Summary
Antiphospholipid antibodies (aPL) have been shown to induce tissue factor (TF) 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)⍺ and lipopolysaccharide (LPS) was strongly dependent
on the activation of endosomal NOX. While TNF⍺ 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.
Keywords
Tissue factor / factor VII - thrombosis - antiphospholipid antibodies - endosome -
NADPH oxidase