Endothelial CD2AP Binds the Receptor ICAM-1 To Control Mechanosignaling, Leukocyte Adhesion, and the Route of Leukocyte Diapedesis In Vitro [INNATE IMMUNITY AND INFLAMMATION]

Inflammation is driven by excessive transmigration (diapedesis) of leukocytes from the blood to the tissue across the endothelial cell monolayer that lines blood vessels. Leukocyte adhesion, crawling, and transmigration are regulated by clustering of the endothelial mechanosensitive receptor intercellular adhesion molecule-1 (ICAM-1). Whereas several proteins are known to promote ICAM-1 function, the molecular mechanisms that limit ICAM-1–mediated adhesion to prevent excessive leukocyte transmigration remain unknown. We identify the endothelial actin-binding protein CD2-associated protein (CD2AP) as a novel interaction partner of ICAM-1. Loss of CD2AP stimulates the dynamics of ICAM-1 clustering, which facilitates the formation of ICAM-1 complexes on the endothelial cell surface. Consequently, neutrophil adhesion is increased, but crawling is decreased. In turn, this promotes the neutrophil preference for the transcellular over the paracellular transmigration route. Mechanistically, CD2AP is required for mechanosensitive ICAM-1 downstream signaling toward activation of the PI3K, and recruitment of F-actin and of the actin-branching protein cortactin. Moreover, CD2AP is necessary for ICAM-1–induced Rac1 recruitment and activation. Mechanical force applied on ICAM-1 impairs CD2AP binding to ICAM-1, suggesting that a tension-induced negative feedback loop promotes ICAM-1–mediated neutrophil crawling and paracellular transmigration. To our knowledge, these data show for the first time that the mechanoreceptor ICAM-1 is negatively regulated by an actin-binding adaptor protein, i.e., CD2AP, to allow a balanced and spatiotemporal control of its adhesive function. CD2AP is important in kidney dysfunction that is accompanied by inflammation. Our findings provide a mechanistic basis for the role of CD2AP in inflamed vessels, identifying this adaptor protein as a potential therapeutic target.

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