A lymphocyte–microglia–astrocyte axis in chronic active multiple sclerosis

Multiple sclerosis (MS) lesions that do not resolve in the months after they form harbour ongoing demyelination and axon degeneration, and are identifiable in vivo by their paramagnetic rims on MRI scans 1 – 3 . Here, to define mechanisms underlying this disabling, progressive neurodegenerative stat...

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Veröffentlicht in:	Nature (London) Jg. 597; H. 7878; S. 709 - 714
Hauptverfasser:	Absinta, Martina, Maric, Dragan, Gharagozloo, Marjan, Garton, Thomas, Smith, Matthew D., Jin, Jing, Fitzgerald, Kathryn C., Song, Anya, Liu, Poching, Lin, Jing-Ping, Wu, Tianxia, Johnson, Kory R., McGavern, Dorian B., Schafer, Dorothy P., Calabresi, Peter A., Reich, Daniel S.
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	London Nature Publishing Group UK 30.09.2021 Nature Publishing Group
Schlagworte:	13/51 45/91 59/57 631/250/2501 631/378/371 64/60 692/53/2422 692/617/375/1411/1666 Ablation Animals Antigen presentation Astrocytes Astrocytes - pathology Autoimmune diseases Biomarkers Brain - pathology Chemical compounds Complement activation Complement C1q - antagonists & inhibitors Complement C1q - metabolism Complement component C1q Degeneration Demyelination Dendritic cells Encephalomyelitis Encephalomyelitis, Autoimmune, Experimental - pathology Experimental allergic encephalomyelitis Female Gene expression Gene sequencing Humanities and Social Sciences Humans Immune system Inflammation Inflammation - pathology Lesions Lymphocytes Lymphocytes - pathology Magnetic Resonance Imaging Male Mice Mice, Inbred C57BL Microglia Microglia - pathology Middle Aged multidisciplinary Multiple sclerosis Multiple Sclerosis - diagnostic imaging Multiple Sclerosis - pathology Neurodegeneration Neurodegenerative diseases Neuronal-glial interactions Pharmacology Phenotypes Physiological aspects Plasma Proteins RNA-Seq Science Science (multidisciplinary) Substantia alba Transcription Transcriptome Variance analysis White Matter - pathology United States
ISSN:	0028-0836, 1476-4687, 1476-4687
Online-Zugang:	Volltext
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Zusammenfassung:	Multiple sclerosis (MS) lesions that do not resolve in the months after they form harbour ongoing demyelination and axon degeneration, and are identifiable in vivo by their paramagnetic rims on MRI scans 1 – 3 . Here, to define mechanisms underlying this disabling, progressive neurodegenerative state 4 – 6 and foster development of new therapeutic agents, we used MRI-informed single-nucleus RNA sequencing to profile the edge of demyelinated white matter lesions at various stages of inflammation. We uncovered notable glial and immune cell diversity, especially at the chronically inflamed lesion edge. We define ‘microglia inflamed in MS’ (MIMS) and ‘astrocytes inflamed in MS’, glial phenotypes that demonstrate neurodegenerative programming. The MIMS transcriptional profile overlaps with that of microglia in other neurodegenerative diseases, suggesting that primary and secondary neurodegeneration share common mechanisms and could benefit from similar therapeutic approaches. We identify complement component 1q (C1q) as a critical mediator of MIMS activation, validated immunohistochemically in MS tissue, genetically by microglia-specific C1q ablation in mice with experimental autoimmune encephalomyelitis, and therapeutically by treating chronic experimental autoimmune encephalomyelitis with C1q blockade. C1q inhibition is a potential therapeutic avenue to address chronic white matter inflammation, which could be monitored by longitudinal assessment of its dynamic biomarker, paramagnetic rim lesions, using advanced MRI methods. Single-nucleus transcriptomics defines a diverse set of immune and glial cells at the chronically inflamed leading edge of demyelinated white matter lesions in patients with multiple sclerosis.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 MA, JPL, and PL performed the nuclei extraction and snRNA-seq experiments; MA and KRJ performed the bioinformatic analysis; MA and DM performed the immunostainings and immunofluorescence multiplex; AS, MG, TG, MS, JJ, DPS and PC performed the animal studies; MA, DSR and TW performed the MRI studies; PC and KCF performed the genotyping study; MA, DSR, PC, DPS, and DMG discussed and interpreted findings; MA and DSR designed the study and wrote the manuscript. All co-authors read, revised and approved the manuscript. Author contributions
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-021-03892-7