The proinflammatory mediators C3a and C5a are essential for liver regeneration.
Complement has been implicated in liver repair after toxic injury. Here, we demonstrate that complement components are essential for liver regeneration, and mediate their effect by interacting with key signaling networks that promote hepatocyte proliferation. C3- or C5-deficient mice exhibited high mortality, parenchymal damage, and impaired liver regeneration after partial hepatectomy. Mice with dual C3 and C5 deficiency had a more exacerbated phenotype that was reversed by combined C3a and C5a reconstitution. Interception of C5a receptor signaling resulted in suppression of IL-6/TNFalpha induction and lack of C3 and C5a receptor stimulation attenuated nuclear factor-kappaB/STAT-3 activation after hepatectomy. These data indicate that C3a and C5a, two potent inflammatory mediators of the innate immune response, contribute essentially to the early priming stages of hepatocyte regeneration.
Strey
Christoph W
CW
Protein Chemistry Laboratory, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Markiewski
Maciej
M
Mastellos
Dimitrios
D
Tudoran
Ruxandra
R
Spruce
Lynn A
LA
Greenbaum
Linda E
LE
Lambris
John D
JD
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology; D015926:Complement C3a / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015936:Complement C5a / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D006498:Hepatectomy; D022781:Hepatocytes / Q000502:physiology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008115:Liver Regeneration / Q000502:physiology*; D016177:Macrophage-1 Antigen / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D016177:Macrophage-1 Antigen; D016328:NF-kappa B; D044087:Receptor, Anaphylatoxin C5a; D011951:Receptors, Complement; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D015926:Complement C3a; D015936:Complement C5a