The proinflammatory mediators C3a and C5a are essential for liver regeneration
Open accessAbstract
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.
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Complement molecules C3a and C5a activate canonical JAK-STAT3 signaling via cytokine intermediates in models of retinal and liver regeneration.
“The complement molecules C3a and C5a have been shown to activate the canonical JAK-STAT3 signaling via cytokine intermediates in models of retinal and liver regeneration (Haynes et al., 2013; He et al., 2009; Strey et al., 2003).”
From Complement C3aR Inactivation Attenuates Tau Pathology and Reverses an Immune Network Deregulated in Tauopathy Models and Alzheimer’s Disease (2018) · cites this paper as Strey et al., 2003
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- Authors
- Strey, C. W., Markiewski, M., Mastellos, D., Tudoran, R., Spruce, L. A., Greenbaum, L. E., & Lambris, J. D.
- Affiliations
- University of Pennsylvania (US)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2003-09-15
- Volume
- 198
- Issue
- 6
- Pages
- 913-923
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2194207
- OpenAlex
- W2167870644
- Cited by
- 436
- References
- 49
- Citations by year
- 2026: 12 · 2025: 13 · 2024: 10 · 2023: 12 · 2022: 17 · 2021: 13 · 2020: 15 · 2019: 14 · 2018: 14 · 2017: 22 · 2016: 22 · 2015: 21 · 2014: 28 · 2013: 28 · 2012: 18
- FWCI
- 13.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01gm056698-04)
- National Institute of General Medical Sciences (GM-62134, GM 56698, R01GM062134)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 59422, R01DK059422)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- complement system, C3a, C5a, liver regeneration, partial hepatectomy, hepatocyte proliferation, C3 deficiency, C5 deficiency, interleukin-6, TNF-α, NF-κB, STAT3, innate immunity, inflammatory mediators
- MeSH terms
- Animals, Cell Cycle, DNA-Binding Proteins, Hepatectomy, Liver, Liver Regeneration, Mice, Inbred C57BL, Receptors, Complement, Tumor Necrosis Factor-alpha, Signal Transduction, Trans-Activators, Antigens, CD, Interleukin-6, Complement C3a, Complement C5a, Macrophage-1 Antigen, NF-kappa B, Mice, Knockout, Hepatocytes, Receptor, Anaphylatoxin C5a, STAT3 Transcription Factor, Mice
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