Monomeric C-reactive protein modulates classic complement activation on necrotic cells

M. Mihlan, A.M. Blom, K. Kupreishvili, N. Lauer, K. Stelzner, F. Bergstrom, H.W.M. Niessen, P.F. Zipfel

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)4198-4210
Number of pages12
JournalFASEB Journal
Volume25
Issue number12
DOIs
Publication statusPublished - Dec 2011

Cite this

Mihlan, M., Blom, A. M., Kupreishvili, K., Lauer, N., Stelzner, K., Bergstrom, F., ... Zipfel, P. F. (2011). Monomeric C-reactive protein modulates classic complement activation on necrotic cells. FASEB Journal, 25(12), 4198-4210. https://doi.org/10.1096/fj.11-186460