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Relocalization of junctional adhesion molecule A during inflammatory stimulation of brain endothelial cells

Svetlana M Stamatovic1, Nikola Sladojevic, Richard F Keep

  • 1Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.

Molecular and Cellular Biology
|June 27, 2012
PubMed

Insights

Junctional adhesion molecule A (JAM-A) relocates during inflammation, moving from cell junctions to the surface to aid immune cell migration across the blood-brain barrier via macropinocytosis.

Area of Science:

  • Cell Biology
  • Immunology
  • Neuroscience

Background:

  • Junctional adhesion molecule A (JAM-A) is a transmembrane protein crucial for endothelial cell-cell interactions.
  • Under inflammatory conditions, JAM-A transitions to a leukocyte adhesion molecule, facilitating immune cell transmigration.
  • The blood-brain barrier (BBB) integrity is dynamically regulated during inflammation.

Purpose of the Study:

  • To investigate the dynamic behavior and functional role of JAM-A during inflammatory remodeling of the BBB.
  • To elucidate the mechanisms underlying JAM-A redistribution and its involvement in paracellular route formation.

Main Methods:

  • Utilized brain endothelial cells stimulated with chemokine (C-C motif) ligand 2 (CCL2).
  • Employed tracer studies with dextran-Texas Red to track JAM-A internalization and trafficking.
  • Investigated the role of macropinocytosis and specific Rab proteins (Rab5, Rab4) using inhibitors and small interfering RNA.
  • Analyzed the involvement of RhoA and Rho kinase signaling pathways.

Main Results:

  • CCL2 induced JAM-A redistribution from interendothelial cell areas to the apical surface.
  • JAM-A internalization via macropinocytosis was observed within ~10 minutes, followed by sorting through Rab34/Rab5 and Rab4-positive endosomes.
  • Internalized JAM-A was recycled to the apical membrane by ~20 minutes.
  • Macropinocytosis inhibition and Rab5/Rab4 depletion blocked JAM-A relocalization.
  • RhoA and Rho kinase signaling pathways were implicated in JAM-A redistribution.

Conclusions:

  • JAM-A plays a critical role in leukocyte adhesion and transendothelial migration during inflammation at the BBB.
  • Macropinocytosis and subsequent endosomal sorting/recycling are key mechanisms for JAM-A redistribution.
  • RhoA/Rho kinase signaling pathways regulate JAM-A dynamics during BBB remodeling.

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