A novel role of complement: Mice deficient in the fifth component of complement (C5) exhibit impaired liver regeneration

Components of innate immunity have recently been implicated in the regulati on of developmental processes, Most strikingly, complement factors appear t o be involved in limb regeneration in certain urodele species. Prompted by these observations and anticipating a conserved role of complement in mamma lian regeneration, we have now investigated the involvement of complement c omponent C5 in liver regeneration, using a murine model of CCl4-induced liv er toxicity and mice genetically deficient in C5, CS-deficient mice showed severely defective liver regeneration and persistent parenchymal necrosis a fter exposure to CCl4. In addition, these mice showed a marked delay in the re-entry of hepatocytes into the cell cycle (S phase) and diminished mitot ic activity, as demonstrated, respectively, by the absence of 5-bromo-2' -d eoxyuridine incorporation in hepatocytes, and the rare occurrence of mitose s in the liver parenchyma, Reconstitution of CS-deficient mice with murine C5 or C5a significantly restored hepatocyte regeneration after toxic injury . Furthermore, blockade of the C5a receptor (C5R) abrogated the ability of hepatocytes to proliferate in response to liver injury, providing a mechani sm by which C5 exerts its function, and establishing a critical role for C5 aR signaling in the early events leading to hepatocyte proliferation. These results support a novel role for C5 in liver regeneration and strongly imp licate the complement system as an important immunoregulatory component of hepatic homeostasis.