Versican promotes T helper 17 cytotoxic inflammation and impedes oligodendrocyte precursor cell remyelination

Samira Ghorbani, Emily Jelinek, Rajiv Jain, Benjamin Buehner, Cenxiao Li, Brian M. Lozinski, Susobhan Sarkar, Deepak K. Kaushik, Yifei Dong, Thomas N. Wight, Soheila Karimi-Abdolrezaee, Geert J. Schenk, Eva M. Strijbis, Jeroen Geurts, Ping Zhang, Chang-Chun Ling and V. Wee Yong ()
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Samira Ghorbani: University of Calgary
Emily Jelinek: University of Calgary
Rajiv Jain: University of Calgary
Benjamin Buehner: University of Calgary
Cenxiao Li: University of Calgary
Brian M. Lozinski: University of Calgary
Susobhan Sarkar: University of Calgary
Deepak K. Kaushik: University of Calgary
Yifei Dong: University of Calgary
Thomas N. Wight: Benaroya Research Institute
Soheila Karimi-Abdolrezaee: University of Manitoba
Geert J. Schenk: Amsterdam Neuroscience, MS Center Amsterdam
Eva M. Strijbis: Neurology, Amsterdam Neuroscience, MS Center Amsterdam
Jeroen Geurts: Amsterdam Neuroscience, MS Center Amsterdam
Ping Zhang: University of Calgary
Chang-Chun Ling: University of Calgary
V. Wee Yong: University of Calgary

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Remyelination failure in multiple sclerosis (MS) contributes to progression of disability. The deficient repair results from neuroinflammation and deposition of inhibitors including chondroitin sulfate proteoglycans (CSPGs). Which CSPG member is repair-inhibitory or alters local inflammation to exacerbate injury is unknown. Here, we correlate high versican-V1 expression in MS lesions with deficient premyelinating oligodendrocytes, and highlight its selective upregulation amongst CSPG members in experimental autoimmune encephalomyelitis (EAE) lesions modeling MS. In culture, purified versican-V1 inhibits oligodendrocyte precursor cells (OPCs) and promotes T helper 17 (Th17) polarization. Versican-V1-exposed Th17 cells are particularly toxic to OPCs. In NG2CreER:MAPTmGFP mice illuminating newly formed GFP+ oligodendrocytes/myelin, difluorosamine (peracetylated,4,4-difluoro-N-acetylglucosamine) treatment from peak EAE reduces lesional versican-V1 and Th17 frequency, while enhancing GFP+ profiles. We suggest that lesion-elevated versican-V1 directly impedes OPCs while it indirectly inhibits remyelination through elevating local Th17 cytotoxic neuroinflammation. We propose CSPG-lowering drugs as potential dual pronged repair and immunomodulatory therapeutics for MS.

Date: 2022
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DOI: 10.1038/s41467-022-30032-0

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