The oxidase activity of vascular adhesion protein-1 (VAP-1) induces endothelial E- and P-selectins and leukocyte binding

Abstract

Leukocyte migration from the blood into tissues is pivotal in immune homeostasis and in inflammation. During the multistep extravasation cascade, endothelial selectins (P-and E-selectin) and vascular adhesion protein-1 (VAP-1), a cell-surfaceexpressed oxidase, are important in tethering and rolling. Here, we studied the signaling functions of the catalytic activity of VAP-1. Using human endothelial cells transfected with wild-type VAP-1 and an enzymatically inactive VAP-1 point mutant, we show that transcription and translation of E-and P-selectins are induced through the enzymatic activity of VAP-1. Moreover, use of VAP-1-deficient animals and VAP-1-deficient animals carrying the human VAP-1 as a transgene show a VAP-enzyme activity-dependent induction of P-selectin in vivo. Up-regulation of P-selectin was found both in high endothelial venules in lymphoid tissues and in flat-walled vessels in noninflamed tissues. VAP-1 activity in vivo led to in- IntroductionCoordinated function of the multistep leukocyte extravasation cascade is a prerequisite for leukocyte emigration from the blood into the tissue. Many adhesion and signaling molecules have well-established roles in this process. 1,2 On endothelial cells, selectins (P-selectin [CD62P] and E-selectin [CD62E]) mediate tethering of bloodborne cells to vascular endothelium, and the subsequent rolling along the endothelial lining in a sheardependent manner. 3 The rolling cells can be exposed to activating stimuli, such as chemokines, which can trigger firm, integrindependent adhesion of the leukocytes in the vessel. Finally, the leukocytes diapedese through the vessel wall using adhesion molecules from immunoglobulin and other superfamilies as well as local protease activity.In addition to these well-established interplayers, other molecules are involved in leukocyte trafficking. Among these, enzymes expressed on the cell surface that have their catalytic domains outside the plasma membrane (ectoenzymes) have emerging roles in leukocyte migration. 4 Vascular adhesion protein-1 (VAP-1, also known as amine oxidase copper containing-3 [AOC3]) is an ectoenzyme that belongs to the specific subgroup of oxidases known as semicarbazide-sensitive amine oxidases (SSAOs). 5,6 It catalyzes a reaction in which a primary amine is oxidatively deaminated into an aldehyde, and then hydrogen peroxide and ammonium are released. 7,8 VAP-1/SSAO is a bifunctional molecule that can support leukocyte adhesion under shear conditions via enzymeactivity-dependent and enzyme-activity-independent ways. 4 Monoclonal anti-VAP-1 antibodies that do not block its oxidase activity effectively block lymphocyte and granulocyte binding to endothelial cells in vitro and in vivo. Small-molecule SSAO enzyme inhibitors, on the other hand, are equally effective in perturbing leukocyte-endothelial contacts in vitro and in vivo. [9][10][11][12][13][14] The ability of the oxidase reaction to regulate the expression and/or function of other molecules involved in the emigration process is largely unknown.We h...

Ischemia‐reperfusion injury is attenuated in VAP‐1‐deficient mice and by VAP‐1 inhibitors

“…However, we find this unlikely, since the inhibitor attenuated disease more effectively also in the transgenic mice, in which VAP-1 expression is confined to endothelial cells only. Finally, the enzymatic activity of VAP-1 has been shown to induce the expression or activity of other adhesion molecules, chemokines and transcription factors through the production of biologically active end-products [34][35][36]. This may be relevant in the current models, since the anti-VAP-1 mAb do not interfere with the catalytic activity of VAP-1, and thereby cannot prevent these secondary signaling effects.…”

Sialyl lewisx antigen-expressing human CD4+ T and CD8+ T cells as initial immune responders in memory phenotype subsets

“…Fucose-containing sLe x is a ligand for the adhesion molecules E-selectin and P-selectin [16,17], which are highly expressed on inflamed endothelial cells [25][26][27]. The binding between sLe x and selectins has been known to be important for regulation of leukocyte migration into inflamed tissues [28 -30].…”

VAP-1–Mediated M2 Macrophage Infiltration Underlies IL-1β– but Not VEGF-A–Induced Lymph- and Angiogenesis

“…16 However, whether VAP-1 is expressed in lymphatics and whether it contributes to lymphangiogenesis is unknown. 2,5,17,18 …”