Carboxypeptidase B2 deficiency reveals opposite effects of complement C3a and C5a in a murine polymicrobial sepsis model.
BACKGROUND AND OBJECTIVES
Carboxypeptidase B2 (CPB2) is a basic carboxypeptidase with fibrin and complement C3a and C5a as physiological substrates. We hypothesized that in polymicrobial sepsis, CPB2-deficient mice would have sustained C5a activity, leading to disease exacerbation.


METHODS
Polymicrobial sepsis was induced by cecal ligation and puncture (CLP).


RESULTS
Contrary to our hypothesis, Cpb2(-/-) mice had significantly improved survival, with reduced lung edema, less liver and kidney damage, and less disseminated intravascular coagulation. Hepatic pro-CPB2 was induced by CLP, leading to increased pro-CPB2 levels. Thrombomodulin present on mesothelium supported thrombin activation of pro-CPB2. Both wild-type and Cpb2(-/-) animals treated with a C5a receptor antagonist had improved survival, demonstrating that C5a was detrimental in this model. Treatment with a fibrinolysis inhibitor, tranexamic acid, caused a decrease in survival in both genotypes; however, the Cpb2(-/-) animals retained their survival advantage. Administration of a C3a receptor antagonist exacerbated the disease in both wild-type and Cpb2(-/-) mice and eliminated the survival advantage of Cpb2(-/-) mice. C5a receptor is expressed in both peritoneal macrophages and neutrophils; in contrast, C3a receptor expression is restricted to peritoneal macrophages, and C3a induced signaling in macrophages but not neutrophils.


CONCLUSIONS
While C5a exacerbates the peritonitis, resulting in a deleterious generalized inflammatory state, C3a activation of peritoneal macrophages may limit the initial infection following CLP, thereby playing a diametrically opposing protective role in this polymicrobial sepsis model.
['Shao|Z|Z|', 'Nishimura|T|T|', 'Leung|L L K|LL|', 'Morser|J|J|']
D000818:Animals D000933:Antifibrinolytic Agents D001778:Blood Coagulation Disorders D025901:Carboxypeptidase B2 D002432:Cecum D002478:Cells, Cultured D015926:Complement C3a D015936:Complement C5a D004195:Disease Models, Animal D004789:Enzyme Activation D005337:Fibrin D018836:Inflammation Mediators D007970:Leukopenia D008026:Ligation D008099:Liver D008262:Macrophage Activation D017737:Macrophages, Peritoneal D008297:Male D008810:Mice, Inbred C57BL D018345:Mice, Knockout D010538:Peritonitis D065840:Protective Factors D011677:Punctures D012307:Risk Factors D018805:Sepsis D013917:Thrombin D018180:Thrombomodulin D013997:Time Factors
carboxypeptidase B2 sepsis fibrinolysis anaphylatoxin inflammation