A novel role of complement: Mice deficient in the fifth component of complement (C5) exhibit impaired liver regeneration
A novel role of complement: Mice deficient in the fifth component of complement (C5) exhibit impaired liver regeneration
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DOI：
10.4049/jimmunol.166.4.2479
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发表时间：
2001-02-15
影响因子：
4.4
通讯作者：
Lambris, JD
中科院分区：
文献类型：
--
作者：
Mastellos, D;Papadimitriou, JC;Lambris, JD
先天免疫的组成部分最近被认为与发育过程的调节有关，最引人注目的是，补体因子似乎与某些狐猴物种的肢体再生有关。根据这些观察结果，并预测补体在哺乳动物再生中的保守作用，我们现在研究了补体成分C5在肝脏再生中的作用，使用CCl4诱导的肝毒性小鼠模型和C5基因缺陷小鼠，cs缺陷小鼠在暴露于CCl4后表现出严重的肝脏再生缺陷和持续的实质坏死。此外，这些小鼠表现出肝细胞重新进入细胞周期（S期）的明显延迟和有丝分裂活性降低，分别通过肝细胞中没有5-溴-2' -脱氧尿苷掺入和肝实质中很少发生有丝分裂来证明，用小鼠C5或C5a重建cs缺陷小鼠可显着恢复毒性损伤后的肝细胞再生。此外，阻断C5a受体（C5R）可降低肝细胞对肝损伤的增殖能力，提供了C5发挥其功能的机制，并确立了C5aR信号在导致肝细胞增殖的早期事件中的关键作用。这些结果支持C5在肝脏再生中的新作用，并强烈暗示补体系统是肝脏稳态的重要免疫调节成分。
Components of innate immunity have recently been implicated in the regulation of developmental processes, Most strikingly, complement factors appear to be involved in limb regeneration in certain urodele species. Prompted by these observations and anticipating a conserved role of complement in mammalian regeneration, we have now investigated the involvement of complement component C5 in liver regeneration, using a murine model of CCl4-induced liver toxicity and mice genetically deficient in C5, CS-deficient mice showed severely defective liver regeneration and persistent parenchymal necrosis after 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 mitotic activity, as demonstrated, respectively, by the absence of 5-bromo-2' -deoxyuridine incorporation in hepatocytes, and the rare occurrence of mitoses 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 mechanism by which C5 exerts its function, and establishing a critical role for C5aR signaling in the early events leading to hepatocyte proliferation. These results support a novel role for C5 in liver regeneration and strongly implicate the complement system as an important immunoregulatory component of hepatic homeostasis.