Carboxypeptidase B2 and N play different roles in regulation of activated complements C3a and C5a in mice.

Essentials Two basic carboxypeptidases are present in plasma, B2 (CPB2) and N (CPN). Cpb2 ^-/- and Cpn ^-/- mice were challenged in a hemolytic uremic syndrome (HUS) model vs. wild type. Cpb2 ^-/- exacerbates HUS while Cpn ^-/- exacerbates cobra venom factor challenge vs. wild type mice. CPB2 and CPN have overlapping but non-redundant roles.
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.
(© 2018 International Society on Thrombosis and Haemostasis.)