CCL2 disrupts the adherens junction: Implications for neuroinflammation

Toni K. Roberts, Eliseo A. Eugenin, Lillie Lopez, Ignacio A. Romero, Babette B. Weksler, Pierre Olivier Couraud, Joan W. Berman

Research output: Contribution to journalArticle

56 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1213-1233
Number of pages21
JournalLaboratory Investigation
Volume92
Issue number8
DOIs
StatePublished - Aug 1 2012

Keywords

  • CD31
  • MCP-1
  • PECAM-1
  • VE-cadherin
  • endothelial cells
  • neuroinflammation
  • β-catenin

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Roberts, T. K., Eugenin, E. A., Lopez, L., Romero, I. A., Weksler, B. B., Couraud, P. O., & Berman, J. W. (2012). CCL2 disrupts the adherens junction: Implications for neuroinflammation. Laboratory Investigation, 92(8), 1213-1233. https://doi.org/10.1038/labinvest.2012.80