Identification of an antiangiogenic FGF2-binding site in the N terminus of the soluble pattern recognition receptor PTX3.
Long-pentraxin 3 (PTX3) is a soluble pattern recognition receptor with non-redundant functions in inflammation and innate immunity. PTX3 comprises a pentraxin-like C-terminal domain involved in complement activation via C1q interaction and an N-terminal extension with unknown functions. PTX3 binds fibroblast growth factor-2 (FGF2), inhibiting its pro-angiogenic and pro-restenotic activity. Here, retroviral transduced endothelial cells (ECs) overexpressing the N-terminal fragment PTX3-(1-178) showed reduced mitogenic activity in response to FGF2. Accordingly, purified recombinant PTX3-(1-178) binds FGF2, prevents PTX3/FGF2 interaction, and inhibits FGF2 mitogenic activity in ECs. Also, the monoclonal antibody mAb-MNB4, which recognizes the PTX3-(87-99) epitope, prevents FGF2/PTX3 interaction and abolishes the FGF2 antagonist activity of PTX3. Consistently, the synthetic peptides PTX3-(82-110) and PTX3-(97-110) bind FGF2 and inhibit the interaction of FGF2 with PTX3 immobilized to a BIAcore sensor chip, FGF2-dependent EC proliferation, and angiogenesis in vivo. Thus, the data identify a FGF2-binding domain in the N-terminal extension of PTX3 spanning the PTX3-(97-110) region, pointing to a novel function for the N-terminal extension of PTX3 and underlining the complexity of the PTX3 molecule for modular humoral pattern recognition.
Camozzi
Maura
M
Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology, School of Medicine, University of Brescia, 25123 Brescia, Italy.
Rusnati
Marco
M
Bugatti
Antonella
A
Bottazzi
Barbara
B
Mantovani
Alberto
A
Bastone
Antonio
A
Inforzato
Antonio
A
Vincenti
Silvia
S
Bracci
Luisa
L
Mastroianni
Domenico
D
Presta
Marco
M
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002097:C-Reactive Protein / Q000737:chemistry*; D002417:Cattle; D015922:Complement C1q / Q000737:chemistry; D000939:Epitopes / Q000737:chemistry; D016222:Fibroblast Growth Factor 2 / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D017386:Sequence Homology, Amino Acid; D000683:Serum Amyloid P-Component / Q000737:chemistry*; D000099153:Pentraxins
D002097:C-Reactive Protein; D015922:Complement C1q; D000939:Epitopes; D016222:Fibroblast Growth Factor 2; D000683:Serum Amyloid P-Component; D000099153:Pentraxins