Deficiencies of carboxypeptidase N and carboxypeptidase B2 have opposite effects in a virulent mouse E. coli sepsis model.

BACKGROUND

Two basic carboxypeptidases circulate in plasma, procarboxypeptidase B2, which is activated to carboxypeptidase B2 (CPB2), and carboxypeptidase N (CPN). These enzymes inactivate complement anaphylatoxins, C3a and C5a, with high C5a being toxic.

OBJECTIVES

To test the hypothesis that these carboxypeptidases would affect Escherichia coli sepsis in mice differently because CPN is constitutively active while procarboxypeptidase B2 beeds to be locally activated.

METHODS

Mice deficient in CPB2, CPN, or both enzymes were infected with E. coli and their health and survival was compared to wild-type mice. Clinical chemistry, complete blood count, and bacterial load were assessed.

RESULTS

Lack of CPB2 prolonged survival while lack of CPN shortened survival compared to wild-type mice. Liver damage was higher in double deficient mice that were also thrombocytopenic, and CPN-deficient mice were leukopenic. Bacterial load was higher in CPB2 and double deficient mice and lower in CPN-deficient mice.

CONCLUSION

CPN provides first-line protection against excessive C3a and C5a, accounting for the shortened survival in CPN-deficient mice in this sepsis model, despite reduced E. coli load. CPB2 serves a supportive role by primarily inactivating C3a locally. Apparently, CPB2 deficiency led to enhanced local levels of protective C3a and prolonged survival in the CPB2-deficient mice in this model, while the lack of CPN exacerbated the infection.