TY - JOUR
T1 - FHR-1 binds to C-reactive protein and enhances rather than inhibits complement activation
AU - Csincsi, Ádám I.
AU - Szabó, Zsóka
AU - Bánlaki, Zsófia
AU - Uzonyi, Barbara
AU - Cserhalmi, Marcell
AU - Kárpáti, Éva
AU - Tortajada, Agustín
AU - Caesar, Joseph J.E.
AU - Prohászka, Zoltán
AU - Jokiranta, T. Sakari
AU - Lea, Susan M.
AU - De Córdoba, Santiago Rodríguez
AU - Józsi, Mihály
PY - 2017/7/1
Y1 - 2017/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85021173129&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1600483
DO - 10.4049/jimmunol.1600483
M3 - Article
AN - SCOPUS:85021173129
VL - 199
SP - 292
EP - 303
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 1
ER -