FHR-1 binds to C-reactive protein and enhances rather than inhibits complement activation

Ádám I. Csincsi, Zsóka Szabó, Zsófia Bánlaki, Barbara Uzonyi, Marcell Cserhalmi, Éva Kárpáti, Agustín Tortajada, Joseph J.E. Caesar, Zoltán Prohászka, T. Sakari Jokiranta, Susan M. Lea, Santiago Rodríguez De Córdoba, Mihály Józsi

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22 Citations (Scopus)


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 agerelated macular degeneration.

Original languageEnglish
Pages (from-to)292-303
Number of pages12
JournalJournal of Immunology
Issue number1
Publication statusPublished - 1 Jul 2017
Externally publishedYes

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