The RhoA GEF, LARG, mediates ICAM-1-dependent mechanotransduction in endothelial cells to stimulate transendothelial migration

• Published in: The Journal of immunology (1950) Vol. 192; no. 7; pp. 3390 - 3398
• Main Authors: Lessey-Morillon, Elizabeth C., Osborne, Lukas D., Monaghan-Benson, Elizabeth, Guilluy, Christophe, O’Brien, E. Timothy, Superfine, Richard, Burridge, Keith
• Format: Journal Article
• Language: English
• Published: 28.02.2014
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1302525

RhoA-mediated cytoskeletal rearrangements in endothelial cells (ECs) play an active role in leukocyte transendothelial cell migration (TEM), a normal physiological process in which leukocytes cross the endothelium to enter the underlying tissue. While much has been learned about RhoA signaling pathways downstream from ICAM-1 in ECs, little is known about the consequences of the tractional forces that leukocytes generate on ECs as they migrate over the surface before TEM. We have found that after applying mechanical forces to ICAM-1 clusters, there is an increase in cellular stiffening and enhanced RhoA signaling compared to ICAM-1 clustering alone. We have identified that the RhoA GEF LARG/ARHGEF12 acts downstream of clustered ICAM-1 to increase RhoA activity and that this pathway is further enhanced by mechanical force on ICAM-1. Depletion of LARG decreases leukocyte crawling and inhibits TEM. This is the first report of endothelial LARG regulating leukocyte behavior and EC stiffening in response to tractional forces generated by leukocytes.