CCL2 disrupts the adherens junction

Implications for neuroinflammation

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

Research output: Contribution to journalArticle

47 Citations (Scopus)

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
Externally publishedYes

Fingerprint

CD31 Antigens
Adherens Junctions
Catenins
Central Nervous System
Blood-Brain Barrier
Junctional Adhesion Molecules
Leukocytes
SH2 Domain-Containing Protein Tyrosine Phosphatases
Chemokine CCL2
Phosphoprotein Phosphatases
Phosphoric Monoester Hydrolases
Endothelium
Tyrosine
Pathology
Inflammation
Membranes
Brain

Keywords

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

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Molecular Biology

Cite this

Roberts, T. K., Eugenin, E., 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

CCL2 disrupts the adherens junction : Implications for neuroinflammation. / Roberts, Toni K.; Eugenin, Eliseo; Lopez, Lillie; Romero, Ignacio A.; Weksler, Babette B.; Couraud, Pierre Olivier; Berman, Joan W.

In: Laboratory Investigation, Vol. 92, No. 8, 01.08.2012, p. 1213-1233.

Research output: Contribution to journalArticle

Roberts, TK, Eugenin, E, Lopez, L, Romero, IA, Weksler, BB, Couraud, PO & Berman, JW 2012, 'CCL2 disrupts the adherens junction: Implications for neuroinflammation', Laboratory Investigation, vol. 92, no. 8, pp. 1213-1233. https://doi.org/10.1038/labinvest.2012.80
Roberts, Toni K. ; Eugenin, Eliseo ; Lopez, Lillie ; Romero, Ignacio A. ; Weksler, Babette B. ; Couraud, Pierre Olivier ; Berman, Joan W. / CCL2 disrupts the adherens junction : Implications for neuroinflammation. In: Laboratory Investigation. 2012 ; Vol. 92, No. 8. pp. 1213-1233.
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