Toll-like receptor 4 and β2 glycoprotein I interaction on endothelial cells

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by thrombotic events and/or pregnancy morbidity in the persistent presence of antiphospholipid antibodies (aPL). aPL targeting (2) glycoprotein I (anti-(2)GPI Abs) provide the main pathogenic autoantibody subset. In monocytes, platelets and endothelial cells (ECs), the interaction of circulating aPL with membrane-bound (2)GPI results in cell activation, and EC perturbation provides an important player in clotting. Several receptors have been suggested to mediate (2)GPI/EC binding. AnnexinA2 provides a high-affinity binding site for (2)GPI but, since it does not span the cell membrane, an adaptor protein is required to trigger signal. Consistent evidence supports the role of Toll-like receptor (TLR) 4 as co-receptor for (2)GPI on ECs. (2)GPI was recently reported to behave as lipopolysaccharide (LPS) scavenger. In monocytes, TLR4 activation was shown to be apparent, due to LPS/(2)GPI complexes. Conversely, our findings in ECs demonstrate that (2)GPI interacts directly with TLR4, and that such interaction may contribute to (2)GPI-dependent aPL-mediated EC activation. LPS enhanced anti-(2)GPI Ab binding to EC only at cell-activating concentrations, able to up-regulate TLR4. This invitro model may explain why LPS behaves as a second hit increasing the expression of (2)GPI in vascular tissues and triggering aPL-mediated thrombosis invivo.