, Le, Phuong U., Nadaf, Javad, Monlong, Jean, Riva, Gabriele, Allache, Redouane, Baig, Salma, Yan, Xiaohua, Bourgey, Mathieu, Lee, Changseok, Wang, Yu Chang David, Yong, V. Wee, Guiot, Marie-Christine, Najafabadi, Hamed, Misic, Bratislav, Antel, Jack, Bourque, Guillaume, Ragoussis, Jiannis, and Petrecca, Kevin

Published
2020
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36. Microglial control of astrocytes in response to microbial metabolites

Author

Rothhammer, Veit, Borucki, Davis M., Tjon, Emily C., Takenaka, Maisa C., Chao, Chun-Cheih, Ardura-Fabregat, Alberto, de Lima, Kalil Alves, Gutiérrez-Vázquez, Cristina, Hewson, Patrick, Staszewski, Ori, Blain, Manon, Healy, Luke, Neziraj, Tradite, Borio, Matilde, Wheeler, Michael, Dragin, Loic Lionel, Laplaud, David A., Antel, Jack, Alvarez, Jorge Ivan, Prinz, Marco, and Quintana, Francisco J.

Published
2018
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44. Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor

Author

Rothhammer, Veit, Mascanfroni, Ivan D, Bunse, Lukas, Takenaka, Maisa C, Kenison, Jessica E, Mayo, Lior, Chao, Chun-Cheih, Patel, Bonny, Yan, Raymond, Blain, Manon, Alvarez, Jorge I, Kébir, Hania, Anandasabapathy, Niroshana, Izquierdo, Guillermo, Jung, Steffen, Obholzer, Nikolaus, Pochet, Nathalie, Clish, Clary B, Prinz, Marco, Prat, Alexandre, Antel, Jack, and Quintana, Francisco J

Published
2016
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48. Regional and age‐related diversity of human mature oligodendrocytes

Author

Yaqubi, Moein, primary, Luo, Julia Xiao Xuan, additional, Baig, Salma, additional, Cui, Qiao‐Ling, additional, Petrecca, Kevin, additional, Desu, Haritha, additional, Larochelle, Catherine, additional, Afanasiev, Elia, additional, Hall, Jeffery A., additional, Dudley, Roy, additional, Srour, Myriam, additional, Haglund, Lisbet, additional, Ouellet, Jean, additional, Georgiopoulos, Miltiadis, additional, Santaguida, Carlo, additional, Sonnen, Joshua A., additional, Healy, Luke M., additional, Stratton, Jo Anne, additional, Kennedy, Timothy E., additional, and Antel, Jack P., additional

Published
2022
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