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

Martina Absinta (), Dragan Maric, Marjan Gharagozloo, Thomas Garton, Matthew D. Smith, Jing Jin, Kathryn C. Fitzgerald, Anya Song, Poching Liu, Jing-Ping Lin, Tianxia Wu, Kory R. Johnson, Dorian B. McGavern, Dorothy P. Schafer, Peter A. Calabresi and Daniel S. Reich ()
Additional contact information
Martina Absinta: Johns Hopkins University School of Medicine
Dragan Maric: National Institutes of Health
Marjan Gharagozloo: Johns Hopkins University School of Medicine
Thomas Garton: Johns Hopkins University School of Medicine
Matthew D. Smith: Johns Hopkins University School of Medicine
Jing Jin: Johns Hopkins University School of Medicine
Kathryn C. Fitzgerald: Johns Hopkins University School of Medicine
Anya Song: University of Massachusetts Medical School
Poching Liu: National Heart, Lung, and Blood Institute, National Institutes of Health
Jing-Ping Lin: National Institutes of Health
Tianxia Wu: National Institutes of Health
Kory R. Johnson: National Institutes of Health
Dorian B. McGavern: National Institutes of Health
Dorothy P. Schafer: University of Massachusetts Medical School
Peter A. Calabresi: Johns Hopkins University School of Medicine
Daniel S. Reich: National Institutes of Health

Nature, 2021, vol. 597, issue 7878, 709-714

Abstract: Abstract 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 scans1–3. Here, to define mechanisms underlying this disabling, progressive neurodegenerative state4–6 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.

Date: 2021
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DOI: 10.1038/s41586-021-03892-7

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