C1-inhibitor polymers activate the FXII-dependent kallikrein–kinin system: Implication for a role in hereditary angioedema

• Published in: Biochimica et biophysica acta 2015-06, Vol.1850 (6), p.1336-1342
• Main Authors: Madsen, Daniel Elenius, Sidelmann, Johannes Jakobsen, Biltoft, Daniel, Gram, Jørgen, Hansen, Soren
• Format: Article
• Language: English
• Subjects: Angioedemas, Hereditary - blood; Angioedemas, Hereditary - enzymology; Angioedemas, Hereditary - genetics; Angioedemas, Hereditary - physiopathology; Blotting, Western; Case-Control Studies; Coagulation factor XII; Complement C1 esterase inhibitor; Complement C1 Inactivator Proteins - genetics; Complement C1 Inactivator Proteins - metabolism; Complement C1 Inhibitor Protein; Denmark; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Factor XIIa - metabolism; Genetic Predisposition to Disease; Hereditary angioedema; Humans; Kallikrein-kinin system; Kallikreins - blood; Kinetics; Kinins - blood; Mutation; Native Polyacrylamide Gel Electrophoresis; Phenotype; Polymerization; Serpinopathy
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2015.03.005

The FXII-dependent kallikrein–kinin system (KKS) is tightly regulated by the serine protease inhibitor (serpin) C1-inhibitor (C1-inh). When regulation of the FXII-dependent KKS fails, which is the case in hereditary angioedema (HAE), patients consequently experience invalidating edema attacks. HAE is caused by mutations in the C1-inh encoding gene, and we recently demonstrated that some mutations give rise to the presence of polymerized C1-inh in the plasma of HAE patients. C1-inh polymers corresponding to the size of polymers observed in vivo were produced using heat denaturation and gel filtration. The ability of these polymers to facilitate FXII activation was assessed in vitro in an FXII activation bandshift assay. After spiking of plasma with C1-inh polymers, kallikrein generation was analyzed in a global kallikrein generation method. Prekallikrein consumption in the entire Danish HAE cohort was analyzed using an ELISA method. C1-inh polymers mediated FXII activation, and a dose dependent kallikrein generation in plasma spiked with C1-inh polymers. An increased (pre)kallikrein consumption was observed in plasma samples from HAE patients presenting with C1-inh polymers in vivo. Polymerization of the C1-inh transforms the major inhibitor of the FXII-dependent KKS, into a potent activator of the very same system. The C1-inh polymers might play a role in the pathophysiology of HAE, but several diseases are characterized by the presence of serpin polymers. The role of serpin polymers has so far remained elusive, but our results indicate that such polymers can play a role as inflammatory mediators through the FXII-dependent KKS. •C1-inh polymers mediate FXII dependent activation of the kallikrein–kinin system.•Upon polymerization the C1-inh loses its inhibitory capacity.•HAE patients with C1-inh polymers show increased (pre)kallikrein consumption.