Proteins of the Factor H protein family bind to C-reactive protein and regulate complement activity on apoptotic and necrotic host cells

Mihlan, Michael

The complement system protects the host against foreign organisms and induces a non-inflammatory phagocytosis of damaged or mutated host cells. Complement regulators protect intact host cells against complement attack and prevent inflammatory reactions. Factor H is the main soluble regulator of the alternative complement pathway. Factor H binds to host cells and blocks the alternative complement activation to prevent cell- and tissue damages. In addition, Factor H binds the acute phase protein C-reactive protein (CRP). CRP opsonizes apoptotic and necrotic host cells and microbial invaders for phagocytosis by activating the classical complement cascade. However, the amplification loop via the alternative pathway and the pro-inflammatory terminal complement pathway are inhibited. Here I analyzed the role of Factor H binding to CRP in this limitation of complement. Furthermore, the Factor H related (CFHR) proteins CFHR-1, CFHR-4A, and CFHR-4B, which have a high similarity to Factor H, were functionally characterized. In this work I show, that Factor H, CFHR 4A, and CFHR-4B bind different isoforms of CRP. Factor H binds monomeric CRP (mCRP), while CFHR-4A/4B bind pentameric CRP (pCRP). Moreover, the analyzed proteins of the Factor H protein family regulate complement at the surface of cellular debris. Factor H and CFHR 1 inhibit complement and protect cellular debris from inflammatory complement attack, while CFHR 4A/4B enhance the cell opsonization through recruitment of pCRP. In addition, Factor H enhances the phagocytosis of apoptotic particles and inhibits the release of the pro-inflammatory cytokine TNF-αand the chemokine IL-8. These effects of Factor H are enhanced by mCRP. Thus, Factor H, CFHR-1, CFHR-4A/4B, and CRP maintain a beneficial balance between complement activation and inhibition which is crucial to prevent inflammation and ultimately the development of autoimmune diseases.

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Mihlan, Michael: Proteins of the Factor H protein family bind to C-reactive protein and regulate complement activity on apoptotic and necrotic host cells. 2010.

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