We have identified pentraxin-2 as a novel partner for FX in the circulation and their plasma levels are inter-dependent
FX and pentraxin-2 cooperate with SR-AI to prevent their uptake by macrophages
Recently, we have identified scavenger receptor-AI (SR-AI) as a receptor for coagulation factor X (FX), mediating the formation of a FX-reservoir at the macrophage-surface (Muczynski, Blood 2016 127:778). Here, we demonstrate that the FX/SR-AI-complex comprises a third protein, pentraxin-2. The presence of pentraxin-2 is essential to prevent internalization of FX by SR-AI, while the presence of FX is needed to interfere with internalization of pentraxin-2. Binding studies showed that FX, SR-AI and pentraxin-2 independently bind to each other (Kd,app: 0.2-0.7 microM). Surprisingly, immuno-precipitation experiments revealed that FX and pentraxin-2 circulate as a complex in plasma, and complex formation involves the FX activation peptide. No binding of pentraxin-2 to other vitamin K-dependent proteins was observed. shRNA-mediated inhibition of pentraxin-2 levels in mice resulted not only in reduced levels of pentraxin-2, but also in similarly reduced FX levels. Moreover, pentraxin-2 and FX levels were correspondingly reduced in SR-AI-deficient mice. Analysis of 71 human plasma samples uncovered a strong correlation between FX and pentraxin-2 plasma levels. Furthermore, plasma samples of patients with reduced FX levels (congenital/acquired FX deficiency or after anti-vitamin K treatment) were characterized by concomitantly decreased pentraxin-2 levels. In conclusion, we identified pentraxin-2 as a novel partner for FX, and both proteins cooperate to prevent their SR-AI-mediated uptake by macrophages. Interestingly, their respective plasma levels are inter-dependent. These findings seem of relevance in perspective of ongoing clinical trials, in which plasma-depletion of pentraxin-2 is used as a therapeutical approach in the management of systemic amyloidosis.
- Submitted June 24, 2016.
- Accepted February 11, 2017.
- Copyright © 2017 American Society of Hematology
To view this item, select one of the options below.
If you already have a subscription, you may gain access using your ASH username and password.
Log in through your institution
Subscribe to the Journal - Subscribe to the print and/or online journal.