Evidence for non-traditional activation of complement factor C3 during murine liver regeneration

Area of Science:

• Immunology
• Hepatology
• Complement System Biology

Background:

• Complement signaling plays a role in hepatic regeneration.
• The precise mechanisms of complement activation during liver regeneration are not fully understood.

Purpose of the Study:

• To investigate the role of complement activation pathways in hepatic regeneration following partial hepatectomy.
• To identify potential non-traditional mechanisms of C3 activation during liver regeneration.

Main Methods:

• Partial hepatectomy was performed on wildtype mice, C3-null, C4-null, and factor B-null mice.
• C4-null mice were treated with a factor B neutralizing antibody (mAb 1379).
• Hepatic regeneration was assessed by measuring cyclin D1 expression, DNA synthesis, and mitosis.
• In vitro assays investigated the ability of plasmin and thrombin to activate C3 in mouse plasma.

Main Results:

• C3-null mice showed impaired hepatic regeneration compared to wildtype mice.
• C4-null and factor B-null mice exhibited normal liver regeneration.
• Mice with disrupted classical and alternative pathways (C4-null treated with mAb 1379) also showed normal regeneration.
• In vitro, both plasmin and thrombin activated C3, with plasmin acting independently of classical and alternative pathways.

Conclusions:

• C3 is essential for normal hepatic regeneration.
• Classical, lectin, and alternative complement pathways are not required for hepatic regeneration.
• Non-traditional mechanisms likely mediate C3 activation during liver regeneration.
• Plasmin is a potential contributor to non-traditional complement activation in vivo during liver regeneration.