Blocking PDGF-CC signaling ameliorates multiple sclerosis-like neuroinflammation by inhibiting disruption of the blood–brain barrier

Abstract Disruption of blood–brain barrier (BBB) integrity is a feature of various neurological disorders. Here we found that the BBB is differently affected during the preclinical, progression and remission phase of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclero...

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Autores principales:	Manuel Zeitelhofer, Milena Z. Adzemovic, Christine Moessinger, Christina Stefanitsch, Carina Strell, Lars Muhl, Lou Brundin, Linda Fredriksson, Tomas Olsson, Ulf Eriksson, Ingrid Nilsson
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/18f04bdb2bef420e877bfd4a06c159be
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spelling	oai:doaj.org-article:18f04bdb2bef420e877bfd4a06c159be2021-12-02T13:34:55ZBlocking PDGF-CC signaling ameliorates multiple sclerosis-like neuroinflammation by inhibiting disruption of the blood–brain barrier10.1038/s41598-020-79598-z2045-2322https://doaj.org/article/18f04bdb2bef420e877bfd4a06c159be2020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79598-zhttps://doaj.org/toc/2045-2322Abstract Disruption of blood–brain barrier (BBB) integrity is a feature of various neurological disorders. Here we found that the BBB is differently affected during the preclinical, progression and remission phase of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We have identified an upregulation of pro-inflammatory and pro-angiogenic factors in the BBB transcriptome and down-regulation of endothelial tight junction members coinciding with elevated BBB leakage specifically during the progression phase. These changes were antagonized by blocking PDGFRα signaling with the small tyrosine kinase inhibitor imatinib. Moreover, targeting the PDGFRα ligand PDGF-CC using a neutralizing antibody, facilitated recovery of BBB integrity and improvement of EAE symptoms. Intracerebroventricular injection of PDGF-CC induced upregulation, whereas blocking PDGF-CC during EAE led to downregulation of Tnfa and Il1a at the BBB. Our findings suggest that blocking PDGF-CC counteracts fundamental aspects of endothelial cell activation and disruption of the BBB by decreasing Tnfa and Il1a expression. We also demonstrate that both PDGF-CC and its receptor PDGFRα were upregulated in MS lesions indicating that blocking PDGF-CC may be considered a novel treatment for MS.Manuel ZeitelhoferMilena Z. AdzemovicChristine MoessingerChristina StefanitschCarina StrellLars MuhlLou BrundinLinda FredrikssonTomas OlssonUlf ErikssonIngrid NilssonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-21 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Manuel Zeitelhofer Milena Z. Adzemovic Christine Moessinger Christina Stefanitsch Carina Strell Lars Muhl Lou Brundin Linda Fredriksson Tomas Olsson Ulf Eriksson Ingrid Nilsson Blocking PDGF-CC signaling ameliorates multiple sclerosis-like neuroinflammation by inhibiting disruption of the blood–brain barrier
description	Abstract Disruption of blood–brain barrier (BBB) integrity is a feature of various neurological disorders. Here we found that the BBB is differently affected during the preclinical, progression and remission phase of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). We have identified an upregulation of pro-inflammatory and pro-angiogenic factors in the BBB transcriptome and down-regulation of endothelial tight junction members coinciding with elevated BBB leakage specifically during the progression phase. These changes were antagonized by blocking PDGFRα signaling with the small tyrosine kinase inhibitor imatinib. Moreover, targeting the PDGFRα ligand PDGF-CC using a neutralizing antibody, facilitated recovery of BBB integrity and improvement of EAE symptoms. Intracerebroventricular injection of PDGF-CC induced upregulation, whereas blocking PDGF-CC during EAE led to downregulation of Tnfa and Il1a at the BBB. Our findings suggest that blocking PDGF-CC counteracts fundamental aspects of endothelial cell activation and disruption of the BBB by decreasing Tnfa and Il1a expression. We also demonstrate that both PDGF-CC and its receptor PDGFRα were upregulated in MS lesions indicating that blocking PDGF-CC may be considered a novel treatment for MS.
format	article
author	Manuel Zeitelhofer Milena Z. Adzemovic Christine Moessinger Christina Stefanitsch Carina Strell Lars Muhl Lou Brundin Linda Fredriksson Tomas Olsson Ulf Eriksson Ingrid Nilsson
author_facet	Manuel Zeitelhofer Milena Z. Adzemovic Christine Moessinger Christina Stefanitsch Carina Strell Lars Muhl Lou Brundin Linda Fredriksson Tomas Olsson Ulf Eriksson Ingrid Nilsson
author_sort	Manuel Zeitelhofer
title	Blocking PDGF-CC signaling ameliorates multiple sclerosis-like neuroinflammation by inhibiting disruption of the blood–brain barrier
title_short	Blocking PDGF-CC signaling ameliorates multiple sclerosis-like neuroinflammation by inhibiting disruption of the blood–brain barrier
title_full	Blocking PDGF-CC signaling ameliorates multiple sclerosis-like neuroinflammation by inhibiting disruption of the blood–brain barrier
title_fullStr	Blocking PDGF-CC signaling ameliorates multiple sclerosis-like neuroinflammation by inhibiting disruption of the blood–brain barrier
title_full_unstemmed	Blocking PDGF-CC signaling ameliorates multiple sclerosis-like neuroinflammation by inhibiting disruption of the blood–brain barrier
title_sort	blocking pdgf-cc signaling ameliorates multiple sclerosis-like neuroinflammation by inhibiting disruption of the blood–brain barrier
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/18f04bdb2bef420e877bfd4a06c159be
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Blocking PDGF-CC signaling ameliorates multiple sclerosis-like neuroinflammation by inhibiting disruption of the blood–brain barrier

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