title: Toll-like receptor 4 and β2 glycoprotein I interaction on endothelial cells.
abstract: 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.
authors.affiliation: Experimental Laboratory of Immunological and Rheumatologic Researches, IRCCS Istituto Auxologico Italiano, Milan, Italy Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: M O
authors.initials: MO
authors.lastname: Borghi
authors.affiliation: Experimental Laboratory of Immunological and Rheumatologic Researches, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Raschi
authors.affiliation: Experimental Laboratory of Immunological and Rheumatologic Researches, IRCCS Istituto Auxologico Italiano, Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Grossi
authors.affiliation: Experimental Laboratory of Immunological and Rheumatologic Researches, IRCCS Istituto Auxologico Italiano, Milan, Italy Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
authors.forename: C B
authors.initials: CB
authors.lastname: Chighizola
authors.affiliation: Experimental Laboratory of Immunological and Rheumatologic Researches, IRCCS Istituto Auxologico Italiano, Milan, Italy Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy pierluigi.meroni@unimi.it.
authors.forename: P L
authors.initials: PL
authors.lastname: Meroni
mesh_terms: D017306:Annexin A2 / Q000502:physiology; D017152:Antibodies, Antiphospholipid / Q000276:immunology; D042783:Endothelial Cells / Q000502:physiology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D053482:beta 2-Glycoprotein I / Q000502:physiology*
chemical_list: C472822:ANXA2 protein, human; D017306:Annexin A2; D017152:Antibodies, Antiphospholipid; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D053482:beta 2-Glycoprotein I
keywords: Anticardiolipin antibodies; antiphospholipid syndrome; thrombosis