Stiffness-Induced Endothelial DLC-1 Expression Forces Leukocyte Spreading through Stabilization of the ICAM-1 Adhesome

Lilian Schimmel, Miesje van der Stoel, Carmela Rianna, Anne-Marieke van Stalborch, Aafke de Ligt, Mark Hoogenboezem, Simon Tol, Jos van Rijssel, Robert Szulcek, Harm Jan Bogaard, Patrick Hofmann, Reinier Boon, Manfred Radmacher, Vivian de Waard, Stephan Huveneers, Jaap D van Buul

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)3115-3124
Number of pages10
JournalCell Reports
Volume24
Issue number12
DOIs
Publication statusPublished - 18 Sep 2018

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