Leukocyte Breaching of Endothelial Barriers: The Actin Link

Leukocyte transendothelial migration (TEM) takes place across micron-wide gaps in specific post-capillary venules generated by the transmigrating leukocyte. Because endothelial cells contain a dense cytoskeletal network, transmigrating leukocytes must overcome these mechanical barriers as they squeeze their nuclei through endothelial gaps and pores. Recent findings suggest that endothelial cells are not a passive barrier, and upon engagement by transmigrating leukocytes trigger extensive dynamic modifications of their actin cytoskeleton. Unexpectedly, endothelial contractility functions as a restrictor of endothelial gap enlargement rather than as a facilitator of gap formation as was previously suggested. In this review we discuss current knowledge regarding how accurately timed endothelial actin-remodeling events are triggered by squeezing leukocytes and coordinate leukocyte TEM while preserving blood vessel integrity. Leukocytes access tissues by migrating through the walls of post-capillary venules at endothelial cell junctions or through transcellular pores. New evidence suggests that both the leukocytes and the endothelial cells they pass through are active participants in the opening of these endothelial gaps and pores. Leukocyte-driven clustering of apical and junctional endothelial adhesion molecules triggers coordinated remodeling of the endothelial actin cytoskeleton. Actin-coordinated gap sealing restricts plasma leakage through blood vessels during leukocyte TEM.