Premium
High‐molecular‐weight kininogen and its cleavage product bradykinin are critical in the pathogenesis of autoantibody‐induced arthritis
Author(s) -
Wu Yi
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb450
Subject(s) - kininogen , arthritis , endocrinology , pathogenesis , medicine , autoantibody , bradykinin , chemistry , rheumatoid arthritis , high molecular weight kininogen , type ii collagen , proinflammatory cytokine , kallikrein , immunology , inflammation , receptor , antibody , biochemistry , enzyme
High‐molecular‐weight kininogen (HK) is a major component of plasma kallikrein‐kinin system (KKS), the activation of which mediates the cleavage of HK to release bradykinin (BK). BK is a nonapeptide with potent proinflammatory and vasoactive activities. Although patients with rheumatoid arthritis (RA) exhibits the activation of the KKS and the cleavage of HK in plasma, the role of HK in arthritis pathogenesis has never been characterized. In this study we characterized the phenotype of our newly‐generated HK‐deficient (Kng1 −/− ) mice in arthritis. To induce autoantibody‐induced arthritis, two groups of Kng1 +/+ and Kng1 −/− mice were injected intraperitoneally with anti‐type II collagen antibody cocktail (4 mg) on day 0 and lipopolysaccharide (LPS, 50 μg) on day 3. Although wild‐type (WT) mice developed severe arthritis, the Kng1 −/− mice exhibited significantly attenuated disease severity as evaluated by joint diameter change and clinical scores (p<0.0001). Compared with WT mice, Kng1 −/− mice displayed reduced synovial hyperplasia and cartilage erosions, and decreased protein and mRNA levels of IL‐1b and IL‐6 in joint tissue (p<0.001). BK level and kallikrein activity in Kng1 −/− plasma were significantly lower than that of WT mice. Incubation with Collagen‐anti‐collagen complex mediated BK production in human plasma. In consistence with the phenotype of Kng1 −/− mice, the mice lacking BK receptors also displayed a reduced arthritis severity, as well as a decrease in IL‐1b and IL‐6 production in joint tissue. Our results the first genetic evidence demonstrating an important role of plasma HK in the pathogenesis of arthritis, and the blockade of HK cleavage to prevent BK production might be a novel therapeutic strategy for RA treatment.