An essential role of high-molecular-weight kininogen in endotoxemia

• Published in: The Journal of experimental medicine Vol. 214; no. 9; pp. 2649 - 2670
• Main Authors: Yang, Aizhen, Xie, Zhanli, Wang, Bo, Colman, Robert W, Dai, Jihong, Wu, Yi
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 04.09.2017; The Rockefeller University Press
• Subjects: Binding sites; Bradykinin; Chains; E coli; Endotoxemia; Kininogens; Lipopolysaccharides; Mice; Monoclonal antibodies; Mortality; Replenishment; Rodents; Sepsis
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.20161900

In this study, we show that mice lacking high-molecular-weight kininogen (HK) were resistant to lipopolysaccharide (LPS)-induced mortality and had significantly reduced circulating LPS levels. Replenishment of HK-deficient mice with human HK recovered the LPS levels and rendered the mice susceptible to LPS-induced mortality. Binding of HK to LPS occurred through the O-polysaccharide/core oligosaccharide, consistent with the ability to bind LPS from , , , and different strains. Binding of LPS induced plasma HK cleavage to the two-chain form (HKa, containing a heavy chain [HC] and a light chain [LC]) and bradykinin. Both HKa and the LC, but not the HC, could disaggregate LPS. The light chain bound LPS with high affinity ( = 1.52 × 10 M) through a binding site in domain 5 (DHG15). A monoclonal antibody against D5 significantly reduced LPS-induced mortality and circulating LPS levels in wild-type mice. Thus, HK, as a major LPS carrier in circulation, plays an essential role in endotoxemia.