Role of Complement CRP complexes in Inflammation and Organ Dysfunction
Final Report Abstract
In this project, the monomeric form of CRP, i.e. mCRP has been linked to the human disorders AMD (age related macular degeneration) and myocardial infarction, and the biological role of this new CRP variant was identified. mCRP is formed on the surface of modified self particles, binds complement regulators and allows their safe removal. We characterized mCRP generation on the surface of necrotic epithelial cells and myocardiocytes and demonstrated that mCRP assist in the non inflammatory, silent removal of these cellular fragments. In addition we identified MDA (Malondialedhyde), a lipid peroxidation product as a related complement recruiting surface protein. Both mCRP and MDA recruit the central complement regulators FHL1 and Factor H to modified surfaces and the bound inhibitors enhance uptake, i.e. phagocytosis and display antiinflammatory activity. The AMD associated sequence variations of FHL1 and Factor H (Tyr 402 to His 402) affect the binding intensity to mCRP and to MDA. The risk variants of both proteins, which bind with lower intensity have a reduced anti inflammatory activity. Thus explaining disease pathology for AMD, and likely for other inflammatory autoimmune diseases.
Publications
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2009. Human complement factor H-related protein 4 binds and recruits native pentameric C- reactive protein to necrotic cells. Mol Immunol. 2009 46: 335-44
Mihlan M, Hebecker M, Dahse HM, Hälbich S, Huber-Lang M, Dahse R, Zipfel PF, Józsi M
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(2011) CRP modulates classical complement activation on necrotic cells FASEB J. 25:4198-210
Mihlan, M, Blom AM, Kupreishvili K, Lauer N, Stelzner K, Bergström, F, Niessen HWM, Zipfel PF
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2011. Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature 478: 76-81
Weismann D, Hartvigsen K, Lauer N, Bennett KL, Scholl HP, Charbel Issa P, Cano M, Brandstätter H, Tsimikas S, Skerka C, Superti-Furga G, Handa JT, Zipfel PF, Witztum JL, Binder CJ
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2011. Complement regulation at necrotic cell lesions is impaired by the age-related macular degeneration-associated factor-H His402 risk variant. J Immunol. 187: 4374-83
Lauer N, Mihlan M, Hartmann A, Schlötzer-Schrehardt U, Keilhauer C, Scholl HP, Charbel Issa P, Holz F, Weber BH, Skerka C, Zipfel PF
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2011. Monomeric CRP contributes to complement control in fluid phase and on cellular surfaces and increases phagocytosis by recruiting factor H. Cell Death Differ. 16:1630-40
Mihlan M, Stippa S, Józsi M, Zipfel PF
