Blood-Brain Barrier and Immune Cell Transmigration: CCL2/MCP-1 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). The chemokine CCL2/MCP-1 is elevated in the CNS during neuroinflammatory conditions and is a potent inducer of BBB disruption. CCL2/MCP-1 binds to CCR2 on brain ECs to initiate intracellular signaling cascades that result in the dynamic reorganization of junction complexes and EC retraction. CCL2/MCP-1 induces the phosphorylation of TJ proteins, resulting in their disassembly and/or redistribution from the cell border. JAM proteins will relocate to the apical surface of ECs where they participate in adhesive interactions with leukocyte integrins. CCL2/MCP-1 signaling also induces reorganization of F-Actin microfilaments into stress fibers, which increases centripetal tension inside the cell resulting in cell retraction.

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