Author:
Zeitelhofer Manuel,Adzemovic Milena Z.,Moessinger Christine,Stefanitsch Christina,Strell Carina,Muhl Lars,Brundin Lou,Fredriksson Linda,Olsson Tomas,Eriksson Ulf,Nilsson Ingrid
Abstract
AbstractDisruption 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.
Funder
Neurofonden
Karolinska Institutet
Tore Nilsons Stiftelse
EMBO fellowship
Vetenskapsrådet
Hållsten Research Foundation
Royal Swedish Academy of Sciences
Karolinska Institute
Publisher
Springer Science and Business Media LLC
Cited by
13 articles.
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