title: Monomeric CRP contributes to complement control in fluid phase and on cellular surfaces and increases phagocytosis by recruiting factor H.
abstract: Complement forms the first defense line of innate immunity and has an important role in the non-inflammatory clearance of apoptotic and necrotic cells. Factor H is one essential complement inhibitor that binds to the acute phase reactant C-reactive protein (CRP). By using recombinant proteins, calcium-independent binding of Factor H to monomeric CRP (mCRP), but not to pentameric CRP (pCRP), was shown. In addition to the two known CRP-binding sites, a novel third site was localized within the C-terminus. This region is frequently mutated in the hemolytic uremic syndrome and the mutant proteins show reduced mCRP binding. In this study, we show that mCRP directs Factor H to the surface of apoptotic and necrotic endothelial cells and identify phosphocholine as one binding moiety for this complex. Factor H-mCRP complexes enhance C3b inactivation both in the fluid phase and on the surface of damaged cells and inhibit the production of pro-inflammatory cytokines. By recruiting the soluble complement inhibitor Factor H to the surface of damaged cells, mCRP blocks the progression of the complement cascade beyond the step of the C3 convertase, prevents the formation of inflammatory activation products, and thus contributes to the safe removal of opsonized damaged cells and particles.
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Jena 07745, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Mihlan
authors.forename: S
authors.initials: S
authors.lastname: Stippa
authors.forename: M
authors.initials: M
authors.lastname: Józsi
authors.forename: P F
authors.initials: PF
authors.lastname: Zipfel
mesh_terms: D017209:Apoptosis; D002097:C-Reactive Protein / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D003179:Complement C3b / Q000378:metabolism*; D017242:Complement Factor H / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D010587:Phagocytosis; D010767:Phosphorylcholine / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization
chemical_list: D010767:Phosphorylcholine; D003179:Complement C3b; D017242:Complement Factor H; D002097:C-Reactive Protein