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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • C-Reactive Protein / chemistry
  • C-Reactive Protein / immunology*
  • C-Reactive Protein / metabolism*
  • C-Reactive Protein / pharmacology
  • Complement Activation*
  • Complement C3-C5 Convertases
  • Complement C3b / immunology
  • Complement C3b / pharmacology
  • Complement C3b Inactivator Proteins / immunology*
  • Complement C3b Inactivator Proteins / metabolism*
  • Complement C3b Inactivator Proteins / pharmacology
  • Complement Factor H
  • Extracellular Matrix / drug effects
  • Extracellular Matrix / immunology
  • Human Umbilical Vein Endothelial Cells / drug effects
  • Human Umbilical Vein Endothelial Cells / immunology
  • Humans
  • Ligands
  • Macular Degeneration / immunology
  • Protein Binding
  • Serum Amyloid P-Component / immunology
  • Serum Amyloid P-Component / metabolism

Substances

  • CFHR1 protein, human
  • Complement C3b Inactivator Proteins
  • Ligands
  • Serum Amyloid P-Component
  • complement factor H, human
  • PTX3 protein
  • Complement C3b
  • Complement Factor H
  • C-Reactive Protein
  • Complement C3-C5 Convertases