Effect of fibrinogen, fibrin, and fibrin degradation products on transendothelial migration of leukocytes

In spite of numerous studies on the involvement of fibrinogen in transendothelial migration of leukocytes and thereby inflammation, there is still no clear understanding of which fibrin(ogen) species can stimulate leukocyte transmigration. Although we have previously proposed that interaction of fibrin with the VLDL receptor (VLDLR) promotes leukocyte transmigration, there is no direct experimental evidence for the involvement of fibrin in this process. To address these questions, we performed systematic studies of interaction of VLDLR with fibrinogen, fibrin, and their isolated recombinant BβN- and βN-domains, respectively, and the effect of various fibrin(ogen) species on transendothelial migration of leukocytes. The results obtained revealed that freshly purified fibrinogen does not interact with VLDLR in solution and has practically no effect on leukocyte transmigration. They also indicate that the VLDLR-binding site is cryptic in fibrinogen and becomes accessible upon its adsorption onto a surface or upon its conversion into fibrin. We also found that the D-D:E1 complex and higher molecular mass fibrin degradation products, as well as soluble fibrin and fibrin polymers (clots) anchored to the endothelial monolayer, promote leukocyte transmigration mainly through the VLDL receptor-dependent pathway. Thus, the results of the present study suggest that fibrin degradation products and soluble fibrin that may be present in the circulation in vivo, as well as fibrin clots that may be deposited on the surface of inflamed endothelium, promote leukocyte transmigration. These findings further clarify the molecular mechanisms underlying the fibrin-VLDLR-dependent pathway of leukocyte transmigration and provide an explanation for a possible (patho)physiological role of this pathway.