To reach sites of infection leukocytes have to exit the blood stream by crossing the vascular endothelium. This process has been shown to take place through inter-endothelial cell junctions (or a paracellular route). However, two new studies in Nature Cell Biology confirm previous observations that leukocytes can also cross the endothelium by traversing the endothelial cell cytoplasm, and outline the mechanism by which they initiate this transcellular migration.

Leukocyte binding to endothelial cells induces clustering of adhesion molecules such as ICAM-1. In the first study, Millán and colleagues found that antibody-induced ICAM-1 clustering in HUVECs leads to ICAM-1 recruitment to caveolin-1-rich areas and to the internalization of both proteins. Furthermore, using time-lapse epifluorescence and total internal reflection fluorescence microscopy, they were able to show the translocation of ICAM-1 to basolateral membranes through vesicular structures which form a transcellular channel.

When T-lymphocytes were incubated with ICAM-1-GFP or caveolin-YFP expressing HUVECs, they extended protrusions into the endothelial cell cytoplasm that became surrounded by ICAM-1, caveolin and actin stress fibres. These findings led the authors to propose a model whereby lymphocytes search for sites through which to traverse endothelial cells by pushing down protrusions and triggering the formation of a caveolin-1-enriched transcellular passage.

In a second study, Nieminen and colleagues show that the vimentin intermediate filament network also has a critical role in transcellular migration. They found that ICAM-1 expression and clustering in endothelial cells was severely reduced in vimentin-null mice compared with wild-type, suggesting that vimentin helps to stabilize endothelial cell-leukocyte interactions. In addition to the effects on endothelial cells, the organization of integrin-1 on peripheral blood monocytes was severely affected, and their ability to transmigrate was remarkably reduced in vim^-/- mice. These results suggest that intermediate filaments have a critical role in the organization and expression of surface adhesion molecules, as well as in the subsequent formation a transmigration cup, which engulfs and translocates leukocytes to the basal membrane of endothelial cells.

It will be interesting to see whether signalling downstream of caveolin-1 impinges on the vimentin network to induce the cytoskeletal changes required to translocate leukocytes through the endothelial cell cytoplasm. Future studies may also help shed light on the factors that dictate whether cells take the trans- or para- cellular route to cross the endothelium, and whether the route of migration influences the response to infection.

Author: Monica Hoyos-Flight