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

Yang, Aimei; Xie, Zhanli; Wang, Bo; Colman, Robert W.; Dai, Jihong; Yu, Wu

doi:10.1084/jem.20161900

Cited by 30 publications

(22 citation statements)

References 62 publications

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“…Mice lacking HK ( Kng1 −/− ) were generated in our previous studies ( 22 ). Double knockout mice lacking both bradykinin receptors ( B1RB2R −/− ) were purchased from the Jackson Laboratory (Bar Harbor, ME, USA).…”

Section: Methodsmentioning

confidence: 99%

The Plasma Kallikrein–Kininogen Pathway Is Critical in the Pathogenesis of Colitis in Mice

et al. 2018

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The kallikrein–kinin system (KKS) consists of two serine proteases, prekallikrein (pKal) and factor XII (FXII), and a cofactor, high-molecular-weight kininogen (HK). Upon activation of the KKS, HK is cleaved to release bradykinin. Although the KKS is activated in humans and animals with inflammatory bowel disease (IBD), its role in the pathogenesis of IBD has not been characterized. In the present study, we determined the role of the KKS in the pathogenesis of IBD using mice that lack proteins involved in the KKS. In two colitis models, induced by dextran sulfate sodium (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS), mice deficient in HK, pKal, or bradykinin receptors displayed attenuated phenotypes, including body weight loss, disease activity index, colon length shortening, histological scoring, and colonic production of cytokines. Infiltration of neutrophils and inflammatory monocytes in the colonic lamina propria was reduced in HK-deficient mice. Reconstitution of HK-deficient mice through intravenous injection of HK recovered their susceptibility to DSS-induced colitis, increased IL-1β levels in the colon tissue and bradykinin concentrations in plasma. In contrast to the phenotypes of other mice lacking other proteins involved in the KKS, mice lacking FXII had comparable colonic inflammation to that observed in wild-type mice. The concentration of bradykinin was significantly increased in the plasma of wild-type mice after DSS-induced colitis. In vitro analysis revealed that DSS-induced pKal activation, HK cleavage, and bradykinin plasma release were prevented by the absence of pKal or the inhibition of Kal. Unlike DSS, TNBS-induced colitis did not trigger HK cleavage. Collectively, our data strongly suggest that Kal, acting independently of FXII, contributes to experimental colitis by promoting bradykinin release from HK.

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Section: Methodsmentioning

confidence: 99%

The Plasma Kallikrein–Kininogen Pathway Is Critical in the Pathogenesis of Colitis in Mice

et al. 2018

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“…When human congenital FXI-deficient plasma was used, addition of Pep19-2.5 prevented HK degradation nearly complete over Binding of Pep19-2.5 to LPS prevents binding to HK. It has been recently shown that HK is an important LPS carrier and binding of LPS to HK triggers the inflammatory response 5 . Thus, blocking LPS binding to HK with Pep19-2.5 might be a promising strategy to prevent systemic inflammatory reactions.…”

Section: Pep19-25 Prevents Degradation Of Hk In Plasmamentioning

confidence: 99%

The synthetic LPS binding peptide 19-2.5 interferes with clotting and prevents degradation of high molecular weight kininogen in plasma

Köhler

Ehler

Kreikemeyer

et al. 2020

Sci Rep

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Sepsis and septic shock are life-threatening conditions and remain an important medical problem, emphasizing the need to identify novel therapeutic approaches. Coagulation dysfunction, hypotension, disturbed microcirculation and multiorgan failure occur frequently. These severe conditions result from an overwhelming inflammatory response, induced by pathogen and damage associated molecular patterns (PAMPs and DAMPs) released into the bloodstream. In the present study, we demonstrated that the synthetic Lipopolysaccharid (LPS)-binding peptide 19-2.5 interferes with the activation of the coagulation and contact system. Moreover, binding of LPS to high molecular weight kininogen (HK), one of the major LPS carrier in blood, could be prevented by the peptide. Thus, peptide 19-2.5 might represent a promising target in the treatment of endotoxemia and sepsis, not only by its antiinflammatory potential, but also by the anticoagulant effect, together with its ability to prevent degradation of HK.Sepsis and septic shock are complications of bacterial infections that are associated with high mortality rates, despite the availability of antibiotics and improved intensive care. Complications from these life-threatening infections often arise when the initial appropriate host response to the invading pathogen is excessively amplified and progressively uncontrolled. A systemic activation of proteolytic host cascades, such as the coagulation and contact systems, together with a massive release of proinflammatory cytokines, can be deleterious for the host 1 .The majority of sepsis complications is caused by a disproportionate immune response to bacterial products, mainly lipopolysaccharide (LPS) in case of Gram-negative bacteria. LPS is localized in the outer layer of the membrane and is exposed on the bacterial surface. LPS contributes to the integrity of the outer membrane and protects the bacterium against the action of bile salts and lipophilic antibiotics. In sepsis, LPS can be released continuously due to cell growth and division, but also due to killed bacteria after an antibiotic treatment 2 .Free LPS is one of the most potent immune-stimulatory molecules, it can provoke a vigorous systemic inflammatory response and even minute doses may have lethal consequences for the host 3 . The response of host immune cells to LPS is initiated by its interaction with plasma proteins such as LPS-binding protein (LBP) and the specific receptor binding protein CD14 (soluble or membrane-bound), which finally leads to cell activation through the Toll-like receptor 4 (TLR4) 4 . Additionally, the plasma protein high molecular weight kininogen (HK) has been recently described to bind LPS and trigger inflammatory reactions. This might play a critical role for the LPS induced inflammatory response, as mice lacking HK, were resistant to LPS-induced mortality 5 . HK is mainly a cofactor of the human contact system, which consists of the serine proteases factor XI (FXI), factor XII (FXII), and plasma kallikrein (PK). HK circulates in a complex wi...

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“…In an exciting paper, Yang and colleagues provide new insights into the role of the contact system in mouse models of endotoxemia . They show with compelling data, that HK is a major contributor to LPS‐induced lethality.…”

Section: Hk As Playmaker In Lethal Endotoxemiamentioning

confidence: 99%

High‐molecular‐weight kininogen: breaking bad in lethal endotoxemia

Hofman

Maat

Maas

2018

Journal of Thrombosis and Haemostasis

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To cite this article: Hofman ZLM, De Maat S, Maas C. High-molecular-weight kininogen: breaking bad in lethal endotoxemia. J Thromb Haemost 2018; 16: 193-5. Kinin formation is a powerful inflammatory process. In the intravascular compartment, bradykinin (RPPGFSPFR) is uniquely released from high-molecular-weight kininogen (HK) after activation of the plasma contact system (reviewed in [1]) and acts on its cognate kinin B2 receptor (B2R), which is constitutively expressed on endothelial cells. The action of carboxypeptidase N (which removes C-terminal arginines) converts bradykinin into des-Arg 9 -bradykinin. Active thrombin-activatable fibrinolysis inhibitor may exert a similar role during blood coagulation and bacterial infection. Des-Arg 9 -bradykinin is a potent agonist of kinin B1 receptor (B1R), which is expressed by endothelial cells and extravasated leukocytes at sites of inflammation. Altogether, both forms of bradykinin induce vascular leakage and mediate pain. Several kininases in plasma and tissue enzymatically degrade bradykinin to restrict its activity, thereby preventing widespread systemic vascular leakage and subsequent hypotension.Severe systemic bacterial infections (sepsis) are hallmarked by high activity of the (innate) immune and hemostatic system, in efforts to restrain and fight off invading pathogens. In particular, in the later and more dangerous phases of sepsis, mediators of the failing innate immune system cause damage to host tissues. A crucial feature of sepsis is a rapidly decreasing blood pressure (septic shock), caused by the systemic action of vasoactive mediators. With the increasing threat of multi-resistant infections, there is a dire need for increased mechanistic understanding, enabling development of new therapeutic approaches.Lipopolysaccharide (LPS), from the outer membrane of gram-negative bacteria is a notorious trigger of potent innate immune responses. Because of its amphipathic nature, LPS aggregates in a plasma environment. However, in order to elicit an innate immune response, it needs to be disaggregated into monomers. These monomers are recognized by LPS-binding protein (LBP), which presents them to CD14. Subsequently, signaling of the Toll-like receptor 4 (TLR4)-MD-2 complex leads to production of proinflammatory cytokines. However, whereas CD14, TLR4 and MD-2 are essential for LPS-induced mortality, LBP is not [2], suggesting the presence of other LPS-binding proteins. Over the past decade several proteins have been identified to bind LPS, but none proved essential for LPS-induced mortality. HK as playmaker in lethal endotoxemiaIn an exciting paper, Yang and colleagues provide new insights into the role of the contact system in mouse models of endotoxemia [3]. They show with compelling data, that HK is a major contributor to LPS-induced lethality. In an experimental model of lethal endotoxemia, by administration of LPS, wild-type (WT) mice generally succumb to the challenge between 10 and 50 h, as a result of multi-organ failure. In contrast, Kng À/À mice (...

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

Cited by 30 publications

References 62 publications

The Plasma Kallikrein–Kininogen Pathway Is Critical in the Pathogenesis of Colitis in Mice

The Plasma Kallikrein–Kininogen Pathway Is Critical in the Pathogenesis of Colitis in Mice

The synthetic LPS binding peptide 19-2.5 interferes with clotting and prevents degradation of high molecular weight kininogen in plasma

High‐molecular‐weight kininogen: breaking bad in lethal endotoxemia

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