Toll-like receptor 4 and β 2 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 β₂ glycoprotein I (anti-β₂GPI Abs) provide the main pathogenic autoantibody subset. In monocytes, platelets and endothelial cells (ECs), the interaction of circulating aPL with membrane-bound β₂GPI results in cell activation, and EC perturbation provides an important player in clotting. Several receptors have been suggested to mediate β₂GPI/EC binding. AnnexinA2 provides a high-affinity binding site for β₂GPI 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 β₂GPI on ECs. β₂GPI was recently reported to behave as lipopolysaccharide (LPS) scavenger. In monocytes, TLR4 activation was shown to be apparent, due to LPS/β₂GPI complexes. Conversely, our findings in ECs demonstrate that β₂GPI interacts directly with TLR4, and that such interaction may contribute to β₂GPI-dependent aPL-mediated EC activation. LPS enhanced anti-β₂GPI Ab binding to EC only at cell-activating concentrations, able to up-regulate TLR4. This in vitro model may explain why LPS behaves as a second hit increasing the expression of β₂GPI in vascular tissues and triggering aPL-mediated thrombosis in vivo.