A complement-dependent balance between hepatic ischemia/reperfusion injury and liver regeneration in mice.
Massive liver resection and small-for-size liver transplantation pose a therapeutic challenge, due to increased susceptibility of the remnant/graft to ischemia reperfusion injury (IRI) and impaired regeneration. We investigated the dual role of complement in IRI versus regeneration in mice. Complement component 3 (C3) deficiency and complement inhibition with complement receptor 2-complement receptor 1-related protein y (CR2-Crry, an inhibitor of C3 activation) provided protection from hepatic IRI, and while C3 deficiency also impaired liver regeneration following partial hepatectomy (PHx), the effect of CR2-Crry in this context was dose dependent. In a combined model of IRI and PHx, either C3 deficiency or high-dose CR2-Crry resulted in steatosis, severe hepatic injury, and high mortality, whereas low-dose CR2-Crry was protective and actually increased hepatic proliferative responses relative to control mice. Reconstitution experiments revealed an important role for the C3a degradation product acylation-stimulating protein (ASP) in the balance between inflammation/injury versus regeneration. Furthermore, liver regeneration was dependent on the putative ASP receptor, C5L2. Several potential mechanisms of hepatoprotection and recovery were identified in mice treated with low-dose CR2-Crry, including enhanced IL-6 expression and STAT3 activation, reduced hepatic ATP depletion, and attenuated oxidative stress. These data indicate that a threshold of complement activation, involving ASP and C5L2, promotes liver regeneration and suggest a balance between complement-dependent injury and regeneration.
He
Songqing
S
Department of Microbiology and Immunology, Darby Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Atkinson
Carl
C
Qiao
Fei
F
Cianflone
Katherine
K
Chen
Xiaoping
X
Tomlinson
Stephen
S
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D003176:Complement C3 / Q000502:physiology*; D006498:Hepatectomy; D006801:Humans; D015850:Interleukin-6 / Q000502:physiology; D008099:Liver / Q000098:blood supply*; D008115:Liver Regeneration; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D015427:Reperfusion Injury / Q000209:etiology*; D050796:STAT3 Transcription Factor / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
C527099:CR2-Crry fusion protein, mouse; D003176:Complement C3; D015850:Interleukin-6; D011993:Recombinant Fusion Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000410:Alanine Transaminase