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1. CLEC16A in astrocytes promotes mitophagy and limits pathology in a multiple sclerosis mouse model

Author

Kadowaki, Atsushi, Wheeler, Michael A., Li, Zhaorong, Andersen, Brian M., Lee, Hong-Gyun, Illouz, Tomer, Lee, Joon-Hyuk, Ndayisaba, Alain, Zandee, Stephanie E. J., Basu, Himanish, Chao, Chun-Cheih, Mahler, Joao V., Klement, Wendy, Neel, Dylan, Bergstresser, Matthew, Rothhammer, Veit, Lipof, Gabriel, Srun, Lena, Soleimanpour, Scott A., Chiu, Isaac, Prat, Alexandre, Khurana, Vikram, and Quintana, Francisco J.

Published
2025
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2. Nasal anti-CD3 monoclonal antibody ameliorates traumatic brain injury, enhances microglial phagocytosis and reduces neuroinflammation via IL-10-dependent Treg–microglia crosstalk

Author

Izzy, Saef, Yahya, Taha, Albastaki, Omar, Abou-El-Hassan, Hadi, Aronchik, Michael, Cao, Tian, De Oliveira, Marilia Garcia, Lu, Kuan-Jung, Moreira, Thais G., da Silva, Patrick, Boucher, Masen L., Beauchamp, Leah C., S. LeServe, Danielle, Brandao, Wesley Nogueira, Carolina Durão, Ana, Lanser, Toby, Montini, Federico, Lee, Joon-Hyuk, Bernstock, Joshua D., Kaul, Megha, Pasquarelli-do-Nascimento, Gabriel, Chopra, Kusha, Krishnan, Rajesh, Mannix, Rebekah, Rezende, Rafael M., Quintana, Francisco J., Butovsky, Oleg, and Weiner, Howard L.

Published
2025
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5. Deletion of murine astrocytic vesicular nucleotide transporter increases anxiety and depressive-like behavior and attenuates motivation for reward

Author

Huang, Qian, Lee, Hiu Ham, Volpe, Bryan, Zhang, Qingchen, Xue, Chang, Liu, Brian C., Abuhasan, Yahia R., Li, Lingyun, Yang, Jeremy S., Egholm, Julie, Gutierrez-Vazquez, Cristina, Li, Allen, Lee, Alyssa, Tang, Sharon, Wong, Chun Wa, Liu, Tiemin, Huang, Yuan, Ramos, Raddy L., Stout, Randy F., El Ouaamari, Abdelfattah, Quintana, Francisco J., Lowell, Bradford B., Kahn, C. Ronald, Pothos, Emmanuel N., and Cai, Weikang

Published
2025
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6. Implementation and validation of single-cell genomics experiments in neuroscience

Author

Colonna, Marco, Konopka, Genevieve, Liddelow, Shane A., Nowakowski, Tomasz, Awatramani, Rajeshwar, Bateup, Helen S., Cadwell, Cathryn R., Caglayan, Emre, Chen, Jerry L., Gillis, Jesse, Kampmann, Martin, Krienen, Fenna, Marsh, Samuel E., Monje, Michelle, O’Dea, Michael R., Patani, Rickie, Pollen, Alex A., Quintana, Francisco J., Scavuzzo, Marissa, Schmitz, Matthew, Sloan, Steven A., Tesar, Paul J., Tollkuhn, Jessica, Tosches, Maria Antonietta, Urbanek, Madeleine E., Werner, Jonathan M., Bayraktar, Omer A., Gokce, Ozgun, and Habib, Naomi

Published
2024
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11. 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

12. Identification of astrocyte regulators by nucleic acid cytometry

Author

Clark, Iain C, Wheeler, Michael A, Lee, Hong-Gyun, Li, Zhaorong, Sanmarco, Liliana M, Thaploo, Shravan, Polonio, Carolina M, Shin, Seung Won, Scalisi, Giulia, Henry, Amy R, Rone, Joseph M, Giovannoni, Federico, Charabati, Marc, Akl, Camilo Faust, Aleman, Dulce M, Zandee, Stephanie EJ, Prat, Alexandre, Douek, Daniel C, Boritz, Eli A, Quintana, Francisco J, and Abate, Adam R

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Biological Sciences, Neurosciences, Neurodegenerative, Multiple Sclerosis, Human Genome, Autoimmune Disease, Genetics, Biotechnology, Brain Disorders, 2.1 Biological and endogenous factors, Neurological, Inflammatory and immune system, Animals, Humans, Mice, Astrocytes, Encephalomyelitis, Autoimmune, Experimental, Gene Expression Regulation, Mice, Knockout, Microfluidics, Single-Cell Gene Expression Analysis, Nucleic Acids, Gene Editing, General Science & Technology
Abstract

Multiple sclerosis is a chronic inflammatory disease of the central nervous system1. 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.

Published
2023

13. HIV silencing and cell survival signatures in infected T cell reservoirs

Author

Clark, Iain C, Mudvari, Prakriti, Thaploo, Shravan, Smith, Samuel, Abu-Laban, Mohammad, Hamouda, Mehdi, Theberge, Marc, Shah, Sakshi, Ko, Sung Hee, Pérez, Liliana, Bunis, Daniel G, Lee, James S, Kilam, Divya, Zakaria, Saami, Choi, Sally, Darko, Samuel, Henry, Amy R, Wheeler, Michael A, Hoh, Rebecca, Butrus, Salwan, Deeks, Steven G, Quintana, Francisco J, Douek, Daniel C, Abate, Adam R, and Boritz, Eli A

Subjects
Genetics, Infectious Diseases, HIV/AIDS, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Infection, Humans, CD4-Positive T-Lymphocytes, Cell Proliferation, Cell Survival, DNA, Viral, Gene Expression Regulation, Viral, HIV Infections, HIV-1, Immunologic Memory, Microfluidics, Necroptosis, Signal Transduction, Transcriptome, Virus Latency, Anti-Retroviral Agents, General Science & Technology
Abstract

Rare CD4 T cells that contain HIV under antiretroviral therapy represent an important barrier to HIV cure1-3, 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.

Published
2023

14. 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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15. The astrocyte-produced growth factor HB-EGF limits autoimmune CNS pathology

Author

Linnerbauer, Mathias, Lößlein, Lena, Vandrey, Oliver, Peter, Anne, Han, Yanan, Tsaktanis, Thanos, Wogram, Emile, Needhamsen, Maria, Kular, Lara, Nagel, Lisa, Zissler, Julia, Andert, Marie, Meszaros, Lisa, Hanspach, Jannis, Zuber, Finnja, Naumann, Ulrike J., Diebold, Martin, Wheeler, Michael A., Beyer, Tobias, Nirschl, Lucy, Cirac, Ana, Laun, Frederik B., Günther, Claudia, Winkler, Jürgen, Bäuerle, Tobias, Jagodic, Maja, Hemmer, Bernhard, Prinz, Marco, Quintana, Francisco J., and Rothhammer, Veit

Published
2024
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19. 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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20. Charting the cellular biogeography in colitis reveals fibroblast trajectories and coordinated spatial remodeling

Author

Cadinu, Paolo, Sivanathan, Kisha N., Misra, Aditya, Xu, Rosalind J., Mangani, Davide, Yang, Evan, Rone, Joseph M., Tooley, Katherine, Kye, Yoon-Chul, Bod, Lloyd, Geistlinger, Ludwig, Lee, Tyrone, Mertens, Randall T., Ono, Noriaki, Wang, Gang, Sanmarco, Liliana, Quintana, Francisco J., Anderson, Ana C., Kuchroo, Vijay K., Moffitt, Jeffrey R., and Nowarski, Roni

Published
2024
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21. Lactate limits CNS autoimmunity by stabilizing HIF-1α in dendritic cells

Author

Sanmarco, Liliana M., Rone, Joseph M., Polonio, Carolina M., Fernandez Lahore, Gonzalo, Giovannoni, Federico, Ferrara, Kylynne, Gutierrez-Vazquez, Cristina, Li, Ning, Sokolovska, Anna, Plasencia, Agustin, Faust Akl, Camilo, Nanda, Payal, Heck, Evelin S., Li, Zhaorong, Lee, Hong-Gyun, Chao, Chun-Cheih, Rejano-Gordillo, Claudia M., Fonseca-Castro, Pedro H., Illouz, Tomer, Linnerbauer, Mathias, Kenison, Jessica E., Barilla, Rocky M., Farrenkopf, Daniel, Stevens, Nikolas A., Piester, Gavin, Chung, Elizabeth N., Dailey, Lucas, Kuchroo, Vijay K., Hava, David, Wheeler, Michael A., Clish, Clary, Nowarski, Roni, Balsa, Eduardo, Lora, Jose M., and Quintana, Francisco J.

Published
2023
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22. B-cell-specific checkpoint molecules that regulate anti-tumour immunity

Author

Bod, Lloyd, Kye, Yoon-Chul, Shi, Jingwen, Torlai Triglia, Elena, Schnell, Alexandra, Fessler, Johannes, Ostrowski, Stephen M., Von-Franque, Max Y., Kuchroo, Juhi R., Barilla, Rocky M., Zaghouani, Sarah, Christian, Elena, Delorey, Toni Marie, Mohib, Kanishka, Xiao, Sheng, Slingerland, Nadine, Giuliano, Christopher J., Ashenberg, Orr, Li, Zhaorong, Rothstein, David M., Fisher, David E., Rozenblatt-Rosen, Orit, Sharpe, Arlene H., Quintana, Francisco J., Apetoh, Lionel, Regev, Aviv, and Kuchroo, Vijay K.

Published
2023
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23. 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

24. Protein design-scapes generated by microfluidic DNA assembly elucidate domain coupling in the bacterial histidine kinase CpxA

Author

Clark, Iain C, Mensa, Bruk, Ochs, Christopher J, Schmidt, Nathan W, Mravic, Marco, Quintana, Francisco J, DeGrado, William F, and Abate, Adam R

Subjects
Amino Acid Sequence, Bacterial Proteins, DNA, Enzyme Activation, Gene Expression, Gene Library, Microfluidics, Models, Molecular, Molecular Conformation, Protein Engineering, Protein Interaction Domains and Motifs, Protein Kinases, Structure-Activity Relationship, droplet microfluidics, rational library design, protein engineering, histidine kinase, signal transduction
Abstract

The randomization and screening of combinatorial DNA libraries is a powerful technique for understanding sequence-function relationships and optimizing biosynthetic pathways. Although it can be difficult to predict a priori which sequence combinations encode functional units, it is often possible to omit undesired combinations that inflate library size and screening effort. However, defined library generation is difficult when a complex scan through sequence space is needed. To overcome this challenge, we designed a hybrid valve- and droplet-based microfluidic system that deterministically assembles DNA parts in picoliter droplets, reducing reagent consumption and bias. Using this system, we built a combinatorial library encoding an engineered histidine kinase (HK) based on bacterial CpxA. Our library encodes designed transmembrane (TM) domains that modulate the activity of the cytoplasmic domain of CpxA and variants of the structurally distant "S helix" located near the catalytic domain. We find that the S helix sets a basal activity further modulated by the TM domain. Surprisingly, we also find that a given TM motif can elicit opposing effects on the catalytic activity of different S-helix variants. We conclude that the intervening HAMP domain passively transmits signals and shapes the signaling response depending on subtle changes in neighboring domains. This flexibility engenders a richness in functional outputs as HKs vary in response to changing evolutionary pressures.

Published
2021

25. Reactive astrocyte nomenclature, definitions, and future directions

Author

Escartin, Carole, Galea, Elena, Lakatos, András, O’Callaghan, James P, Petzold, Gabor C, Serrano-Pozo, Alberto, Steinhäuser, Christian, Volterra, Andrea, Carmignoto, Giorgio, Agarwal, Amit, Allen, Nicola J, Araque, Alfonso, Barbeito, Luis, Barzilai, Ari, Bergles, Dwight E, Bonvento, Gilles, Butt, Arthur M, Chen, Wei-Ting, Cohen-Salmon, Martine, Cunningham, Colm, Deneen, Benjamin, De Strooper, Bart, Díaz-Castro, Blanca, Farina, Cinthia, Freeman, Marc, Gallo, Vittorio, Goldman, James E, Goldman, Steven A, Götz, Magdalena, Gutiérrez, Antonia, Haydon, Philip G, Heiland, Dieter H, Hol, Elly M, Holt, Matthew G, Iino, Masamitsu, Kastanenka, Ksenia V, Kettenmann, Helmut, Khakh, Baljit S, Koizumi, Schuichi, Lee, C Justin, Liddelow, Shane A, MacVicar, Brian A, Magistretti, Pierre, Messing, Albee, Mishra, Anusha, Molofsky, Anna V, Murai, Keith K, Norris, Christopher M, Okada, Seiji, Oliet, Stéphane HR, Oliveira, João F, Panatier, Aude, Parpura, Vladimir, Pekna, Marcela, Pekny, Milos, Pellerin, Luc, Perea, Gertrudis, Pérez-Nievas, Beatriz G, Pfrieger, Frank W, Poskanzer, Kira E, Quintana, Francisco J, Ransohoff, Richard M, Riquelme-Perez, Miriam, Robel, Stefanie, Rose, Christine R, Rothstein, Jeffrey D, Rouach, Nathalie, Rowitch, David H, Semyanov, Alexey, Sirko, Swetlana, Sontheimer, Harald, Swanson, Raymond A, Vitorica, Javier, Wanner, Ina-Beate, Wood, Levi B, Wu, Jiaqian, Zheng, Binhai, Zimmer, Eduardo R, Zorec, Robert, Sofroniew, Michael V, and Verkhratsky, Alexei

Subjects
Neurosciences, Brain Disorders, Neurological, Aging, Animals, Astrocytes, Brain, Brain Diseases, Brain Injuries, Humans, Spinal Cord, Spinal Cord Injuries, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

Reactive astrocytes are astrocytes undergoing morphological, molecular, and functional remodeling in response to injury, disease, or infection of the CNS. Although this remodeling was first described over a century ago, uncertainties and controversies remain regarding the contribution of reactive astrocytes to CNS diseases, repair, and aging. It is also unclear whether fixed categories of reactive astrocytes exist and, if so, how to identify them. We point out the shortcomings of binary divisions of reactive astrocytes into good-vs-bad, neurotoxic-vs-neuroprotective or A1-vs-A2. We advocate, instead, that research on reactive astrocytes include assessment of multiple molecular and functional parameters-preferably in vivo-plus multivariate statistics and determination of impact on pathological hallmarks in relevant models. These guidelines may spur the discovery of astrocyte-based biomarkers as well as astrocyte-targeting therapies that abrogate detrimental actions of reactive astrocytes, potentiate their neuro- and glioprotective actions, and restore or augment their homeostatic, modulatory, and defensive functions.

Published
2021

26. PD-L1 positive astrocytes attenuate inflammatory functions of PD-1 positive microglia in models of autoimmune neuroinflammation

Author

Linnerbauer, Mathias, Beyer, Tobias, Nirschl, Lucy, Farrenkopf, Daniel, Lößlein, Lena, Vandrey, Oliver, Peter, Anne, Tsaktanis, Thanos, Kebir, Hania, Laplaud, David, Oellinger, Rupert, Engleitner, Thomas, Alvarez, Jorge Ivan, Rad, Roland, Korn, Thomas, Hemmer, Bernhard, Quintana, Francisco J., and Rothhammer, Veit

Published
2023
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27. DNA vaccine encoding heat shock protein 90 protects from murine lupus

Author

Liu, Aijing, Shi, Fu-Dong, Cohen, Irun R, Castaldo, Giuseppe, Matarese, Giuseppe, Quintana, Francisco J, and La Cava, Antonio

Subjects
Biomedical and Clinical Sciences, Immunology, Prevention, Immunization, Kidney Disease, Biotechnology, Vaccine Related, Autoimmune Disease, Clinical Research, Lupus, Prevention of disease and conditions, and promotion of well-being, 3.4 Vaccines, Inflammatory and immune system, Animals, Autoantibodies, Disease Models, Animal, Heat-Shock Proteins, Lupus Erythematosus, Systemic, Mice, Mice, Inbred NZB, Vaccines, DNA, Systemic lupus erythematosus, Heat shock proteins, DNA vaccine, Autoimmunity, T regulatory cells, Clinical Sciences, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract

BackgroundSystemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies to multiple self-antigens, including heat shock proteins (HSP). Because of the increased expression of HSP90 and abnormal immune responses to it in SLE, we investigated whether an HSP90 DNA vaccine could modulate the development and clinical manifestations of SLE in lupus-prone mice.Methods(NZB x NZW)F1 (NZB/W) mice were vaccinated with DNA constructs encoding HSP90 or control plasmids or vehicle. The mice were then monitored for survival, circulating anti-dsDNA autoantibodies, and immune phenotypes. Renal disease was evaluated by immunohistochemistry and by the measurement of proteinuria.ResultsVaccination with HSP90 DNA reduced lupus disease manifestations and prolonged the survival of NZB/W mice. The protective effects of the HSP90 DNA vaccine associated with the induction of tolerogenic dendritic cells (DCs) and an expansion of T regulatory cells (Tregs).ConclusionsThe beneficial effects of DNA vaccination with HSP90 in murine SLE support the possibility of HSP90-based therapeutic modalities of intervention in SLE.

Published
2020

28. Targeted Single-Cell RNA and DNA Sequencing With Fluorescence-Activated Droplet Merger

Author

Clark, Iain C, Delley, Cyrille L, Sun, Chen, Thakur, Rohan, Stott, Shannon L, Thaploo, Shravan, Li, Zhaorong, Quintana, Francisco J, and Abate, Adam R

Subjects
Genetics, Biotechnology, Vaccine Related, Human Genome, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Cell Line, Tumor, Fluorescence, High-Throughput Nucleotide Sequencing, Humans, Sequence Analysis, DNA, Sequence Analysis, RNA, Single-Cell Analysis, Analytical Chemistry, Other Chemical Sciences
Abstract

Analyzing every cell in a diverse sample provides insight into population-level heterogeneity, but abundant cell types dominate the analysis and rarer populations are scarcely represented in the data. To focus on specific cell types, the current paradigm is to physically isolate subsets of interest prior to analysis; however, it remains difficult to isolate and then single-cell sequence such populations because of compounding losses. Here, we describe an alternative approach that selectively merges cells with reagents to achieve enzymatic reactions without having to physically isolate cells. We apply this technique to perform single-cell transcriptome and genome sequencing of specific cell subsets. Our method for analyzing heterogeneous populations obviates the need for pre- or post-enrichment and simplifies single-cell workflows, making it useful for other applications in single-cell biology, combinatorial chemical synthesis, and drug screening.

Published
2020

29. Serum antibodies to phosphatidylcholine in MS.

Author

Sádaba, Maria Cruz, Rothhammer, Veit, Muñoz, Úrsula, Sebal, Cristina, Escudero, Esther, Kivisäkk, Pia, Garcia Sanchez, Maria Isabel, Izquierdo, Guillermo, Hauser, Stephen L, Baranzini, Sergio E, Oksenberg, Jorge R, Álvarez-Lafuente, Roberto, Bakshi, Rohit, Weiner, Howard L, and Quintana, Francisco J

Subjects
Humans, Multiple Sclerosis, Lactosylceramides, Phosphatidylcholines, Immunoglobulin G, Immunoglobulin M, Autoantibodies, Cohort Studies, Adult, Aged, Aged, 80 and over, Middle Aged, Female, Male, Young Adult, Biomarkers, Brain Disorders, Prevention, Autoimmune Disease, Neurodegenerative, Neurosciences
Abstract

To evaluate the value of serum immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies reactive with phosphatidylcholine (PC) and lactosylceramide (LC) as biomarkers in MS. We developed an ultrasensitive ELISA technique to analyze serum IgG and IgM antibodies to LC and PC, which we used to analyze samples from 362 patients with MS, 10 patients with non-MS myelin diseases (Non-MSMYDs), 11 patients with nonmyelin neurologic diseases (Non-MYNDs), and 80 controls. MS serum samples included clinically isolated syndrome (CIS, n = 17), relapsing-remitting MS (RRMS, n = 62), secondary progressive MS (SPMS, n = 50), primary progressive MS (PPMS, n = 37), and benign MS (BENMS, n = 36). We detected higher levels of serum IgM antibodies to PC (IgM-PC) in MS than control samples; patients with CIS and RRMS showed higher IgM-PC levels than patients with SPMS, PPMS, and BENMS and controls. MS and control samples did not differ in serum levels of IgM antibodies reactive with LC, nor in IgG antibodies reactive with LC or PC. Serum IgM-PC antibodies are elevated in patients with MS, particularly during the CIS and RRMS phases of the disease. Thus, serum IgM-PC is a candidate biomarker for early inflammatory stages of MS. This study provides Class III evidence that serum antibodies to PC are elevated in patients with MS. The study is rated Class III because of the case control design and the risk of spectrum bias: antibody levels in patients with MS were compared with healthy controls.

Published
2020

31. Identification of environmental factors that promote intestinal inflammation

Author

Sanmarco, Liliana M., Chao, Chun-Cheih, Wang, Yu-Chao, Kenison, Jessica E., Li, Zhaorong, Rone, Joseph M., Rejano-Gordillo, Claudia M., Polonio, Carolina M., Gutierrez-Vazquez, Cristina, Piester, Gavin, Plasencia, Agustin, Li, Lucinda, Giovannoni, Federico, Lee, Hong-Gyun, Faust Akl, Camilo, Wheeler, Michael A., Mascanfroni, Ivan, Jaronen, Merja, Alsuwailm, Moneera, Hewson, Patrick, Yeste, Ada, Andersen, Brian M., Franks, Diana G., Huang, Chien-Jung, Ekwudo, Millicent, Tjon, Emily C., Rothhammer, Veit, Takenaka, Maisa, de Lima, Kalil Alves, Linnerbauer, Mathias, Guo, Lydia, Covacu, Ruxandra, Queva, Hugo, Fonseca-Castro, Pedro Henrique, Bladi, Maha Al, Cox, Laura M., Hodgetts, Kevin J., Hahn, Mark E., Mildner, Alexander, Korzenik, Joshua, Hauser, Russ, Snapper, Scott B., and Quintana, Francisco J.

Published
2022
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32. 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

38. Activin-A limits Th17 pathogenicity and autoimmune neuroinflammation via CD39 and CD73 ectonucleotidases and Hif1-α–dependent pathways

Author

Morianos, Ioannis, Trochoutsou, Aikaterini I., Papadopoulou, Gina, Semitekolou, Maria, Banos, Aggelos, Konstantopoulos, Dimitris, Manousopoulou, Antigoni, Kapasa, Maria, Wei, Ping, Lomenick, Brett, Belaidi, Elise, Kalamatas, Themis, Karageorgiou, Klinta, Doskas, Triantafyllos, Sallusto, Federica, Pan, Fan, Garbis, Spiros D., Quintana, Francisco J., and Xanthou, Georgina

Published
2020

43. Self-tunable engineered yeast probiotics for the treatment of inflammatory bowel disease

Author

Scott, Benjamin M., Gutiérrez-Vázquez, Cristina, Sanmarco, Liliana M., da Silva Pereira, Jessica A., Li, Zhaorong, Plasencia, Agustín, Hewson, Patrick, Cox, Laura M., O'Brien, Madelynn, Chen, Steven K., Moraes-Vieira, Pedro M., Chang, Belinda S.W., Peisajovich, Sergio, and Quintana, Francisco J.

Subjects
Care and treatment, Usage, Health aspects, Genetically modified organisms -- Usage -- Health aspects, Inflammatory bowel diseases -- Care and treatment, Probiotics -- Usage -- Health aspects, Yeasts (Fungi) -- Usage -- Health aspects, Yeast fungi -- Usage -- Health aspects
Abstract

Author(s): Benjamin M. Scott [sup.1] [sup.2] [sup.3] [sup.9] , Cristina Gutiérrez-Vázquez [sup.4] , Liliana M. Sanmarco [sup.4] , Jessica A. da Silva Pereira [sup.4] , Zhaorong Li [sup.4] , Agustín [...], Inflammatory bowel disease (IBD) is a complex chronic inflammatory disorder of the gastrointestinal tract. Extracellular adenosine triphosphate (eATP) produced by the commensal microbiota and host cells activates purinergic signaling, promoting intestinal inflammation and pathology. Based on the role of eATP in intestinal inflammation, we developed yeast-based engineered probiotics that express a human P2Y2 purinergic receptor with up to a 1,000-fold increase in eATP sensitivity. We linked the activation of this engineered P2Y2 receptor to the secretion of the ATP-degrading enzyme apyrase, thus creating engineered yeast probiotics capable of sensing a pro-inflammatory molecule and generating a proportional self-regulated response aimed at its neutralization. These self-tunable yeast probiotics suppressed intestinal inflammation in mouse models of IBD, reducing intestinal fibrosis and dysbiosis with an efficacy similar to or higher than that of standard-of-care therapies usually associated with notable adverse events. By combining directed evolution and synthetic gene circuits, we developed a unique self-modulatory platform for the treatment of IBD and potentially other inflammation-driven pathologies. A synthetic yeast-based therapeutic that secretes an ATP-degrading enzyme in response to pro-inflammatory extracellular ATP in the gut reduces intestinal inflammation, fibrosis and dysbiosis in mouse models of colitis and enteritis.

Published
2021
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44. Tryptophan metabolism drives dynamic immunosuppressive myeloid states in IDH-mutant gliomas

Author

Friedrich, Mirco, Sankowski, Roman, Bunse, Lukas, Kilian, Michael, Green, Edward, Ramallo Guevara, Carina, Pusch, Stefan, Poschet, Gernot, Sanghvi, Khwab, Hahn, Markus, Bunse, Theresa, Münch, Philipp, Gegner, Hagen M., Sonner, Jana K., von Landenberg, Anna, Cichon, Frederik, Aslan, Katrin, Trobisch, Tim, Schirmer, Lucas, Abu-Sammour, Denis, Kessler, Tobias, Ratliff, Miriam, Schrimpf, Daniel, Sahm, Felix, Hopf, Carsten, Heiland, Dieter H., Schnell, Oliver, Beck, Jürgen, Böttcher, Chotima, Fernandez-Zapata, Camila, Priller, Josef, Heiland, Sabine, Gutcher, Ilona, Quintana, Francisco J., von Deimling, Andreas, Wick, Wolfgang, Prinz, Marco, and Platten, Michael

Published
2021
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49. A cell-based drug delivery platform for treating central nervous system inflammation

Author

Levy, Oren, Rothhammer, Veit, Mascanfroni, Ivan, Tong, Zhixiang, Kuai, Rui, De Biasio, Michael, Wang, Qingping, Majid, Tahir, Perrault, Christelle, Yeste, Ada, Kenison, Jessica E., Safaee, Helia, Musabeyezu, Juliet, Heinelt, Martina, Milton, Yuka, Kuang, Heidi, Lan, Haoyue, Siders, William, Multon, Marie-Christine, Rothblatt, Jonathan, Massadeh, Salam, Alaamery, Manal, Alhasan, Ali H., Quintana, Francisco J., and Karp, Jeffrey M.

Published
2021
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50. Gut-licensed IFNγ+ NK cells drive LAMP1+TRAIL+ anti-inflammatory astrocytes

Author

Sanmarco, Liliana M., Wheeler, Michael A., Gutiérrez-Vázquez, Cristina, Polonio, Carolina Manganeli, Linnerbauer, Mathias, Pinho-Ribeiro, Felipe A., Li, Zhaorong, Giovannoni, Federico, Batterman, Katelyn V., Scalisi, Giulia, Zandee, Stephanie E. J., Heck, Evelyn S., Alsuwailm, Moneera, Rosene, Douglas L., Becher, Burkhard, Chiu, Isaac M., Prat, Alexandre, and Quintana, Francisco J.

Published
2021
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