Complementing regeneration

Complement proteins and complement activation products with effector functions include complement opsonins (C1q, MBL, and C3d), anaphylatoxins (C3a and C5a), and the membrane attack complex (MAC). The complement system also comprises a variety of cellbound and soluble complement regulatory proteins that act on different activation pathways or at different steps in the cascade, and which prevent pathologic complement activation on normal host surfaces (Figure 1). Complement has a well-known role in host defense, as well as pathological host cell injury when inappropriately activated, but complement is becoming increasingly implicated in a wide spectrum of additional pathophysiological mechanisms, including repair and regeneration (reviewed in [1]). Indeed, it is now clear that in some pathological conditions, complement can have a dual-edged effect and is involved in both potentiating injury as well as stimulating recovery. There is currently a great interest in the therapeutic application of complement inhibitors, but it will be important to understand the complement-dependent mechanisms involved in the balance between injury and recovery in order to apply an optimal therapeutic strategy. In recent work, we described a novel complement inhibitor that illustrates this point. It has been known for some time that complement is important for liver regeneration, and that receptor engagement by the complement activation products C3a and C5a provides an essential signal that leads to the priming of hepatocyte regeneration [2]. Liver regeneration is important for recovery after liver resection, the most common type of liver surgery, and thus inhibiting complement early in the pathway would block the generation of C3a and C5a and impair recovery. On the other hand, resection is usually performed under ischemic conditions, and it has been shown that blocking complement early in the pathway protects against ischemia reperfusion injury (IRI). We developed a complement inhibitor, CR2-CD59, that targets to sites of complement activation (via CR2 moiety) and that inhibits only the MAC, allowing generation of C3a and C5a (Figure 1) [3]. We found that when administered after hepatic ischemia and reperfusion, CR2-CD59 was as protective as CR2Crry, an inhibitor of C3 activation, thus implicating the MAC as the prime mediator of hepatic IRI. However, in a clinically relevant model involving both ischemia/ reperfusion and resection, CR2-CD59 was protective and enhanced regeneration, whereas CR2-Crry significantly worsened outcome. CR2-CD59 prevented MAC-mediated mitochondrial depolarization, and allowed a C3a/5amediated increase in TNF and IL-6 levels that was Editorial