See also Groot PG, Urbanus RT. Cellular signaling by antiphospholipid antibodies. This issue, pp 773–5 and Gris JC. The hidden activism of the misnamed. This issue, pp 776–8.
NF-κB is activated from endosomal compartments in antiphospholipid antibodies-treated human monocytes
Version of Record online: 22 MAY 2014
© 2014 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 12, Issue 5, pages 779–791, May 2014
How to Cite
NF-κB is activated from endosomal compartments in antiphospholipid antibodies-treated human monocytes. J Thromb Haemost 2014; 12: 779–91., , , , .
Manuscript handled by: P. H. Reitsma
Final decision: P. H. Reitsma, 12 February 2014
- Issue online: 22 MAY 2014
- Version of Record online: 22 MAY 2014
- Accepted manuscript online: 24 FEB 2014 12:13PM EST
- Manuscript Accepted: 12 FEB 2014
- Manuscript Received: 20 DEC 2013
- Swiss National Fonds. Grant Number: 310030–127639
- ISTH2007 Presidential Fund
- antiphospholipid antibodies;
- innate immunity;
- NF-κ B;
- toll-like receptors
The antiphospholipid antibody syndrome (APS) is an autoimmune disease associated with arterial or venous thrombosis and/or recurrent fetal loss and is caused by pathogenic antiphospholipid antibodies (aPLA). We recently demonstrated that Toll-like receptor 2 (TLR2) and CD14 contribute to monocyte activation of aPLA.
To study the mechanisms of cell activation by aPLA, leading to pro-coagulant and pro-inflammatory responses.
Methods and Results
For this study, we used purified antibodies from the plasmas of 10 different patients with APS and healthy donors. We demonstrate that aPLA, but not control IgG, co-localizes with TLR2 and TLR1 or TLR6 on human monocytes. Blocking antibodies to TLR2, TLR1 or TLR6, but not to TLR4, decreased TNF and tissue factor (TF) responses to aPLA. Pharmacological and siRNA approaches revealed the importance of the clathrin/dynamin-dependent endocytic pathway in cell activation by aPLA. In addition, soluble aPLA induced NF-κB activation, while bead-immobilized aPLA beads, which cannot be internalized, were unable to activate NF-κB. Internalization of aPLA in monocytes and NF-κB activation were dependent on the presence of CD14.
We show that TLR2 and its co-receptors, TLR1 and TLR6, contribute to the pathogenicity of aPLA, that aPLA are internalized via clathrin- and CD14-dependent endocytosis and that endocytosis is required for NF-κB activation. Our results contribute to a better understanding of the APS and provide a possible therapeutic approach.