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.
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We acknowledge support of Deutsche Forschungsgemeinschaft and Wilhelm Sander-Stiftung to B.E. and S.M. We are grateful to W. Bode, J. Roes, Peter Lohse, Pia Lohse and A. Moseman for helpful suggestions and comments. We thank G. Längst (University of Regensburg) and K. Rippe (University of Heidelberg) for preparation of isolated nucleosomes, M. Monestier (Temple University), H. Wardemann and R. Hurwitz (Max-Planck-Institut für Infektionsbiologie) for providing H2A-H2B–DNA–specific antibody, DNA-specific antibody and human neutrophil elastase–specific antibody, K. Schledzewski (University of Heidelberg) for supplying the stabilin-2–positive antibody, L. Petersen (NovoNordisk) for donating rVIIa and D. Kirchhofer (Genentech) for providing mouse tissue factor–specific antibody. L.G. was supported by Deutsche Forschungsgemeinschaft-Forschergruppe 440 and by Rudolf-Marx-Stipendium from Gesellschaft für Thrombose-und Hämostaseforschung. K.B. and C.R. were participants of Deutsche Forschungsgemeinschaft-Graduiertenkolleg 438.
The authors declare no competing financial interests.
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Massberg, S., Grahl, L., von Bruehl, M. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 16, 887–896 (2010) doi:10.1038/nm.2184
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