Leukocyte extravasation from the blood stream to the peripheral tissues is a critical step in the immune response. In vivo it can broadly be broken down into four distinct steps, namely chemoattraction, rolling adhesion, tight adhesion and finally TEM or diapedesis. Initially, leukocytes adhere loosely to the vascular wall and roll along its luminal surface before being arrested by more firm adhesive interactions. They then undergo diapedesis—the penetrative phase of passage through the endothelial cell barrier. ICAM-1 and VCAM-1 on the surface of endothelial cells are key in mediating firm adhesion of leukocytes. ICAM-1 acts as a gatekeeper of lymphocyte TEM by binding to activated β2 integrins, namely LFA-1. Following engagement, ICAM-1 redistributes to perijunctional areas, which are also the sites of active diapedesis.

At the UCL Institute of Ophthalmology I studied the process of TEM at the blood-brain barrier and I observed that during lymphocyte TEM, ICAM-1 signalling diverges into pathways regulating lymphocyte diapedesis, and other pathways modulating gene expression thereby contributing to the long-term inflammatory response of the endothelium (Dragoni et al., J Immunol. 2017). Specifically I showed that endothelial MAPKs ERK, p38, and JNK mediate diapedesis-related and diapedesis-unrelated functions of ICAM-1. All three MAPKs are activated by ICAM-1 engagement and are involved in ICAM-1-dependent expression of inflammatory mediators in cerebral endothelial cells. Endothelial JNK and to a much lesser degree p38 are the principal MAPKs involved in facilitating diapedesis of lymphocytes across the endothelium. Furthermore, activation of endothelial ICAM-1/JNK leads to phosphorylation of paxillin, its association with VE-cadherin, and internalization of the latter. Importantly ICAM-1-induced phosphorylation of paxillin is required for lymphocyte TEM and converged functionally with VE-cadherin phosphorylation.