Lymphocyte migration through brain endothelial cell monolayers involves signaling through endothelial ICAM-1 via a...

Area of Science:

• Neuroimmunology
• Cellular Biology
• Vascular Biology

Background:

• Lymphocyte extravasation into the central nervous system (CNS) is crucial for immune surveillance and inflammatory responses.
• Endothelial cell (EC) Intercellular Adhesion Molecule-1 (ICAM-1) plays a key role in lymphocyte adhesion and transmigration across the blood-brain barrier (BBB).
• ICAM-1 signaling within brain ECs is implicated in regulating BBB permeability and immune cell trafficking.

Purpose of the Study:

• To investigate the signaling pathways in brain ECs triggered by ICAM-1 ligation, mimicking lymphocyte adhesion.
• To elucidate the role of the Rho GTPase pathway and actin cytoskeleton dynamics in ICAM-1-mediated lymphocyte migration.
• To determine the contribution of ECs to T lymphocyte transmigration across the BBB.

Main Methods:

• Utilized antibody (Ab) ligation of endothelial ICAM-1 to simulate lymphocyte adhesion.
• Applied cytochalasin D to disrupt actin cytoskeleton and C3 transferase to inhibit Rho proteins.
• Measured T lymphocyte migration through EC monolayers, actin reorganization, and Rho GTP loading.

Main Results:

• ICAM-1 cross-linking induced actin cytoskeleton reorganization and Rho GTPase activation in brain ECs.
• Cytochalasin D inhibited ICAM-1-stimulated cortactin phosphorylation and T lymphocyte migration.
• C3 transferase significantly inhibited T lymphocyte transmigration, Rho-GTP loading, and actin reorganization, but not lymphocyte adhesion or cortactin phosphorylation.

Conclusions:

• Brain vascular ECs actively facilitate T lymphocyte migration across the BBB via ICAM-1 signaling.
• ICAM-1-mediated transmigration involves ICAM-1-stimulated actin cytoskeleton rearrangement and functional EC Rho proteins.
• The Rho GTPase pathway is critical for ICAM-1-induced endothelial cell changes supporting lymphocyte migration.