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Hematopoiesis
Vitronectin stabilizes intravascular adhesion of neutrophils by coordinating b2 integrin clustering
Gabriele Zuchtriegel,1,2 Bernd Uhl,1,2 Robert Pick,2 Michaela Ramsauer,1,2 Julian Dominik,2 Laura A. Mittmann,1,2 Martin Canis,2 Sandip Kanse,3 Markus Sperandio,2 Fritz Krombach,1 and Christoph A. Reichel1, 2
1Walter Brendel Center of Experimental Medicine, Ludwig-Maximilians-Universität München, Munich, Germany; 2Department of Otorhinolaryngology, Klinikum der Universität München, Munich, Germany and 3Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway
ABSTRACT
The recruitment of neutrophils from the microvasculature to the site of injury or infection represents a key event in the inflamma- tory response. Vitronectin (VN) is a multifunctional macromole- cule abundantly present in blood and extracellular matrix. The role of this glycoprotein in the extravasation process of circulating neutrophils remains elusive. Employing advanced in vivo/ex vivo imaging techniques in different mouse models as well as in vitro methods, we uncovered a previously unrecognized function of VN in the transition of dynamic to static intravascular interactions of neutrophils with microvascular endothelial cells. These distinct properties of VN require the heteromer- ization of this glycoprotein with plasminogen activator inhibitor-1 (PAI- 1) on the activated venular endothelium and subsequent interactions of this protein complex with the scavenger receptor low-density lipopro- tein receptor-related protein-1 on intravascularly adhering neutrophils. This induces p38 mitogen-activated protein kinases-dependent intracel- lular signaling events which, in turn, regulates the proper clustering of the b2 integrin lymphocyte function associated antigen-1 on the surface of these immune cells. As a consequence of this molecular interplay, neutrophils become able to stabilize their adhesion to the microvascular endothelium and, subsequently, to extravasate to the perivascular tis- sue. Hence, endothelial-bound VN-PAI-1 heteromers stabilize intravas- cular adhesion of neutrophils by coordinating b2 integrin clustering on the surface of these immune cells, thereby effectively controlling neu- trophil trafficking to inflamed tissue. Targeting this protein complex might be beneficial for the prevention and treatment of inflammatory pathologies.
Introduction
Vitronectin (VN) is a multidomain macromolecule synthesized by the liver and found in platelets.1 Upon release into the extracellular space,2 VN becomes capable of establishing interactions with different proteins involved in diverse biological processes: engaging its somatomedin B domain, VN acts as a ligand for the (soluble) urokinase-type plasminogen activator (uPA) receptor or binds to plasminogen acti- vator inhibitor-1 (PAI-1), thereby extending the half life of this protease inhibitor in fibrinolysis. Through its tripeptide arginine, glycine, and aspartate (RGD) sequence, VN can interact with αvb3, αvb5, αIIbb3, and αvb1 integrins which are expressed on the surface of leukocytes and platelets. In addition, several other molecules (e.g., proteoglycans, heparin, collagens, or kininogen) serve as binding partners of VN immobilizing this glycoprotein in the extracellular matrix (ECM), ultimately regu- lating cell adhesion and migration.3-5 Accordingly, enhanced levels of VN have been detected in various inflammatory pathologies including atherosclerosis, glomeru-
Ferrata Storti Foundation
Haematologica 2021 Volume 106(10):2641-2653
Correspondence:
CHRISTOPH REICHEL
christoph.reichel@med.uni-muenchen.de
Received: May 14, 2019. Accepted: July 16, 2020. Pre-published: July 23, 2020.
https://doi.org/10.3324/haematol.2019.226241 ©2021 Ferrata Storti Foundation
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