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. 2017 Jul 1;199(1):292-303.
doi: 10.4049/jimmunol.1600483. Epub 2017 May 22.

FHR-1 Binds to C-Reactive Protein and Enhances Rather than Inhibits Complement Activation

Ádám I Csincsi  1 , Zsóka Szabó  1 , Zsófia Bánlaki  1 , Barbara Uzonyi  2 , Marcell Cserhalmi  1 , Éva Kárpáti  1 , Agustín Tortajada  3   4 , Joseph J E Caesar  5 , Zoltán Prohászka  6 , T Sakari Jokiranta  7 , Susan M Lea  5 , Santiago Rodríguez de Córdoba  3   4 , Mihály Józsi  8
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Free article

FHR-1 Binds to C-Reactive Protein and Enhances Rather than Inhibits Complement Activation

Ádám I Csincsi et al. J Immunol. .
Free article

Abstract

Factor H-related protein (FHR) 1 is one of the five human FHRs that share sequence and structural homology with the alternative pathway complement inhibitor FH. Genetic studies on disease associations and functional analyses indicate that FHR-1 enhances complement activation by competitive inhibition of FH binding to some surfaces and immune proteins. We have recently shown that FHR-1 binds to pentraxin 3. In this study, our aim was to investigate whether FHR-1 binds to another pentraxin, C-reactive protein (CRP), analyze the functional relevance of this interaction, and study the role of FHR-1 in complement activation and regulation. FHR-1 did not bind to native, pentameric CRP, but it bound strongly to monomeric CRP via its C-terminal domains. FHR-1 at high concentration competed with FH for CRP binding, indicating possible complement deregulation also on this ligand. FHR-1 did not inhibit regulation of solid-phase C3 convertase by FH and did not inhibit terminal complement complex formation induced by zymosan. On the contrary, by binding C3b, FHR-1 allowed C3 convertase formation and thereby enhanced complement activation. FHR-1/CRP interactions increased complement activation via the classical and alternative pathways on surfaces such as the extracellular matrix and necrotic cells. Altogether, these results identify CRP as a ligand for FHR-1 and suggest that FHR-1 enhances, rather than inhibits, complement activation, which may explain the protective effect of FHR-1 deficiency in age-related macular degeneration.

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