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Complex formation with Pentraxin-2 regulates Factor X plasma levels and macrophage interactions

Vincent Muczynski, Gabriel Aymé, Véronique Regnault, Marc Vasse, Delphine Borgel, Paulette Legendre, Amine Bazaa, Amélie Harel, Cécile Loubière, Peter J. Lenting, Cécile V. Denis and Olivier D. Christophe

Key points

  • 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

Abstract

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.