MAFG-driven astrocytes promote CNS inflammation.

Autor: Wheeler MA; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Centre of Excellence for Biomedicine, Brigham and Women's Hospital, Boston, MA, USA., Clark IC; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Tjon EC; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Li Z; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Zandee SEJ; Neuroimmunology Unit, Centre de recherche du CHUM (CRCHUM), Montreal, Quebec, Canada.; Department of Neuroscience, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada., Couturier CP; Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada., Watson BR; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.; Department of Microbiology, Harvard Medical School, Boston, MA, USA., Scalisi G; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Alkwai S; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.; Centre of Excellence for Biomedicine, Brigham and Women's Hospital, Boston, MA, USA.; Centre of Excellence for Biomedicine, Joint Centers of Excellence Program, King Abdulaziz City for Science and Technology (KACST), Riyadh, Saudi Arabia., Rothhammer V; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Rotem A; Department of Physics, Harvard University, Cambridge, MA, USA.; School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA., Heyman JA; Department of Physics, Harvard University, Cambridge, MA, USA.; School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA., Thaploo S; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Sanmarco LM; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA., Ragoussis J; McGill University and Genome Quebec Innovation Centre, Department of Human Genetics, McGill University, Montreal, Quebec, Canada., Weitz DA; Department of Physics, Harvard University, Cambridge, MA, USA.; School of Engineering and Applied Sciences, Harvard University, Cambridge, MA, USA., Petrecca K; Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada., Moffitt JR; Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA, USA.; Department of Microbiology, Harvard Medical School, Boston, MA, USA., Becher B; Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland., Antel JP; Neuroimmunology Unit, Montreal Neurological Institute, Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada., Prat A; Neuroimmunology Unit, Centre de recherche du CHUM (CRCHUM), Montreal, Quebec, Canada.; Department of Neuroscience, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada., Quintana FJ; Ann Romney Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. fquintana@rics.bwh.harvard.edu.; Centre of Excellence for Biomedicine, Brigham and Women's Hospital, Boston, MA, USA. fquintana@rics.bwh.harvard.edu.; Broad Institute of MIT and Harvard, Cambridge, MA, USA. fquintana@rics.bwh.harvard.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2020 Feb; Vol. 578 (7796), pp. 593-599. Date of Electronic Publication: 2020 Feb 12.
DOI: 10.1038/s41586-020-1999-0
Abstrakt: Multiple sclerosis is a chronic inflammatory disease of the CNS 1 . Astrocytes contribute to the pathogenesis of multiple sclerosis 2 , 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.
Databáze: MEDLINE