Journal Article

Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases

Goosmann, Christian, Manukyan, Davit, Holdenrieder, Stefan, Khandagale, Avinash B, Kennerknecht, Elisabeth, Lorenz, Michael, Engelmann, Bernd, Reges, Katja, Braun, Siegmund, Reinhardt, Christoph, Preissner, Klaus T, Grahl, Lenka, Pfeiler, Susanne, Bidzhekov, Kiril, Brinkmann, Volker, Konrad, Ildiko, Spannagl, Michael, von Bruehl, Marie-Luise, Massberg, Steffen

2010

Overview

Neutrophils release the serine proteases neutrophil elastase and cathepsin G, which have microbicidal activity and thereby contribute to the innate immune response. Steffen Massberg et al . now show that these neutrophil serine proteases, in association with extracellular nucleosomes, can also promote coagulation and thrombosis within large blood vessels. In a mouse model of systemic bacterial infection, these proteases spurred intravascular coagulation in the microcirculation of the liver, limiting bacterial tissue invasion. These findings point to a role for thrombosis in antimicrobial defense. Blood neutrophils provide the first line of defense against pathogens but have also been implicated in thrombotic processes. This dual function of neutrophils could reflect an evolutionarily conserved association between blood coagulation and antimicrobial defense, although the molecular determinants and in vivo significance of this association remain unclear. Here we show that major microbicidal effectors of neutrophils, the serine proteases neutrophil elastase and cathepsin G, together with externalized nucleosomes, promote coagulation and intravascular thrombus growth in vivo . The serine proteases and extracellular nucleosomes enhance tissue factor– and factor XII–dependent coagulation in a process involving local proteolysis of the coagulation suppressor tissue factor pathway inhibitor. During systemic infection, activation of coagulation fosters compartmentalization of bacteria in liver microvessels and reduces bacterial invasion into tissue. In the absence of a pathogen challenge, neutrophil-derived serine proteases and nucleosomes can contribute to large-vessel thrombosis, the main trigger of myocardial infarction and stroke. The ability of coagulation to suppress pathogen dissemination indicates that microvessel thrombosis represents a physiological tool of host defense.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/250/2504/223/1699 / 631/443/1338/567 / 631/45/607/468 / 631/45/612/100/1701 / Animals / Biomedical and Life Sciences / Biomedicine / Blood clots / Blood Coagulation - genetics / Blood Coagulation - physiology / Blood Coagulation Factors - metabolism / Blood Coagulation Factors - physiology / Cancer Research / Cathepsin G - genetics / Cathepsin G - metabolism / Cathepsin G - physiology / Coagulation / Fibrin - metabolism / Health aspects / Immunity, Innate - genetics / Immunity, Innate - physiology / Immunology / Infections / Infectious Diseases / Leukocyte Elastase - genetics / Leukocyte Elastase - metabolism / Leukocyte Elastase - physiology / Lipoproteins - metabolism / Metabolic Diseases / Mice / Mice, Knockout / Models, Biological / Molecular Medicine / Myocardial infarction / Myocardial Infarction - genetics / Myocardial Infarction - metabolism / Natural immunity / Neurosciences / Neutrophils / Neutrophils - metabolism / Neutrophils - physiology / Nucleosomes - metabolism / Pathogens / Pathology / Physiological aspects / Physiology / Proteases / Protein Processing, Post-Translational - genetics / Protein Processing, Post-Translational - physiology / Serine / Serine Proteases - genetics / Serine Proteases - metabolism / Serine Proteases - physiology / Signal Transduction - genetics / Signal Transduction - physiology / Stroke - genetics / Stroke - metabolism / Thromboembolism / Tissues