Adhesion molecules in CNS disorders: biomarker and therapeutic targets

Abstract

Mounting evidence has been provided regarding the crucial role of leukocyte extravasation and subsequent inflammatory response in several central nervous system (CNS) disorders. The infiltrated leukocytes release proinflammatory mediators and activate resident cells, leading to tissue injury. Leukocyte-endothelia interaction is critical for leukocyte extravasation and migration from the intravascular space into the tissue during inflammation. The basic physiology of leukocyte-endothelia interaction has been investigated extensively. Traditionally, three kinds of adhesion molecules, selectin, integrin, and immunoglobulin families, are responsible for this multiple-step interaction. Furthermore, blocking adhesion molecule function by genetic knockout, antagonizing antibodies, or inhibitory pharmacological drugs provides neuroprotection, which is associated with a reduction in leukocyte accumulation within the tissue. Detection of the soluble form of adhesion molecules has also been proven to predict outcomes in CNS disorders. Lately, vascular adhesion protein-1, a novel adhesion molecule and endothelial cell surface enzyme, has been implicated as a brake in the rolling step of the adhesion cascade, and also a regulator of leukocyte transmigration step. In this review, we summarize the functions of traditional adhesion molecules as well as vascular adhesion protein-1in the leukocyte adhesion cascade. We also discuss the diagnostic and therapeutic potential of adhesion molecules in CNS disorders.

Figure 1. Adhesion molecules and the leukocyte adhesion cascade

The leukocyte adhesion cascade is a multi-step process that includes tethering, rolling, activation, firm adhesion, and transmigration steps. Classical adhesion molecules, including selectin, integrin, and immunoglobulin, are involved in different phases by supporting leukocyte crossing of the endothelial layer from blood into tissue. Chemokines stimulate leukocyte activation. One novel ectoenzyme, VAP-1, contributes to the rolling, firm adhesion, and transmigration steps. EC: endothelial cell.

Figure 2. Enzymatic function of VAP-1

The figure shows VAP-1 is an endothelial cell semi-carbazide sensitive amine oxidase (SSAO). VAP-1 catalyzes oxidative deamination of primary amines and releases biologically active products, including NH3, aldehydes, and H₂O₂.