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

Mihlan, Michael; Blom, Anna LU ; Kupreishvili, Koba; Lauer, Nadine; Stelzner, Kristin; Mohlin, Frida LU ; Niessen, Hans W. M. and Zipfel, Peter F. (2011) In FASEB Journal 25(12). p.4198-4210
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... (More)
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.-Mihlan, M., Blom, A. M., Kupreishvili, K., Lauer, N., Stelzner, K., Bergstro " m, F., Niessen, H. W. M., Zipfel, P. F. Monomeric C-reactive protein modulates classic complement activation on necrotic cells. FASEB J. 25, 4198-4210 (2011). www.fasebj.org (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
cell death, C1q, C4b-binding protein, myocardial infarction
in
FASEB Journal
volume
25
issue
12
pages
4198 - 4210
publisher
The Federation of American Societies for Experimental Biology
external identifiers
  • wos:000298138100013
  • scopus:82655181511
ISSN
1530-6860
DOI
10.1096/fj.11-186460
language
English
LU publication?
yes
id
ee0877ad-75f6-422b-9ddd-e99ec0e37d36 (old id 2333194)
date added to LUP
2012-02-01 07:37:40
date last changed
2017-10-22 04:08:45
@article{ee0877ad-75f6-422b-9ddd-e99ec0e37d36,
  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.-Mihlan, M., Blom, A. M., Kupreishvili, K., Lauer, N., Stelzner, K., Bergstro " m, F., Niessen, H. W. M., Zipfel, P. F. Monomeric C-reactive protein modulates classic complement activation on necrotic cells. FASEB J. 25, 4198-4210 (2011). www.fasebj.org},
  author       = {Mihlan, Michael and Blom, Anna and Kupreishvili, Koba and Lauer, Nadine and Stelzner, Kristin and Mohlin, Frida and Niessen, Hans W. M. and Zipfel, Peter F.},
  issn         = {1530-6860},
  keyword      = {cell death,C1q,C4b-binding protein,myocardial infarction},
  language     = {eng},
  number       = {12},
  pages        = {4198--4210},
  publisher    = {The Federation of American Societies for Experimental Biology},
  series       = {FASEB Journal},
  title        = {Monomeric C-reactive protein modulates classic complement activation on necrotic cells},
  url          = {http://dx.doi.org/10.1096/fj.11-186460},
  volume       = {25},
  year         = {2011},
}