C3a and C3b Activation Products of the Third Component of Complement (C3) Are Critical for Normal Liver Recovery after Toxic Injury

Markiewski, Maciej M.; Mastellos, Dimitrios C.; Tudoran, Ruxandra; DeAngelis, Robert A.; Strey, Christoph W.; Franchini, Silvia; Wetsel, Rick A.; Erdei, Anna

doi:10.4049/jimmunol.173.2.747

Cited by 161 publications

(147 citation statements)

References 46 publications

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“…31 Studies have shown that C3a and C5a are capable of priming hepatocytes for regeneration, which is mediated by C3a and C5a binding to the C3aR and C5aR on Kupfer cells, a role distinct from the usual inflammatory role ascribed to C3a and C5a. 33,34 The result is consistent with the interpretation that there is more local C5a generation in the liver in the proCPB Ϫ/Ϫ mice in the peritonitis model, thus leading to enhanced liver regeneration and reduced liver necrosis.…”

Section: Discussionsupporting

confidence: 80%

Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo

Nishimura

Myles

Piliposky

et al. 2006

Blood

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Plasma procarboxypeptidase B (proCPB)is activated by the endothelial thrombinprothrombomodulin complex. Activated (CPB) functions as a fibrinolysis inhibitor, but it may play a broader role by inactivating inflammatory mediators. To test this hypothesis, C5a-induced alveolitis was studied in wild-type (WT) and proCPBdeficient mice (proCPB ؊/؊ ). C5a-induced alveolitis, as measured by cell counts and total protein contents in bronchoalveolar lavage fluids, was markedly enhanced in the proCPB ؊/؊ mice. E229K thrombin, a thrombin mutant with minimal clotting activity but retaining its ability to activate protein C and proCPB, attenuated C5a-induced alveolitis in WT but not in proCPB ؊/؊ mice, indicating that its beneficial effect is mediated primarily by its activation of proCPB. Lung tissue histology confirmed these cellular inflammatory responses. Delayed administration of E229K thrombin after the C5a instillation was ineffective in reducing alveolitis in WT mice, suggesting that the beneficial effect of E229K thrombin is due to the direct inhibition of C5a by CPB. Our studies show that thrombin-activatable proCPB, in addition to its role in fibrinolysis, has intrinsic anti-inflammatory functions. Its activation, along with protein C, by the endothelial thrombin-TM complex represents a homeostatic response to counteract the inflammatory mediators generated at the site of vascular injury. IntroductionThe complement system is part of the innate immune system and plays a major role in the host defense against pyrogenic bacterial infection. 1,2 It is also involved in a wide variety of acute and chronic inflammatory disorders, including sepsis, acute respiratory distress syndrome, rheumatoid arthritis, and glomerulonephritis. The complement system consists of multiple proteins in plasma and on cell surfaces and can be activated by 3 distinct pathways, all converging on the cleavage of C3 into C3a and C3b. C3b in turn becomes an essential component of the C5 convertase enzyme complex, leading to cleavage of C5 into C5a and C5b. Both C3a and C5a are strong chemoattractants. 1,2 They cause oxidative burst and enhance phagocytosis and granule enzyme release in neutrophils. They are vasodilators at sites of inflammation. C3a and C5a exert their effects through binding to cellular C3a receptors (C3aR) and C5a receptors (C5aR), respectively. C5aR are found on circulating myeloid cells, including neutrophils, monocytes, eosinophils, and basophils, as well as nonmyeloid cells in many organs, especially in the lung and the liver. 2-4 Widespread up-regulation of the C5aR occurs during sepsis, and mice deficient in C5aR succumbed to bacterial pneumonias in animal models, indicating that C5a/ C5aR signaling is essential in host defenses in the lung and other organs. 5,6 Both C3a and C5a are inhibited by carboxypeptidase N (CPN), a constitutively active plasma carboxypeptidase.Thrombin-activatable procarboxypeptidase B (proCPB), also known as procarboxypeptidase U, procarboxypeptidase R, and thrombin-activatable fibrinolysis inhib...

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Section: Discussionsupporting

confidence: 80%

Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo

Nishimura

Myles

Piliposky

et al. 2006

Blood

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“…Taken together, the data reported here indicate that despite the established requirement for complement factors C3 and C5 during the hepatic regenerative response (Mastellos et al 2001;Strey et al 2003;Markiewski et al 2004), none of the traditional upstream complement activation pathways are absolutely necessary for normal liver regeneration. The most straightforward interpretation of these data is that proteolytic C3 activation during liver regeneration may occur via non-traditional mechanisms.…”

Section: Discussionmentioning

confidence: 65%

“…The results showed that hepatocellular proliferation 36 hours after partial hepatectomy, the time corresponding to peak proliferation in wildtype mice, is comparable in wildtype untreated-, wildtype mAb 1379-treated-, and C4 null mAb 1379-treated mice ( Figure 4A), indicating that disruption of all of the traditional upstream activation pathways of complement signaling does not prevent normal liver regeneration. Taken together with the observation that complement factor C3 is required for normal liver regeneration (Mastellos et Markiewski et al 2004), these data raise the possibility that C3 is activated independently of the classical-, lectindependent-, and alternative-pathways during the hepatic regenerative response. To test this possibility, C3 activation during liver regeneration was quantified in wildtype and mAb 1379-treated C4 null mice subjected to partial hepatectomy by protein immunoblot analysis of mouse plasma for the proteolytic fragment corresponding to activated C3α (Miwa et al 2007).…”

Section: Liver Regeneration and C3 Activation Occur Normally In C4-numentioning

confidence: 88%

“…This link was established by studies demonstrating that liver regeneration is impaired in complement factor C3-null mice, and that such impairment is rescued by exogenous C3 or C3a supplementation (Strey et al 2003; Markiewski et al 2004). Similarly, complement factor C5-deficient mice exhibit abnormal hepatic regeneration which can be rescued by supplementation with exogenous C5 or C5a (Mastellos et al 2001; Strey et al 2003).…”

Section: Introductionmentioning

confidence: 99%

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

Clark

Weymann

Hartman

et al. 2008

Molecular Immunology

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Complement signaling has been implicated as important for normal hepatic regeneration. However, the specific mechanism by which complement is activated during liver regeneration remains undefined. To address this question, we investigated the hepatic regenerative response to partial hepatectomy in wildtype mice, C3-, C4-, and factor B-null mice, and C4-null mice treated with a factor B neutralizing antibody (mAb 1379). The results showed that following partial hepatectomy, C3-null mice exhibit reduced hepatic regeneration compared to wildtype mice as assessed by quantification of hepatic cyclin D1 expression and hepatocellular DNA synthesis and mitosis. In contrast, C4-null mice and factor B-null mice demonstrated normal liver regeneration. Moreover, animals in which all of the traditional upstream C3 activation pathways were disrupted, i.e. C4-null mice treated with mAb 1379, exhibited normal C3 activation and hepatocellular proliferation following partial hepatectomy. In order to define candidate non-traditional mechanisms of C3 activation during liver regeneration, plasmin and thrombin were investigated for their abilities to activate C3 in mouse plasma in vitro. The results showed that both proteases are capable of initiating C3 activation, and that plasmin can do so independent of the classical and alternative pathways.Conclusions-These results show that C3 is required for a normal hepatic regenerative response, but that disruption of the classical-or lectin-dependent pathways (C4-dependent), the alternative pathway (factor B-dependent), or all of these pathways does not impair the hepatic regenerative response, and indicate that non-traditional mechanisms by which C3 is activated during hepatic regeneration must exist. In vitro analysis raises the possibility that plasmin may contribute to nontraditional complement activation during liver regeneration in vivo.

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“…18 Extract Preparation. Nuclear and whole-cell protein extracts from the liver were prepared in the presence of protease and phosphatase inhibitors as previously described.…”

Section: Methodsmentioning

confidence: 99%

A High-Fat Diet Impairs Liver Regeneration in C57BL/6 Mice Through Overexpression of the NF-κB Inhibitor, IκBα * #

et al. 2005

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Despite the growing incidence of obesity, knowledge of how this condition, as well as associated steatosis, affects liver regeneration remains scarce. Many previous studies have used models of steatohepatitis or obesity induced by genetic alterations. In contrast, our studies on liver regeneration have focused on the effects of obesity resulting solely from high amounts of fat in the diet. This model more closely reflects the detrimental effects of dietary habits responsible for increased morbidity due to obesity and its complications in welldeveloped Western societies. Impairment of liver regeneration was observed after partial hepatectomy in mice fed a high-fat diet. Fatty livers were more susceptible to posthepatectomy damage and failure. The underlying molecular mechanism was associated with increased inhibitor of nuclear factor-kappa B alpha (I B␣) expression, which inhibited nuclear factor-kappa B (NF-B) activation and induction of its target genes, cyclin D1 and Bcl-xL, increasing sensitivity to apoptosis initiated by elevated tumor necrosis factor-alpha. In addition, since mice fed with a high-fat diet have higher leptin levels caused by increased adiposity, our work supports the hypothesis that the impairment of regeneration previously seen in genetically obese mice indeed results from liver steatosis rather than the disruption of leptin signaling. In conclusion, high fat in the diet impairs liver regeneration and predisposes steatotic livers to increased injury through I B␣ overexpression and subsequent NF-B inhibition.

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C3a and C3b Activation Products of the Third Component of Complement (C3) Are Critical for Normal Liver Recovery after Toxic Injury

Cited by 161 publications

References 46 publications

Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo

Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo

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

A High-Fat Diet Impairs Liver Regeneration in C57BL/6 Mice Through Overexpression of the NF-κB Inhibitor, IκBα * #

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