Journal
THROMBOSIS AND HAEMOSTASIS
Volume 109, Issue 3, Pages 525-531Publisher
SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN
DOI: 10.1160/TH12-06-0421
Keywords
Tissue factor / factor VII; thrombosis; antiphospholipid antibodies; endosome; NADPH oxidase
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Funding
- Stiftung Pathobiochemie und Molekulare Diagnostik of German United Society of Clinical Chemistry and Laboratory Medicine
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Antiphospholipid antibodies (aPL) have been shown to induce tissue factor (IF) expression in monocytes and endothelial cells. However, the underlying signal transduction has been more or less elusive in the past. We have recently shown that aPL enter the lysosomal route in monocytes and dendritic cells, and subsequently activate endosomal NADPH-oxidase (NOX). The generation of superoxide which is dismutated to hydrogen peroxide upregulates the intracellular toll like receptors (TLR) 7 and 8, and leads to robust production of inflammatory cytokines. Here we show that induction of TF by aPL follows the same signaling pathway. Inhibition of endosomal NOX by the anion channel blocker niflumic acid or capture of superoxide by the radical scavenger N-acetylcysteine blocks TF induction by aPL. Furthermore, monocytes from mice deficient in NOX2 do not increase TF surface expression in response to aPL, while cells from mice deficient in glutathione peroxidase-1 (GPx-1) show an increased response. Unexpectedly, also induction of TF by tumour necrosis factor (TNF)alpha and lipopolysaccharide (LPS) was strongly dependent on the activation of endosomal NOX. While TNF alpha apparently depends almost fully on endosomal NOX, signalling of LPS is only partially dependent on this pathway. These data provide further insight into the well-known role of reactive oxygen species in the induction of TF expression and suggest that endosomal signalling may represent a central coordinating point in this process.
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