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.
Highlights
Disruption of blood–brain barrier (BBB) integrity is a feature of various neurological disorders
For this we first performed a genome wide analysis of the BBB transcriptome on endothelial cell enriched vascular fragments isolated from the spinal cords of: i) myelin oligodendrocyte glycoprotein (MOG)-immunized, imatinib-treated and ii) MOG-immunized, phosphate buffered saline (PBS)-treated C57BL/6N mice sacrificed during the preclinical, progression and remission phase of EAE, respectively
Since platelet-derived growth factor receptor α (PDGFRα) is expressed in perivascular cells in the NVU57,61 we aimed to investigate whether interfering with the PDGF-CC/PDGFRα axis is responsible for the imatinib-mediated preservation of BBB integrity in EAE by analyzing the effect of genetically reducing PDGF-CC levels utilizing Pdgfc deficient mice and neutralizing PDGF-CC monoclonal antibodies, respectively, in autoimmune neuroinflammation
Summary
Disruption of blood–brain barrier (BBB) integrity is a feature of various neurological disorders. 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 during the progression phase. These changes were antagonized by blocking PDGFRα signaling with the small tyrosine kinase inhibitor imatinib. TNF-α and IFN-γ promote both adhesion and migration of leucocytes across the BBB by influencing the expression of various chemokines such as CCL2 to C CL528 This leads to endothelial cell activation and subsequent disruption of BBB integrity, resulting in influx of immune cells into the CNS21,53. Our data strongly indicate the possibility for establishing a novel treatment targeting disruption of BBB integrity during disease progression
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