Although lymphocyte recirculation to the endothelium plays a critical role in the movement of immune cells from the blood into tissues and sites of inflammation, the mechanisms involved in lymphocyte trafficking via the hepatic circulation have yet to be elucidated fully. In this study, we investigated the role of stabilin-2, which is expressed specifically in the sinusoidal endothelium, in the adhesion of lymphocytes to the hepatic endothelium. Stabilin-2-expressing cells mediate the adhesion of PBLs. This interaction was attributed specifically to the interaction of stabilin-2 with alphaMbeta2 integrin. Using mutant stabilin-2 molecules with deletions in the extracellular domain, we mapped the binding site fo... More
Although lymphocyte recirculation to the endothelium plays a critical role in the movement of immune cells from the blood into tissues and sites of inflammation, the mechanisms involved in lymphocyte trafficking via the hepatic circulation have yet to be elucidated fully. In this study, we investigated the role of stabilin-2, which is expressed specifically in the sinusoidal endothelium, in the adhesion of lymphocytes to the hepatic endothelium. Stabilin-2-expressing cells mediate the adhesion of PBLs. This interaction was attributed specifically to the interaction of stabilin-2 with alphaMbeta2 integrin. Using mutant stabilin-2 molecules with deletions in the extracellular domain, we mapped the binding site for alphaMbeta2 integrin to the fasciclin 1 (FAS1) domains of stabilin-2. The specificity of the interaction between alphaMbeta2 integrin and the FAS1 domain was confirmed further by binding assays using neutralizing antibodies. More physiologically, we showed that the down-regulation of stabilin-2 results in the defective binding of lymphocytes to hepatic sinusoidal endothelial cells under conditions of static and physiological flow. Together, these data show that stabilin-2 can reconstitute the lymphocyte-endothelial adhesion cascade under physiological shear stress. We propose a critical role for stabilin-2 in lymphocyte adhesion to specialized endothelia, such as that of the hepatic sinusoid.
