title: Monomeric C-reactive protein modulates classic complement activation on necrotic cells.
abstract: The acute-phase protein C-reactive protein (CRP) recruits C1q to the surface of damaged cells and thereby initiates complement activation. However, CRP also recruits complement inhibitors, such as C4b-binding protein (C4bp) and factor H, which both block complement progression at the level of C3 and inhibits inflammation. To define how CRP modulates the classic complement pathway, we studied the interaction of CRP with the classic pathway inhibitor C4bp. Monomeric CRP (mCRP), but not pentameric CRP (pCRP), binds C4bp and enhances degradation of C4b and C3b. Both C1q, the initiator, and C4bp, the inhibitor of the classic pathway, compete for mCRP binding, and this competition adjusts the local balance of activation and inhibition. After attachment of pCRP to the surface of necrotic rat myocytes, generation of mCRP was demonstrated over a period of 18 h. Similarly, a biological role for mCRP, C1q, and C4bp in the disease setting of acute myocardial infarction was revealed. In this inflamed tissue, mCRP, pCRP, C4bp, C1q, and C4d were detected in acetone-fixed and in unfixed tissue. Protein levels were enhanced 6 h to 5 d after infarction. Thus, mCRP bound to damaged cardiomyocytes recruits C1q to activate and also C4bp to control the classic complement pathway.
authors.affiliation: Department of Infection Biology, Leibniz Institute for Natural Products Research and Infection Biology, Beutenbergstrasse 11a, 07745 Jena, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Mihlan
authors.forename: Anna M
authors.initials: AM
authors.lastname: Blom
authors.forename: Koba
authors.initials: K
authors.lastname: Kupreishvili
authors.forename: Nadine
authors.initials: N
authors.lastname: Lauer
authors.forename: Kristin
authors.initials: K
authors.lastname: Stelzner
authors.forename: Frida
authors.initials: F
authors.lastname: Bergström
authors.forename: Hans W M
authors.initials: HW
authors.lastname: Niessen
authors.forename: Peter F
authors.initials: PF
authors.lastname: Zipfel
mesh_terms: D000818:Animals; D002097:C-Reactive Protein / Q000737:chemistry / Q000378:metabolism*; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism; D002478:Cells, Cultured; D015922:Complement C1q / Q000378:metabolism; D050716:Complement C4b-Binding Protein; D003171:Complement Pathway, Classical / Q000502:physiology*; D006649:Histocompatibility Antigens / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D009203:Myocardial Infarction / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009336:Necrosis; D011485:Protein Binding; D011487:Protein Conformation; D020836:Protein Structure, Quaternary; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020349:Surface Plasmon Resonance
chemical_list: C055609:C4BPA protein, human; D002352:Carrier Proteins; D050716:Complement C4b-Binding Protein; C030929:Crp protein, rat; D006649:Histocompatibility Antigens; D011994:Recombinant Proteins; D015922:Complement C1q; D002097:C-Reactive Protein