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 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.

• Authors: Manuel Zeitelhofer, Milena Z Adzemovic, Christine Moessinger, Christina Stefanitsch, Carina Strell, Lars Muhl, Lou Brundin, Linda Fredriksson, Tomas Olsson, Ulf Eriksson, Ingrid Nilsson
• Journal: Scientific reports (Sci Rep) Vol. 10 Issue 1 Pg. 22383 (12 24 2020) ISSN: 2045-2322 [Electronic] England
• PMID: 33361796 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Neutralizing
• Il1a protein, mouse
• Interleukin-1alpha
• Lymphokines
• Platelet-Derived Growth Factor
• Tumor Necrosis Factor-alpha
• platelet-derived growth factor C

Topics

• Animals
• Antibodies, Neutralizing (pharmacology)
• Blood-Brain Barrier (immunology, pathology)
• Down-Regulation (drug effects, immunology)
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, genetics, immunology, pathology)
• Inflammation (drug therapy, genetics, immunology, pathology)
• Interleukin-1alpha (genetics, immunology)
• Lymphokines (antagonists & inhibitors, genetics, immunology)
• Mice
• Mice, Transgenic
• Multiple Sclerosis (drug therapy, genetics, immunology, pathology)
• Platelet-Derived Growth Factor (antagonists & inhibitors, genetics, immunology)
• Signal Transduction (drug effects, genetics, immunology)
• Tumor Necrosis Factor-alpha (genetics, immunology)