Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


TLR-4 and Annexin A2 Involvement in Endothelial Cell Activation by Anti-Phospholipid Antibodies: Specific Silencing by Small Interfering RNAs.

Raschi2,  Elena, Broggini3,  Valentina, Borghi4,  Maria Orietta, Grossi2,  Claudia, Meroni1,  Pierluigi

Instituto G. Pini University, Milano, Italy
IRCCS Istituto Auxologico Italiano, Milan, Italy
University of Milan, Italy
University of Milan; IRCCS Istituto Auxologico Italiano, Milan, Italy

Background:

Antiphospholipid Syndrome (APS) is characterized by recurrent fetal losses and arterial/venous thrombosis in the presence of anti-phospholipid antibodies (aPL). aPL are directed against anionic phospholipid binding proteins: mainly prothrombin and b2 glycoprotein I (b2GPI). The complex formation between circulating aPL and b2GPI expressed on the cell membranes induces signalling and triggers cell activation. Accordingly, aPL-mediated endothelial cell (EC) perturbation is thought to be a key pathogenic event leading to the prothrombotic diathesis as supported by in vitro and in vivo models. The exact nature of the EC receptors for b2GPI is still matter of research: b2GPI has been shown to bind heparan sulphate, Annexin A2 and apoER2 (on platelets). Furthermore there is also evidence that aPL trigger TLR-4.

Objectives:

to address the role of TLR4 and AnnA2 in anti-b2GPI Abs-mediated EC activation pathway.

Methods:

we performed: i) in vitro experiments with or without blocking antibodies directed to Annexin A2 and TLR-4 ii) small interfering RNA experiments for silencing TLR-4 and Annexin A2 expression in suitably transfected HUVEC.

Results:

aPL binding to HUVEC was partially inhibited by both anti-Annexin A2 and anti-TLR-4 blocking antibodies. Anti-TLR-4 also reduced aPL-induced E-Selectin and ICAM-1 expression. TLR-4 silencing by siRNA significantly inhibited both binding and activation of aPL-exposed HUVEC, while Annexin A2 silencing only affected binding.

Conclusion:

Our results suggest that more than one receptor may be involved in aPL-mediated EC activation. As Annexin A2 is unable to transduce signals into the cells owing to the lack of a cytoplasmic tail, TLR-4 could act as coreceptor. Understanding the nature of the receptor/co-receptor and its interaction with b2GPI will lead to identify new strategies for treatment and prevention of pro-thrombotic and pro-inflammatory state in APS.

To cite this abstract, please use the following information:
Raschi, Elena, Broggini, Valentina, Borghi, Maria Orietta, Grossi, Claudia, Meroni, Pierluigi; TLR-4 and Annexin A2 Involvement in Endothelial Cell Activation by Anti-Phospholipid Antibodies: Specific Silencing by Small Interfering RNAs. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1356
DOI: 10.1002/art.29122

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