CCL2 disrupts the adherens junction: implications for neuroinflammation

Lab Invest. 2012 Aug;92(8):1213-33. doi: 10.1038/labinvest.2012.80. Epub 2012 May 28.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adherens Junctions / metabolism*
  • Antigens, CD / metabolism
  • Brain / blood supply
  • Brain / metabolism
  • Brain / pathology*
  • Cadherins / metabolism
  • Cell Line
  • Cell Membrane Permeability
  • Chemokine CCL2 / metabolism*
  • Encephalitis / metabolism*
  • Encephalitis / pathology
  • Endothelial Cells / metabolism
  • Focal Adhesion Kinase 1 / metabolism
  • Humans
  • Microvessels / immunology
  • Microvessels / pathology
  • Phosphorylation
  • Platelet Endothelial Cell Adhesion Molecule-1 / metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
  • Recombinant Proteins / metabolism
  • beta Catenin / metabolism

Substances

  • Antigens, CD
  • CCL2 protein, human
  • Cadherins
  • Chemokine CCL2
  • Platelet Endothelial Cell Adhesion Molecule-1
  • Recombinant Proteins
  • beta Catenin
  • cadherin 5
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • PTPN11 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11