TY - JOUR
T1 - Stiffness-Induced Endothelial DLC-1 Expression Forces Leukocyte Spreading through Stabilization of the ICAM-1 Adhesome
AU - Schimmel, Lilian
AU - van der Stoel, Miesje
AU - Rianna, Carmela
AU - van Stalborch, Anne-Marieke
AU - de Ligt, Aafke
AU - Hoogenboezem, Mark
AU - Tol, Simon
AU - van Rijssel, Jos
AU - Szulcek, Robert
AU - Bogaard, Harm Jan
AU - Hofmann, Patrick
AU - Boon, Reinier
AU - Radmacher, Manfred
AU - de Waard, Vivian
AU - Huveneers, Stephan
AU - van Buul, Jaap D.
PY - 2018/9/18
Y1 - 2018/9/18
N2 - Leukocytes follow the well-defined steps of rolling, spreading, and crawling prior to diapedesis through endothelial cells (ECs). We found increased expression of DLC-1 in stiffness-associated diseases like atherosclerosis and pulmonary arterial hypertension. Depletion of DLC-1 in ECs cultured on stiff substrates drastically reduced cell stiffness and mimicked leukocyte transmigration kinetics observed for ECs cultured on soft substrates. Mechanistic studies revealed that DLC-1-depleted ECs or ECs cultured on soft substrates failed to recruit the actin-adaptor proteins filamin B, α-actinin-4, and cortactin to clustered ICAM-1, thereby preventing the ICAM-1 adhesome formation and impairing leukocyte spreading. This was rescued by overexpressing DLC-1, resulting in ICAM-1 adhesome stabilization and leukocyte spreading. Our results reveal an essential role for substrate stiffness-regulated endothelial DLC-1, independent of its GAP domain, in locally stabilizing the ICAM-1 adhesome to promote leukocyte spreading, essential for efficient leukocyte transendothelial migration. Leukocyte extravasation depends on local cellular and substrate stiffness. Schimmel et al. identified endothelial DLC-1 as a mediator to translate stiffness to leukocyte behavior. DLC-1 is crucial for the ICAM-1 adhesome, which allows leukocytes to switch from the rolling to the spreading and crawling phase, followed by diapedesis.
AB - Leukocytes follow the well-defined steps of rolling, spreading, and crawling prior to diapedesis through endothelial cells (ECs). We found increased expression of DLC-1 in stiffness-associated diseases like atherosclerosis and pulmonary arterial hypertension. Depletion of DLC-1 in ECs cultured on stiff substrates drastically reduced cell stiffness and mimicked leukocyte transmigration kinetics observed for ECs cultured on soft substrates. Mechanistic studies revealed that DLC-1-depleted ECs or ECs cultured on soft substrates failed to recruit the actin-adaptor proteins filamin B, α-actinin-4, and cortactin to clustered ICAM-1, thereby preventing the ICAM-1 adhesome formation and impairing leukocyte spreading. This was rescued by overexpressing DLC-1, resulting in ICAM-1 adhesome stabilization and leukocyte spreading. Our results reveal an essential role for substrate stiffness-regulated endothelial DLC-1, independent of its GAP domain, in locally stabilizing the ICAM-1 adhesome to promote leukocyte spreading, essential for efficient leukocyte transendothelial migration. Leukocyte extravasation depends on local cellular and substrate stiffness. Schimmel et al. identified endothelial DLC-1 as a mediator to translate stiffness to leukocyte behavior. DLC-1 is crucial for the ICAM-1 adhesome, which allows leukocytes to switch from the rolling to the spreading and crawling phase, followed by diapedesis.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85053045023&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30231995
U2 - https://doi.org/10.1016/j.celrep.2018.08.045
DO - https://doi.org/10.1016/j.celrep.2018.08.045
M3 - Article
C2 - 30231995
SN - 2211-1247
VL - 24
SP - 3115
EP - 3124
JO - Cell Reports
JF - Cell Reports
IS - 12
ER -