title: Complex formation with pentraxin-2 regulates factor X plasma levels and macrophage interactions.
abstract: Recently, we have identified scavenger receptor class A member I (SR-AI) as a receptor for coagulation factor X (FX), mediating the formation of an FX reservoir at the macrophage surface. Here, we demonstrate that the FX/SR-AI-complex comprises a third protein, pentraxin-2 (PTX2). The presence of PTX2 is essential to prevent internalization of FX by SR-AI, and the presence of FX is needed to interfere with internalization of PTX2. Binding studies showed that FX, SR-AI, and PTX2 independently bind to each other (KD,app: 0.2-0.7 μM). Surprisingly, immunoprecipitation experiments revealed that FX and PTX2 circulate as a complex in plasma, and complex formation involves the FX activation peptide. No binding of PTX2 to other vitamin K-dependent proteins was observed. Short hairpin RNA-mediated inhibition of PTX2 levels in mice resulted not only in reduced levels of PTX2, but also in similarly reduced FX levels. Moreover, PTX2 and FX levels were correspondingly reduced in SR-AI-deficient mice. Analysis of 71 human plasma samples uncovered a strong correlation between FX and PTX2 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 PTX2 levels. In conclusion, we identified PTX2 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 interdependent. These findings seem of relevance in perspective of ongoing clinical trials, in which plasma depletion of PTX2 is used as a therapeutical approach in the management of systemic amyloidosis.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche (UMR)_S 1176, University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|Inovarion SAS, Paris, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Muczynski
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche (UMR)_S 1176, University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Aymé
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, UMR_S 1116, Université de Lorraine, Vandoeuvre-lès-Nancy, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Regnault
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche (UMR)_S 1176, University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|Biology Department, Hôpital Foch, Suresnes, France; and.
authors.forename: Marc
authors.initials: M
authors.lastname: Vasse
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche (UMR)_S 1176, University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.|Assistance Public-Hôpiteaux de Paris, Service d'Hématologie Biologique, Hôpital Necker, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Borgel
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche (UMR)_S 1176, University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
authors.forename: Paulette
authors.initials: P
authors.lastname: Legendre
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche (UMR)_S 1176, University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
authors.forename: Amine
authors.initials: A
authors.lastname: Bazaa
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche (UMR)_S 1176, University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Harel
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche (UMR)_S 1176, University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Loubière
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche (UMR)_S 1176, University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lenting
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche (UMR)_S 1176, University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
authors.forename: Cécile V
authors.initials: CV
authors.lastname: Denis
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche (UMR)_S 1176, University Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
authors.forename: Olivier D
authors.initials: OD
authors.lastname: Christophe
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D002097:C-Reactive Protein / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004705:Endocytosis; D005170:Factor X / Q000235:genetics / Q000378:metabolism*; D005171:Factor X Deficiency / Q000097:blood* / Q000235:genetics / Q000473:pathology; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D007700:Kinetics; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009928:Organ Specificity; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014812:Vitamin K / Q000037:antagonists & inhibitors / Q000378:metabolism; D000099153:Pentraxins
chemical_list: D000925:Anticoagulants; D002097:C-Reactive Protein; D005170:Factor X; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D051117:Scavenger Receptors, Class A; D014812:Vitamin K; D000099153:Pentraxins