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Complex formation with pentraxin-2 regulates factor X plasma levels and macrophage interactions
- Source :
- Blood, Blood, American Society of Hematology, 2017, 129 (17), pp.2443-2454. ⟨10.1182/blood-2016-06-724351⟩
- Publication Year :
- 2017
- Publisher :
- American Society of Hematology, 2017.
-
Abstract
- International audience; 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.
- Subjects :
- 0301 basic medicine
[SDV.BIO]Life Sciences [q-bio]/Biotechnology
Vitamin K
[SDV]Life Sciences [q-bio]
Gene Expression
MESH: Factor X
Plasma protein binding
[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology
MESH: Mice, Knockout
Biochemistry
Mice
chemistry.chemical_compound
0302 clinical medicine
MESH: RNA, Small Interfering
MESH: Animals
MESH: Nerve Tissue Proteins
RNA, Small Interfering
Internalization
Receptor
[SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM]
Factor X Deficiency
MESH: Organ Specificity
media_common
Mice, Knockout
MESH: Kinetics
Chemistry
Factor X
Scavenger Receptors, Class A
Hematology
Endocytosis
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
[SDV] Life Sciences [q-bio]
C-Reactive Protein
Organ Specificity
[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
MESH: HEK293 Cells
MESH: Endocytosis
[SDV.IMM]Life Sciences [q-bio]/Immunology
[SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy
Protein Binding
[SDV.SP.MED] Life Sciences [q-bio]/Pharmaceutical sciences/Medication
MESH: Gene Expression
[SDV.IMM] Life Sciences [q-bio]/Immunology
Immunoprecipitation
media_common.quotation_subject
Immunology
Nerve Tissue Proteins
MESH: Anticoagulants
MESH: Factor X Deficiency
[SDV.SP.PG] Life Sciences [q-bio]/Pharmaceutical sciences/Galenic pharmacology
Cell Line
03 medical and health sciences
[SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication
MESH: Mice, Inbred C57BL
MESH: C-Reactive Protein
MESH: Protein Binding
Animals
Humans
Scavenger receptor
MESH: Mice
MESH: Humans
Macrophages
HEK 293 cells
MESH: Macrophages
MESH: Vitamin K
Anticoagulants
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology
[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy
Cell Biology
Molecular biology
[SDV.BIO] Life Sciences [q-bio]/Biotechnology
MESH: Scavenger Receptors, Class A
MESH: Cell Line
Mice, Inbred C57BL
Kinetics
[SDV.SP.PG]Life Sciences [q-bio]/Pharmaceutical sciences/Galenic pharmacology
HEK293 Cells
030104 developmental biology
[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
030215 immunology
Subjects
Details
- Language :
- English
- ISSN :
- 00064971 and 15280020
- Database :
- OpenAIRE
- Journal :
- Blood, Blood, American Society of Hematology, 2017, 129 (17), pp.2443-2454. ⟨10.1182/blood-2016-06-724351⟩
- Accession number :
- edsair.doi.dedup.....49d9b813fa299c4f9438aba9b925dc7c