CCL2 disrupts the adherens junction: implications for neuroinflammation.
Alterations to blood-brain barrier (BBB) adhesion molecules and junctional integrity during neuroinflammation can promote central nervous system (CNS) pathology. The chemokine CCL2 is elevated during CNS inflammation and is associated with endothelial dysfunction. The effects of CCL2 on endothelial adherens junctions (AJs) have not been defined. We demonstrate that CCL2 transiently induces Src-dependent disruption of human brain microvascular endothelial AJ. β-Catenin is phosphorylated and traffics from the AJ to PECAM-1 (platelet endothelial cell adhesion molecule-1), where it is sequestered at the membrane. PECAM-1 is also tyrosine-phosphorylated, an event associated with recruitment of the phosphatase SHP-2 (Src homology 2 domain-containing protein phosphatase) to PECAM-1, β-catenin release from PECAM-1, and reassociation of β-catenin with the AJ. Surface localization of PECAM-1 is increased in response to CCL2. This may enable the endothelium to sustain CCL2-induced alterations in AJ and facilitate recruitment of leukocytes into the CNS. Our novel findings provide a mechanism for CCL2-mediated disruption of endothelial junctions that may contribute to BBB dysfunction and increased leukocyte recruitment in neuroinflammatory diseases.
Department of Pathology, The Albert Einstein College of Medicine, Bronx, NY, USA.
Toni K
TK
Roberts
Eliseo A
EA
Eugenin
Lillie
L
Lopez
Ignacio A
IA
Romero
Babette B
BB
Weksler
Pierre-Olivier
PO
Couraud
Joan W
JW
Berman
D022005:Adherens Junctions / Q000378:metabolism*; D015703:Antigens, CD / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D002460:Cell Line; D002463:Cell Membrane Permeability; D018932:Chemokine CCL2 / Q000378:metabolism*; D004660:Encephalitis / Q000378:metabolism* / Q000473:pathology; D042783:Endothelial Cells / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D055806:Microvessels / Q000276:immunology / Q000473:pathology; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D018932:Chemokine CCL2; D051417:Focal Adhesion Kinase 1; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D011994:Recombinant Proteins; D051176:beta Catenin; D000099152:Cadherin 5; C111835:CCL2 protein, human; C496050:PTK2 protein, human; C516724:PTPN11 protein, human