Summary
Background
There are two basic carboxypeptidases in plasma. Carboxypeptidase B2 (CPB2) is activated from a circulating zymogen, proCPB2, and carboxypeptidase N (CPN) is constitutively active with both inactivating complement C3a and C5a.
Aims
To test the roles of CPB2 and CPN in complement‐driven mouse models of cobra venom factor (CVF) challenge and hemolytic‐uremic syndrome (HUS).
Methods
Cpb2−/−, Cpn−/− and wild‐type (WT) mice were compared in an HUS model induced by Shiga toxin and lipopolysaccharide administration and following CVF administration.
Results
HUS was exacerbated in Cpb2−/− mice more than in Cpn−/− mice, compared with WT mice. Cpb2−/− mice developed the HUS clinical triad of microangiopathic hemolytic anemia, uremia and thrombocytopenia. Treatment with anti‐C5 antibody improved survival of both Cpb2−/− and Cpn−/− mice. In contrast, when challenged acutely with CVF, the reverse phenotype was observed. Cpn−/− mice had markedly worse disease than Cpb2−/− mice, whereas the WT mice were resistant.
Conclusions
CPN and CPB2 play overlapping but non‐redundant roles in regulating complement activation in vivo. The constitutively active CPN is key for inactivation of systemic C5a, whereas CPB2 functions as an on‐demand supplementary anaphylatoxin inhibitor in inactivating excessive C5a formed locally.