title: Truncation of monocyte chemoattractant protein 1 by plasmin promotes blood-brain barrier disruption.
abstract: Previous studies have shown that plasmin cleaves monocyte chemoattractant protein 1 (MCP1; officially known as C-C motif chemokine 2, CCL2) at K104, and this cleavage enhances its chemotactic potency significantly. Accumulating evidence reveals that MCP1 also disrupts the integrity of the blood-brain barrier (BBB). Here, we show that K104Stop-MCP1, truncated at the K104 where plasmin would normally cleave, is more efficient than the full-length protein (FL-MCP1) in compromising the integrity of the BBB in in vitro and in vivo models. K104Stop-MCP1 increases the permeability of BBB in both wild-type mice and mice deficient for tissue plasminogen activator (tPA), which converts plasminogen into active plasmin, suggesting that plasmin-mediated truncation of MCP1 plays an important role in BBB compromise. Furthermore, we show that the mechanisms underlying MCP1-induced BBB disruption involve redistribution of tight junction proteins (occludin and ZO-1) and reorganization of the actin cytoskeleton. Finally, we show that the redistribution of ZO-1 is mediated by phosphorylation of ezrin-radixin-moesin (ERM) proteins. These findings identify plasmin as a key signaling molecule in the regulation of BBB integrity and suggest that plasmin inhibitors might be used to modulate diseases accompanied by BBB compromise.
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11794-8651, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Yao
authors.forename: Stella E
authors.initials: SE
authors.lastname: Tsirka
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000166:cytology / Q000378:metabolism*; D015153:Blotting, Western; D002478:Cells, Cultured; D018932:Chemokine CCL2; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D005341:Fibrinolysin / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D017830:Octoxynol; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010958:Plasminogen / Q000378:metabolism; D011485:Protein Binding; D019108:Tight Junctions / Q000235:genetics / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D062826:Zonula Occludens-1 Protein
chemical_list: D018932:Chemokine CCL2; D004268:DNA-Binding Proteins; C086680:ETV5 protein, human; D008565:Membrane Proteins; D010750:Phosphoproteins; C569042:TJP1 protein, human; C569043:Tjp1 protein, mouse; D014157:Transcription Factors; D062826:Zonula Occludens-1 Protein; D010958:Plasminogen; D017830:Octoxynol; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin