Actin-binding proteins differentially regulate endothelial cell stiffness, ICAM-1 function and neutrophil transmigration

Antje Schaefer, Joost te Riet, Katja Ritz, Mark Hoogenboezem, Eloise C. Anthony, Frederik P.J. Mul, Carlie J. de Vries, Mat J. Daemen, Carl G. Figdor, Jaap D. van Buul, Peter L. Hordijk*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Chronic vascular inflammation is driven by interactions between activated leukocytes and the endothelium. Leukocyte β2-integrins bind to endothelial intercellular adhesion molecule 1 (ICAM-1), which allows leukocyte spreading, crawling and transendothelial migration. Leukocytes scan the vascular endothelium for permissive sites to transmigrate, which suggests that there is apical membrane heterogeneity within the endothelium. However, the molecular basis for this heterogeneity is unknown. Leukocyte adhesion induces ICAM-1 clustering, which promotes its association to the actinbinding proteins filamin B, α-actinin-4 and cortactin. We show that these endothelial proteins differentially control adhesion, spreading and transmigration of neutrophils. Loss of filamin B, α-actinin-4 and cortactin revealed adaptor-specific effects on a nuclear-toperipheral gradient of endothelial cell stiffness. By contrast, increasing endothelial cell stiffness stimulates ICAM-1 function. We identify endothelial α-actinin-4 as a key regulator of endothelial cell stiffness and of ICAM-1-mediated neutrophil transmigration. Finally, we found that the endothelial lining of human and murine atherosclerotic plaques shows elevated levels of α-actinin-4. These results identify endothelial cell stiffness as an important regulator of endothelial surface heterogeneity and of ICAM-1 function, which in turn controls the adhesion and transmigration of neutrophils.

Original languageEnglish
Pages (from-to)4470-4482
Number of pages13
JournalJournal of Cell Science
Volume127
Issue number20
DOIs
Publication statusPublished - 1 Jan 2014

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