Blood-Brain Barrier and Immune Cell Transmigration: ICAM-1/CD54 Signaling Pathways

The BBB is a selective diffusion barrier that is composed of specialized endothelial cells (ECs) that are linked by tight junctions (TJs) and adherens junctions (AJs). These junction complexes can be remodeled during neuroinflammation to form interendothelial gaps that peripheral immune cells will pass through to enter the central nervous system (CNS). Engagement of adhesion molecules on the surface of ECs by leukocyte integrins activates diverse signaling pathways in ECs that result in the dynamic reorganization of junction complexes and EC retraction. Intercellular Adhesion Molecule 1 (ICAM-1/CD54) is an Ig-like adhesion receptor that binds the leukocyte Integrin alpha 4 beta 1 (LFA-1). This interaction induces clustering of ICAM-1/CD54 and activation of intracellular signaling pathways that induce phosphorylation of TJ proteins, resulting in their disassembly and/or redistribution from the cell border. Specifically, ICAM-1/CD54 signaling promotes endocytosis of Occludin and VE-Cadherin. Additionally, ICAM-1/CD54 signaling induces reorganization of F-Actin microfilaments into stress fibers, which increases centripetal tension inside the cell resulting in cell retraction.

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