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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 NG2 CreER :MAPT mGFP 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.

Titel:	Versican promotes T helper 17 cytotoxic inflammation and impedes oligodendrocyte precursor cell remyelination.
Autor/in / Beteiligte Person:	Ghorbani, S ; Jelinek, E ; Jain, R ; Buehner, B ; Li, C ; Lozinski, BM ; Sarkar, S ; Kaushik, DK ; Dong, Y ; Wight, TN ; Karimi-Abdolrezaee, S ; Schenk, GJ ; Strijbis, EM ; Geurts, J ; Zhang, P ; Ling, CC ; Yong, VW
Link:	Full Text Finder (Volltext)
Zeitschrift:	Nature communications, Jg. 13 (2022-05-04), Heft 1, S. 2445
Veröffentlichung:	[London] : Nature Pub. Group, 2022
Medientyp:	academicJournal
ISSN:	2041-1723 (electronic)
DOI:	10.1038/s41467-022-30032-0
Schlagwort:	Animals Cell Differentiation Inflammation pathology Mice Mice, Inbred C57BL Oligodendroglia metabolism Versicans metabolism Encephalomyelitis, Autoimmune, Experimental pathology Multiple Sclerosis pathology Oligodendrocyte Precursor Cells metabolism Remyelination physiology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Nat Commun] 2022 May 04; Vol. 13 (1), pp. 2445. <i>Date of Electronic Publication: </i>2022 May 04. MeSH Terms: Encephalomyelitis, Autoimmune, Experimental* / pathology ; Multiple Sclerosis* / pathology ; Oligodendrocyte Precursor Cells* / metabolism ; Remyelination* / physiology ; Animals ; Cell Differentiation ; Inflammation / pathology ; Mice ; Mice, Inbred C57BL ; Oligodendroglia / metabolism ; Versicans / metabolism References: Nat Rev Dis Primers. 2018 Nov 8;4(1):43. (PMID: 30410033) ; FASEB J. 2005 Oct;19(12):1668-70. (PMID: 16081501) ; Elife. 2016 Sep 27;5:. (PMID: 27671734) ; Nat Immunol. 2011 Mar;12(3):255-63. (PMID: 21278737) ; Neuron. 2018 Feb 21;97(4):742-768. (PMID: 29470968) ; Nat Commun. 2017 May 31;8:15508. (PMID: 28561022) ; Ann Neurol. 2012 Dec;72(6):918-26. (PMID: 23076662) ; Lancet Neurol. 2020 Aug;19(8):678-688. (PMID: 32702337) ; Tissue Cell. 2021 Apr;69:101444. (PMID: 33450651) ; Exp Neurol. 2018 Apr;302:196-204. (PMID: 29374568) ; Exp Neurol. 2019 Nov;321:113032. (PMID: 31398353) ; Ann Neurol. 2012 Sep;72(3):419-32. (PMID: 23034914) ; J Neuroinflammation. 2018 Mar 20;15(1):90. (PMID: 29558941) ; Autoimmun Rev. 2020 Oct;19(10):102647. (PMID: 32801039) ; Cell Stem Cell. 2020 May 7;26(5):617-619. (PMID: 32386552) ; Nat Commun. 2018 Oct 8;9(1):4126. (PMID: 30297691) ; Nat Neurosci. 2017 May;20(5):674-680. (PMID: 28288125) ; Brain. 2008 Jul;131(Pt 7):1749-58. (PMID: 18515322) ; Nat Commun. 2016 Apr 26;7:11312. (PMID: 27115988) ; Exp Neurol. 2013 Sep;247:113-21. (PMID: 23588220) ; Brain. 2018 Apr 1;141(4):1094-1110. (PMID: 29506186) ; Nature. 2009 Jan 1;457(7225):102-6. (PMID: 19122641) ; J Neurochem. 2011 Oct;119(1):176-88. (PMID: 21848846) ; J Biol Chem. 2017 Jan 6;292(1):51-63. (PMID: 27895126) ; Nat Immunol. 2007 Nov;8(11):1217-26. (PMID: 17922015) ; Nature. 2019 Sep;573(7772):130-134. (PMID: 31413369) ; Nat Rev Neurol. 2012 Nov 5;8(11):624-34. (PMID: 23026979) ; Brain. 2021 Aug 17;144(7):1958-1973. (PMID: 33889940) ; J Immunol. 2015 Jan 15;194(2):761-72. (PMID: 25505283) ; Proc Natl Acad Sci U S A. 2021 Aug 24;118(34):. (PMID: 34417310) ; Sci Transl Med. 2017 Dec 6;9(419):. (PMID: 29212715) ; J Neurosci Res. 2020 Jul;98(7):1370-1397. (PMID: 31965607) ; J Neuropathol Exp Neurol. 2001 Dec;60(12):1198-207. (PMID: 11764092) ; Immunity. 2010 Sep 24;33(3):424-36. (PMID: 20870176) ; Nat Rev Immunol. 2017 Mar;17(3):179-194. (PMID: 28138136) ; Nat Commun. 2017 Dec 19;8(1):1990. (PMID: 29259169) ; Brain Behav Immun. 2017 Oct;65:111-124. (PMID: 28559011) ; Nat Rev Drug Discov. 2017 Sep;16(9):617-634. (PMID: 28685761) ; Glia. 2018 Feb;66(2):327-347. (PMID: 29068088) ; ACS Cent Sci. 2019 Jul 24;5(7):1223-1234. (PMID: 31404231) ; Glia. 2015 Sep;63(9):1621-35. (PMID: 25847153) ; J Neuroimmunol. 2010 Jun;223(1-2):55-64. (PMID: 20434781) ; Nature. 2015 Jul 9;523(7559):221-5. (PMID: 25924064) ; Methods Cell Biol. 2018;143:261-279. (PMID: 29310782) ; Cancer Res. 2017 Jun 15;77(12):3231-3243. (PMID: 28416488) ; Brain Res Bull. 2011 Mar 10;84(4-5):306-16. (PMID: 20620201) ; J Neurosci. 2015 Jun 3;35(22):8626-39. (PMID: 26041928) Grant Information: 1049959 Canada CIHR; FDN 167270 Canada CIHR Substance Nomenclature: 126968-45-4 (Versicans) Entry Date(s): Date Created: 20220504 Date Completed: 20220506 Latest Revision: 20220716 Update Code: 20240513 PubMed Central ID: PMC9068758

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