Role of Complement CRP complexes in Inflammation and Organ Dysfunction

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Trauma induces inflammation and tissue- as well as cell damage. The initial insult causes activation of the complement cascade which orchestrates inflammation and tissue destruction. Complement plays an important role in the clearance of trauma induced damaged cells and of apoptotic and necrotic particles. This elimination is enhanced by the soluble acute phase protein C-reactive protein (CRP). In this project we plan to study the interaction of the soluble complement inhibitor Factor H with CRP and the function of the Factor H:CRP complex during trauma and inflammation. We propose a role of this complex in the clearance of damaged particles. Apparently at the surface of damaged particles complement activation proceeds to C3 deposition, but further progression of the is inhibited. The later step is blocked by binding of the soluble complement inhibitors Factor H and C4BP, which attach to the surface of damaged cells in combination with CRP. In addition the role of two novel CRP ligands, the Factor H related proteins FHR-4A and FHR-4B will be studied. Most likely by complexing CRP all three complement regulators (Factor H, FHR-4A and FHR-4B) block amplification of the complement cascade on the surface of damaged cells, inhibit inflammation and allow removal by phagocytes. The understanding of these mechanisms will help to define appropriate complement inhibitors in order to modulate these reactions.