MTZ®-MPI-Award 2022 to Nida Arif

During inflammation or tissue injuries, our body generates an immune response to defend against foreign and harmful substances. This response allows immune cells such as leukocytes to cross the blood vessel wall and reach the site of infection in a process called diapedesis. Intact blood vessel walls are lined by endothelial cells. VE-cadherin is one of the major adhesion molecules of endothelial junctions, which maintains endothelial barrier integrity. Leukocyte diapedesis through the endothelium towards sites of infection is achieved by opening of VE-cadherin-based endothelial cell junctions. In her thesis, Nida Arif aimed to uncover the signaling pathways initiated in endothelial cells after adhesion of leukocytes, which result in the opening of junctions and allow the passage of leukocytes. Her work culminated in a scientific article published in EMBO Journal in February 2021.

One of the principal steps in leukocyte diapedesis is the destabilization of VE-cadherin-based junctions. The lab of Dietmar Vestweber has previously shown that the tyrosine residue Y731 in the cytoplasmic domain of VE-cadherin is the pivotal phosphorylation site that controls leukocyte diapedesis in response to inflammation. In resting endothelial cells, VE-cadherin is constitutively phosphorylated at Y731 and this site is physically protected by catenin binding to the same region of VE-cadherin. Under inflammatory conditions, leukocyte docking to the endothelium induces dephosphorylation of this tyrosine residue, which is catalyzed by the phosphatase SHP2 and is indispensable for leukocyte transmigration.
In the current work of Nida Arif, she revealed the underlying molecular mechanism that supports diapedesis. “We found that PECAM-1, a well-reported diapedesis-supporting adhesion molecule, delivers SHP2 to VE-cadherin, thus mediating direct dephosphorylation of Y731 and thereby promoting the subsequent endocytosis of VE-cadherin,” Nida says. The contribution of PECAM-1 to leukocyte diapedesis in vitro and in vivo is based on targeting VE-cadherin for destabilization of endothelial barrier.

“My results support a diapedesis model, in which leukocyte stimulation triggers an influx of calcium, which leads to actomyosin contraction in endothelial cells,” Nida explains. “This endothelial contractility generates pulling forces on the VE-cadherin-catenin complex, which might modulate the conformation of the complex in a way that renders catenin-masked Y731 exposed, thereby making it accessible for SHP2-mediated dephosphorylation.”

Further work shows that the adhesion of leukocytes to the endothelium leads to the dissociation of p120-catenin from VE-cadherin, which exposes an endocytic signal that results in the activation of the endocytic machinery, thus resulting in internalization of VE-cadherin and the opening of endothelial junctions to allow the passage of leukocytes towards the area of infection.

“My in-depth analysis of the molecular events in endothelial cells during leukocyte diapedesis unraveled the precise signaling mechanisms that culminate in endothelial junctional opening, allowing the movement of leukocytes from the blood vessels to the underlying tissue in order to fight infection,” Nida Arif concludes.

About Nida Arif