Fig. 4

Potential implications of BACE1 cleavage of ST6gal-1 and PSGL-1 on macrophage recruitment. The binding cascade leading to transendothelial migration and recruitment of leukocytes, in this case monocytes, begins with binding interactions between PSGL-1 and P-selectin. These adhesion molecules disrupt flow of monocytes through the blood stream (1) by initiating the rolling and tethering to endothelial cells (2). This binding progresses until the arrest of the monocyte (3) with the addition of VCAM-1 and integrin binding. At this point, VCAM-1/integrin binding takes over and plays a critical role in facilitating transendothelial migration (4,5). BACE1 cleaves ST6gal-1, resulting in decreased sialyation of α4β1 integrin, which increases its binding affinity to VCAM-1. Further, this hyposialyation leads to decreased endothelial cell-cell adhesion. This combination of these effects would likely provide conditions more permissive to macrophage recruitment. Conversely, BACE1 cleavage of PSGL-1 would reduce the amount PSGL-1 available on the cell surface to bind with P-selectin. This would likely reduce the frequency of the initial binding reactions of this cascade and would likely attenuate macrophage recruitment