TLR4 Associated Signaling Disrupters as a New Means to Overcome HERV-W Envelope-Mediated Myelination Deficits

Myelin repair in the adult central nervous system (CNS) is driven by successful differentiation of resident oligodendroglial precursor cells (OPCs) and thus constitutes a neurodegenerative process capable to compensate for functional deficits upon loss of oligodendrocytes and myelin sheaths as it is...

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Autores principales:	Peter Göttle, Kira Schichel, Laura Reiche, Luisa Werner, Annika Zink, Alessandro Prigione, Patrick Küry
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	myelin repair multiple sclerosis (MS) oligodendrocyte toll-like receptor HERV-W ENV Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
Acceso en línea:	https://doaj.org/article/e10dee08bb534ee99fa6938e3b0b25ad
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spelling	oai:doaj.org-article:e10dee08bb534ee99fa6938e3b0b25ad2021-11-30T12:34:18ZTLR4 Associated Signaling Disrupters as a New Means to Overcome HERV-W Envelope-Mediated Myelination Deficits1662-510210.3389/fncel.2021.777542https://doaj.org/article/e10dee08bb534ee99fa6938e3b0b25ad2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fncel.2021.777542/fullhttps://doaj.org/toc/1662-5102Myelin repair in the adult central nervous system (CNS) is driven by successful differentiation of resident oligodendroglial precursor cells (OPCs) and thus constitutes a neurodegenerative process capable to compensate for functional deficits upon loss of oligodendrocytes and myelin sheaths as it is observed in multiple sclerosis (MS). The human endogenous retrovirus type W (HERV-W) represents an MS-specific pathogenic entity, and its envelope (ENV) protein was previously identified as a negative regulator of OPC maturation—hence, it is of relevance in the context of diminished myelin repair. We here focused on the activity of the ENV protein and investigated how it can be neutralized for improved remyelination. ENV-mediated activation of toll like receptor 4 (TLR4) increases inducible nitric oxide synthase (iNOS) expression, prompts nitrosative stress, and results in myelin-associated deficits, such as decreased levels of oligodendroglial maturation marker expression and morphological alterations. The intervention of TLR4 surface expression represents a potential means to rescue such ENV-dependent deficits. To this end, the rescue capacity of specific substances, either modulating V-ATPase activity or myeloid differentiation 2 (MD2)-mediated TLR4 glycosylation status, such as compound 20 (C20), L48H437, or folimycin, was analyzed, as these processes were demonstrated to be relevant for TLR4 surface expression. We found that pharmacological treatment can rescue the maturation arrest of oligodendroglial cells and their myelination capacity and can prevent iNOS induction in the presence of the ENV protein. In addition, downregulation of TLR4 surface expression was observed. Furthermore, mitochondrial integrity crucial for oligodendroglial cell differentiation was affected in the presence of ENV and ameliorated upon pharmacological treatment. Our study, therefore, provides novel insights into possible means to overcome myelination deficits associated with HERV-W ENV-mediated myelin deficits.Peter GöttleKira SchichelLaura ReicheLuisa WernerAnnika ZinkAlessandro PrigionePatrick KüryFrontiers Media S.A.articlemyelin repairmultiple sclerosis (MS)oligodendrocytetoll-like receptorHERV-WENVNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571ENFrontiers in Cellular Neuroscience, Vol 15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	myelin repair multiple sclerosis (MS) oligodendrocyte toll-like receptor HERV-W ENV Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571
spellingShingle	myelin repair multiple sclerosis (MS) oligodendrocyte toll-like receptor HERV-W ENV Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Peter Göttle Kira Schichel Laura Reiche Luisa Werner Annika Zink Alessandro Prigione Patrick Küry TLR4 Associated Signaling Disrupters as a New Means to Overcome HERV-W Envelope-Mediated Myelination Deficits
description	Myelin repair in the adult central nervous system (CNS) is driven by successful differentiation of resident oligodendroglial precursor cells (OPCs) and thus constitutes a neurodegenerative process capable to compensate for functional deficits upon loss of oligodendrocytes and myelin sheaths as it is observed in multiple sclerosis (MS). The human endogenous retrovirus type W (HERV-W) represents an MS-specific pathogenic entity, and its envelope (ENV) protein was previously identified as a negative regulator of OPC maturation—hence, it is of relevance in the context of diminished myelin repair. We here focused on the activity of the ENV protein and investigated how it can be neutralized for improved remyelination. ENV-mediated activation of toll like receptor 4 (TLR4) increases inducible nitric oxide synthase (iNOS) expression, prompts nitrosative stress, and results in myelin-associated deficits, such as decreased levels of oligodendroglial maturation marker expression and morphological alterations. The intervention of TLR4 surface expression represents a potential means to rescue such ENV-dependent deficits. To this end, the rescue capacity of specific substances, either modulating V-ATPase activity or myeloid differentiation 2 (MD2)-mediated TLR4 glycosylation status, such as compound 20 (C20), L48H437, or folimycin, was analyzed, as these processes were demonstrated to be relevant for TLR4 surface expression. We found that pharmacological treatment can rescue the maturation arrest of oligodendroglial cells and their myelination capacity and can prevent iNOS induction in the presence of the ENV protein. In addition, downregulation of TLR4 surface expression was observed. Furthermore, mitochondrial integrity crucial for oligodendroglial cell differentiation was affected in the presence of ENV and ameliorated upon pharmacological treatment. Our study, therefore, provides novel insights into possible means to overcome myelination deficits associated with HERV-W ENV-mediated myelin deficits.
format	article
author	Peter Göttle Kira Schichel Laura Reiche Luisa Werner Annika Zink Alessandro Prigione Patrick Küry
author_facet	Peter Göttle Kira Schichel Laura Reiche Luisa Werner Annika Zink Alessandro Prigione Patrick Küry
author_sort	Peter Göttle
title	TLR4 Associated Signaling Disrupters as a New Means to Overcome HERV-W Envelope-Mediated Myelination Deficits
title_short	TLR4 Associated Signaling Disrupters as a New Means to Overcome HERV-W Envelope-Mediated Myelination Deficits
title_full	TLR4 Associated Signaling Disrupters as a New Means to Overcome HERV-W Envelope-Mediated Myelination Deficits
title_fullStr	TLR4 Associated Signaling Disrupters as a New Means to Overcome HERV-W Envelope-Mediated Myelination Deficits
title_full_unstemmed	TLR4 Associated Signaling Disrupters as a New Means to Overcome HERV-W Envelope-Mediated Myelination Deficits
title_sort	tlr4 associated signaling disrupters as a new means to overcome herv-w envelope-mediated myelination deficits
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/e10dee08bb534ee99fa6938e3b0b25ad
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TLR4 Associated Signaling Disrupters as a New Means to Overcome HERV-W Envelope-Mediated Myelination Deficits

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