title: Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases.
abstract: 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.
authors.affiliation: Deutsches Herzzentrum, Technische Universität, Munich, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
authors.forename: Lenka
authors.initials: L
authors.lastname: Grahl
authors.forename: Marie-Luise
authors.initials: ML
authors.lastname: von Bruehl
authors.forename: Davit
authors.initials: D
authors.lastname: Manukyan
authors.forename: Susanne
authors.initials: S
authors.lastname: Pfeiler
authors.forename: Christian
authors.initials: C
authors.lastname: Goosmann
authors.forename: Volker
authors.initials: V
authors.lastname: Brinkmann
authors.forename: Michael
authors.initials: M
authors.lastname: Lorenz
authors.forename: Kiril
authors.initials: K
authors.lastname: Bidzhekov
authors.forename: Avinash B
authors.initials: AB
authors.lastname: Khandagale
authors.forename: Ildiko
authors.initials: I
authors.lastname: Konrad
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kennerknecht
authors.forename: Katja
authors.initials: K
authors.lastname: Reges
authors.forename: Stefan
authors.initials: S
authors.lastname: Holdenrieder
authors.forename: Siegmund
authors.initials: S
authors.lastname: Braun
authors.forename: Christoph
authors.initials: C
authors.lastname: Reinhardt
authors.forename: Michael
authors.initials: M
authors.lastname: Spannagl
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Preissner
authors.forename: Bernd
authors.initials: B
authors.lastname: Engelmann
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000235:genetics* / Q000502:physiology; D001779:Blood Coagulation Factors / Q000378:metabolism / Q000502:physiology; D056649:Cathepsin G / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D005337:Fibrin / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics* / Q000502:physiology; D019272:Leukocyte Elastase / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008074:Lipoproteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism / Q000502:physiology*; D009707:Nucleosomes / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics / Q000502:physiology; D057057:Serine Proteases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D020521:Stroke / Q000235:genetics / Q000378:metabolism
chemical_list: D001779:Blood Coagulation Factors; D008074:Lipoproteins; D009707:Nucleosomes; C045071:leukocyte procoagulant activity; C051928:lipoprotein-associated coagulation inhibitor; D005337:Fibrin; D057057:Serine Proteases; D056649:Cathepsin G; D019272:Leukocyte Elastase