Microglia-mediated demyelination protects against CD8+ T cell-driven axon degeneration in mice carrying PLP defects

Janos Groh (), Tassnim Abdelwahab, Yogita Kattimani, Michaela Hörner, Silke Loserth, Viktoria Gudi, Robert Adalbert, Fabian Imdahl, Antoine-Emmanuel Saliba, Michael Coleman, Martin Stangel, Mikael Simons and Rudolf Martini ()
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Janos Groh: University Hospital Würzburg
Tassnim Abdelwahab: University Hospital Würzburg
Yogita Kattimani: University Hospital Würzburg
Michaela Hörner: University Hospital Würzburg
Silke Loserth: University Hospital Würzburg
Viktoria Gudi: Hannover Medical School
Robert Adalbert: University of Cambridge
Fabian Imdahl: Helmholtz-Center for Infection Research
Antoine-Emmanuel Saliba: Helmholtz-Center for Infection Research
Michael Coleman: University of Cambridge
Martin Stangel: Hannover Medical School
Mikael Simons: Technical University Munich
Rudolf Martini: University Hospital Würzburg

Nature Communications, 2023, vol. 14, issue 1, 1-21

Abstract: Abstract Axon degeneration and functional decline in myelin diseases are often attributed to loss of myelin but their relation is not fully understood. Perturbed myelinating glia can instigate chronic neuroinflammation and contribute to demyelination and axonal damage. Here we study mice with distinct defects in the proteolipid protein 1 gene that develop axonal damage which is driven by cytotoxic T cells targeting myelinating oligodendrocytes. We show that persistent ensheathment with perturbed myelin poses a risk for axon degeneration, neuron loss, and behavioral decline. We demonstrate that CD8+ T cell-driven axonal damage is less likely to progress towards degeneration when axons are efficiently demyelinated by activated microglia. Mechanistically, we show that cytotoxic T cell effector molecules induce cytoskeletal alterations within myelinating glia and aberrant actomyosin constriction of axons at paranodal domains. Our study identifies detrimental axon-glia-immune interactions which promote neurodegeneration and possible therapeutic targets for disorders associated with myelin defects and neuroinflammation.

Date: 2023
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42570-2

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DOI: 10.1038/s41467-023-42570-2

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